A PUBLICATION OF THE PATRICK C.

WALSH PROSTATE CANCER RESEARCH FUND | THE BRADY UROLOGICAL INSTITUTE | JOHNS HOPKINS MEDICINE

DISCOVERY
VOLUME 12 | WINTER 2016

What Kind of Prostate

Cancer Do I Have?
Epstein Develops a
Less-Confusing System

Carter and Epstein: Making active surveillance safer and the Gleason scores easier to understand.

INSIDE THIS ISSUE:

From the Director
Changing Prostate Cancer ................... 2
Charred Food Bad, Veggies Good .... 6
Prostate Cancer in
African American Men ..................... 7
Immunotherapy for
Prostate Cancer .............................. 8
Genetic Risk for
Prostate Cancer............................. 10
Attacking Early Metastatic
Prostate Cancer............................. 18
Walsh Prostate Cancer
Research Fund Awards
The Research You Have Helped
Make Possible.................................. 19
Bladder, Kidney, and
Testicular Cancer News.................. 24

Active Surveillance:
Good News for Men with
Low-Risk Prostate Cancer

After all the worry the elevated PSA,

then the biopsy the diagnosis is finally
here. You just found out that you have
prostate cancer and the Gleason score
is a 3+3=6. What does that even mean?
You look it up; the literature your
doctor provided says that the score
is the sum of the most common and
second-most common Gleason patterns.
Apparently, the lowest score is 2 (1+1)
and the highest is 10 (5+5) and you are
a 6. That looks like youre on the more
significant end of the spectrum.

Its not easy for most men to

understand their prostate cancer
stage right away, because
the way Gleason scores are
determined is just plain
confusing. Epsteins new system
cuts through the numbers.

The Bradys Active Surveillance program

has reached a milestone: 20 years of
carefully following men with low-risk
prostate cancer. What we have learned
since 1995 can help many men with
low-grade, low-risk prostate cancer,
and their doctors, determine their best
course of treatment, says urologist
H. Ballentine Carter, M.D., the Bernard
L. Schwartz Distinguished Professor
of Urologic Oncology, a pioneer in the
active surveillance of prostate cancer.
There is increasing evidence that
monitoring favorable-risk prostate
cancer does not lead to worse outcomes
when compared to immediate treatment.
This is good news for the majority of
men diagnosed today.

Wrong. Nobody gets a Gleason 2; they

arent ever diagnosed on needle biopsies.
In fact, Gleason 6 is as good as it gets,
says urologist Patrick C. Walsh, M.D.,
University Distinguished Service
Professor of Urology. Its not easy for
most men to figure this out right away,
because the way Gleason scores are
are determined is just plain confusing
unless youre a pathologist, seeing how
a bunch of cells look under the microscope, and noticing which two combined
patterns of cells are most prevalent.

When the Active Surveillance program

first started, many urologists believed
this approach was ill-advised for any
man with a diagnosis of prostate cancer,
Carter notes, for fear of losing the

Brady pathologist Jonathan Epstein,

M.D., the Rose-Lee and Keith Reinhard
Professor of Urologic Pathology,
wants to make it easier for men to
understand their prostate cancer

Continued on page 4

Continued on page 3

WINTER 2016 | DISCOVERY

THE PATRICK C. WALSH

PROSTATE CANCER RESEARCH FUND
Continued from page 1

founders
circle
Anonymous (3)

Partin Honored:
Alan W. Partin, M.D., Ph.D., the Jakurski
Family Director and the Chairman of the
Brady Urological Institute, received a
Distinguished Contribution Award at the
American Urological Associations 2015
annual meeting. Presented by the AUAs
president, William W. Bohnert, M.D.,
the award cites Partins contributions to
science, most importantly, the creation of the
Partin Tables, which are used by urologists
throughout the world.

Mr. and Mrs. Robert B. Aikens

Ambrose Monell Foundation
Mr. and Mrs. Robert C. Baker
Family Foundation
Mary Ann and Bill Becker
George and Mary Nell Berry
Dr. and Mrs. Peter S. Bing
Mr. Keith Bremer
Elva E. and William W. Carty
Jennifer A. Chalsty
John S. Chalsty
The Deeks Family Foundation
R. Christian B. Evensen
Phyllis and Brian L. Harvey
Heather C. and Patrick Henry
Charlton C. and F. Patrick Hughes
Beverly A. and Gary L. McDonald
Jean and Ian MacKechnie
Beth W. and A. Ross Myers
Nancy and Jim ONeal
Jack W. Shay and Thomas C. Quirt
The Frank E. Rath Spang &
Company Charitable Trust
Mr. and Mrs. Paul W. Sandman
The Peter Jay Sharp Foundation
Irene and Bernard L. Schwartz
Virginia and Warren Schwerin
Donald and Susan Sturm
Carolyn and Bill Stutt
Mr. and Mrs. Charles B. Thornton, Jr.
Luciana and Joe Vittoria

changing prostate cancer

What does my diagnosis of prostate cancer mean? For a century, our doctors and
scientists here at the Brady have worked to answer that question on every level. Our
discoveries have transformed the way organ-confined disease is treated and continue
to bring new hope to men with metastatic disease. Our Active Surveillance program,
pioneered by Bal Carter, has helped many men with slow-growing, small-volume
disease avoid surgery safely; and now work by uropathologist Jonathan Epstein is
actually changing the way the disease is diagnosed. For example, Gleason score 3 +3
is its own category, Grade Group 1; Gleason 3 + 4 is Grade Group 2, and Gleason 4 + 3
is Grade group 3. There are only five groups, and Gleason score 8 is a distinct group,
because those men have different disease than men with Gleason scores 9 and 10.
The World Health Organization has accepted this system, and it will soon be used
at hospitals everywhere.
In this exciting issue of Discovery, were proud to tell you about our latest work
in immunotherapy, in dietary prevention, our work with robots, our advances in
understanding genetic risk, our successes in molecular biology, and other breakthroughs including the successful imaging of individual cells of prostate cancer
throughout the body which opens up new targets for treating metastatic disease.
We also bring to you our continuing advances in diagnosis, treatment and active
surveillance of kidney cancer, in refining treatment for bladder cancer, and a new
advance in the laparoscopic treatment of testicular cancer.
Your generosity makes us able to do more, so that we can continue to improve the
lives of people with urological diseases. Thank you for being our partners in discovery.

For additional news and

updates from the Brady Institute,
please follow us on our web
site at urology.jhu.edu or any
of our social media sites:
Facebook: Brady Urology;
Twitter: @brady_urology;
bradyurology.blogspot.com

Best wishes,

Alan W. Partin, M.D., Ph.D.

Jakurski Family Director and
Chairman of The Brady Urological Institute

diagnosis. Jonathan Epstein is unique

in many ways, and one of them is that
he does something that almost no other
pathologist does he actually talks to
patients frequently, says Walsh. He
understands how confusing this system
is for most people to understand, and he
wanted to fix this problem.
Epsteins new system, compared to the
current Gleason system, is far simpler,
with just five groups of cancer. One
innovation is that it puts the confusing
Gleason 7 score which is very
different, depending on whether its 3+4
or 4+3 into two different groups. As
Epstein explains: The current prostate
cancer grading system was developed
between 1966 and 1974 by Donald
Gleason. The system assigns histological
patterns 1 through 5, adding the most
and second-most common patterns
with Gleason scores ranging from 2 to
10. There are more than 25 different
possible combinations with this system.
Doctors and scientists have tried to fix
this; the Gleason system was revised in
2005 and again in 2014. The current
application of Gleason grading differs
dramatically from the original system,
Epstein continues. Scores 2 through
5 are no longer assigned and certain patterns that Gleason defined as a score of
6 are now graded as 7. But the Gleason
7 score itself is still pretty confusing:
A Gleason score 7 can represent mostly
well-differentiated cancer, with a smaller component of more poorly differentiated cancer that would be Gleason
3+4=7 or mostly poorly differentiated
cancer with a smaller component of
well-differentiated cancer, the score
of Gleason 4+3=7. Another weakness
of the Gleason system is that the lowest
score is now assigned a 6, although it is
on a scale of 2-10.
In a study of more than 25,000 men
treated for prostate cancer at Hopkins
and four other institutions, Epstein and
colleagues verified a simplified system
that cuts through the numbers. Epstein
presented the new system at the 2015
meeting of the American Urological
Association in New Orleans. Its more
accurate than the current Gleason

system, with only five grades, Epstein

says, and the lowest grade is 1, as
opposed to 6. This also has the potential
to reduce overtreatment of indolent
prostate cancer, he notes. We hope that
this will permit more rational and less
emotional decision-making; that men
who are assigned a Grade Group 1 out
of 5 will know that their cancer has an
indolent nature. Tumors that are a pure
Grade Group 1 at radical prostatectomy
have no metastatic potential. This
might also reassure men in this group
who choose active surveillance. Some
men with Grade Group 2 tumors may
also be candidates for active surveillance,
or for radiation therapy instead of
surgery depending on their age, extent
of cancer, and general health. In
addition to making a clear distinction
between the two Gleason 7 scores, the
system separates Gleason 8 cancer from
Gleason 9 and 10 tumors. Gleason scores
8-10 are usually combined, Epstein says.
However, although they are high-grade
tumors, they still have significantly
different prognoses. Now, these are
separated into Grade Groups 4 and 5.

HERE IS THE BREAKDOWN FOR

THE NEW GRADE GROUP SYSTEM:
Grade Group 1 (Gleason score 3+3=6)
Grade Group 2 (Gleason score 3+4=7)
Grade Group 3 (Gleason score 4+3=7)
Grade Group 4 (Gleason score 8)
Grade Group 5 (Gleason scores 9-10)
Will this new system be coming
soon to a hospital near you? Yes. It has
been accepted by the World Health
Organization, and will be used in
conjunction with the current system
until it becomes widely accepted and
practiced, says Epstein. n

Radical Prostatectomy
with Two Robots

What could make robot-assisted

laparoscopic radical prostatectomy even
better? How about another robot?
Dan Stoianovici, Ph.D., Director of the
Urology Robotics Program, and his
world-renowned Robotics Laboratory
have designed, built and tested a robot
that maneuvers an ultrasound probe.
This novel robot, called the transrectal
ultrasound probe manipulator (TRUS
robot, for short), allows surgeons to do
something very important: See and
preserve, if no cancer is there the
tiny neurovascular bundles, which
contain the nerves that are needed for
erection, and are critical for recovery
of sexual potency.
In a recent study, working with surgeon
Misop Han, M.D., the David Hall
McConnell Professor in Urology, and
other Brady colleagues, Stoianovici
tested the TRUS robot in a brand-new
procedure called tandem-robot assisted
laparoscopic radical prostatectomy, or
T-RALP, done in 49 men whose average
age was 59. The TRUS robot was used
together with the daVinci surgical robot,
to take ultrasound images at critical
points of the operation, says Stoianovici.
The results showed that the T-RALP
is safe and feasible, and that it can
potentially improve the visualization
of the neurovascular bundles, and
subsequently improve postoperative
recovery of potency in men.

WINTER 2016 | DISCOVERY

Continued from page 1

opportunity to be cured. Virtually every

man diagnosed more than 90 percent
was treated with either some form of
radiation or surgery. All this has changed,
in large part to a better understanding of
what happens to men with favorable risk
prostate cancer who remain untreated.
Brady resident Jeff Tosoian, M.D.,
M.P.H., and Mufaddal Mamawala, the
biostatistician in charge of keeping track
of men in the Bradys Active Surveillance
program, recently reported on what
happened to men who, over the last 15
years, entered this program rather than
undergoing immediate treatment. They
delivered their findings at the American
Urological Associations 2015 meeting
in New Orleans; their results were
published online September 1 and
fast-tracked for publication in the
Journal of Clinical Oncology. About
1,300 men have entered the program so
far. Their average age is 66, Carter says,
and two-thirds of these men entered
with very low-risk prostate cancer.
They had Gleason score 6 cancer in no
more than two biopsy cores; cancer was
present in 50 percent or less of each
core; their PSA density (PSA divided by
prostate volume) was 0.15 or less; and
they had no cancer that could be felt on
a rectal examination. The remaining
one-third of these men had low-risk
prostate cancer. This means that they
had no cancer that could be felt on a
rectal exam, a PSA below 10 ng/ml, and
Gleason 6 cancer on their biopsy.
A number of interesting findings
from this update should help inform
men regarding the safety of active
surveillance, says Carter. First, we
can now tell men that if they qualify
for the active surveillance program
and are monitored carefully, their risk
of dying from another cause instead of
prostate cancer over the next 15 years
after diagnosis is 4 percent (24 to 1).
Fewer than 1 percent only 0.4 percent,
(a risk of 250 to 1) of men in our active
surveillance program either died of
prostate cancer or developed advanced
disease. Second, over 15 years, fewer
than 5 percent of these men developed
4

a more serious grade of cancer (Gleason

4+3 or above).
The key here is who is eligible for the
program: The criteria are very specific
(see above), making sure that only men
with the least risk of having aggressive
cancer even get enrolled. Also, these
men are monitored faithfully, with
regular follow-up visits and biopsies.

The key here is who is eligible

for the program only men
with the least risk of having
aggressive cancer. Also, these
men are monitored faithfully,
with regular follow-up visits
and biopsies.
Our results show that men who are
diagnosed with very low-risk or low-risk
(favorable risk) prostate cancer should
think carefully before pulling the trigger
to treat their cancer, states Carter.
They may well be a candidate for no
immediate treatment and just careful
monitoring. Better understanding
of the kind of cancer a man has
whether his risk of having aggressive
disease is lower or higher means
that more men are opting to wait on
treatment. Today, about 30 to 40
percent of men diagnosed with favorablerisk prostate cancer are being managed
with surveillance, compared to fewer
than 10 percent in 2010. n

Chan Receives Award

A big award for Daniel W. Chan, Ph.D.,
Director of the Clinical Chemistry
Division and Center for Biomarker
Discovery and Translation, and
Co-Director of the Pathology Core
Laboratories: Chan was selected
to receive the Human Proteome
Organizations very first HUPO
Translational Proteomics Award.
This honor, presented at the 2015
HUPO Congress in Madrid, is the
most important proteomics award
in my career, says Chan. n

Active Surveillance: A
Tailor-Made Approach?

Previously, doctors have only

been able to see prostate cancer,
either as a tumor or at metastatic
sites, when there have been
enough cancer cells gathered
together to make a critical mass
that would show up on MRI
or another form of imaging.
There was no way to target
prostate cancer cells specifically.

In our program, we have generally recommended relatively intense monitoring, with

prostate biopsies done annually for most
men, says Carter. However, it may be that
some men could be monitored safely with a
longer interval between biopsies. In a recent
study using data collected over the last 15
years in the Active Surveillance program,
Hopkins medical student Ridwan Alam and
biostatistician Mufaddal Mamawala examined the likelihood that a man in active
surveillance will eventually be diagnosed
on biopsy with a higher-grade cancer that
would likely need treatment. Their results
were published in the Journal of Urology.
They found that the risk of grade reclassification finding a higher grade of
cancer on biopsy is highest during the
first two years on surveillance. About half
of all grade reclassification occurs then, in
men with both very low-risk and low-risk
disease. This is thought to be because the
first biopsy or two might simply have missed
higher-grade cancer that was there all the
time. Grade reclassification also occurred,
outside those first two years, in men with
low-risk, instead of very low-risk disease.
Another striking finding: With each prostate
biopsy that showed the cancer was holding
steady, still indolent, and with no change in
grade, the risk of finding more aggressive
disease fell by 30 percent.
Carter and colleagues have used these
findings to construct a risk calculator for men
on active surveillance. It will be available
soon, and will be easy to use, Carter says.
Men and their physicians will put in the year
of diagnosis, age, PSA density, whether or
not the cancer was found on one or both
sides of the prostate, and total number of
biopsies without reclassification. The calculator will then estimate the risk of finding a
higher grade of cancer at the next biopsy.
Using this risk-assessment tool, Carter has
found that 30 percent of men in the Bradys
active surveillance program have less than
a one-in-10 chance that a repeat biopsy in
the next year would show higher-grade cancer. And 25 percent have a one-in-four risk
of grade reclassification at the next biopsy.
Thus, for men at lowest risk, a prostate biopsy may be deferred for several years.

Breakthrough in Prostate Cancer Imaging

Have any cancer cells escaped the
prostate? This is the question that
every man who has prostate cancer, and
every doctor treating him, wants to
answer. Now theres a way to find out
without making an incision or taking
another biopsy sample. Its a brand new
technique, called PSMA imaging, and it
uses a PET (for positron emission
tomography) scanner.
The technique was developed by Martin
G. Pomper, M.D., Ph.D., the William
R. Brody Professor of Radiology and
Director of the Division of Nuclear
Medicine and Molecular Imaging, and
the original support to develop it came
from a grant made by Patrick C. Walsh
Prostate Cancer Research Fund. This
truly is individualized medicine, and
we can really help patients with it, says
Pomper; in fact, men with prostate cancer from around the world have flown to
Johns Hopkins just to have this test done.
The results from this new radiotracer
have changed how the disease is being
managed in some patients. It, and others
like it being used in Europe, have caught
on like wildfire. At medical meetings
devoted to prostate cancer, sessions are
now being taught on PSMA imaging.

Heres why this is such a breakthrough:

Previously, doctors have only been able
to see prostate cancer, either as a tumor
or at metastatic sites, when there have
been enough cancer cells gathered
together to make a critical mass that
would show up on MRI or another form
of imaging. There was no way to target
prostate cancer cells specifically. But
what if there could be a way to make
those cells light up somehow? With this
in mind, Pomper figured out a way to
engineer a harmless radioactive tracer
that would attach itself specifically
to prostate cancer cells. The tracer
targets something on the surface of
these cells: a molecule called PSMA, for
(prostate-specific membrane antigen).
PSMA is a protein that is present in high
concentrations on the surface of prostate
cancer cells, Pomper says. PET is a
sensitive imaging technique that can
allow us to see tumors deep within
the body. PET works by detecting the
radioactive molecules we made to tag
the prostate cancer cells specifically.

this alphabet soup alert here into

a second-generation, PSMA-targeting
PET agent called DCFPyL. Pomper is
excited about the potential for DCFPyL
to help men throughout the prostate
cancer spectrum. This agent has vastly
higher sensitivity and specificity, and
it provides sharper images, he says.
That will enable us to expand the use
of imaging, not only to primary disease,
but to see if the disease has returned
after initial treatment, to help make
treatment more accurate, and even as
a monitoring tool for men on active
surveillance. We believe that the images
we are getting are the clearest ever
obtained for prostate cancer in a human
being. As a bonus, because PSMA
is also expressed in the blood vessels
of other types of cancers, this technique
may also help spot other tumors,
including certain forms of kidney
cancer, he adds.
Pomper and colleagues recently
published their results in Molecular
Imaging and Biology. n

Previously in Discovery, we reported

that Pomper had discovered and tested
the first PSMA-targeting PET agent in
a clinical trial. Now he has refined
5

WINTER 2016 | DISCOVERY

Charred Food Bad, Veggies Good for the Prostate

This provides even more

evidence that eating vegetables
may protect against cancercausing agents like those in
overcooked meats.
Those of us who love steaks and hot dogs
on the grill were chastened a few years
ago, when scientist Bill Nelson, M.D.,
Ph.D., the Marion I. Knott Director and
Professor of Oncology and Director of the
Sidney Kimmel Comprehensive Cancer
Center, began investigating something
called PhIP. PhIP (a short name for
a long chemical compound) is found in
meats cooked at high temperatures
think of charred burgers, or fried chicken.
It is a pro-carcinogen, a chemical that
turns into something that can attack and
mutate DNA, and is known to cause prostate, breast, and colorectal cancer in rats.
But theres good news: It pays to eat your
veggies. When we fed rats tomatoes and
broccoli along with PhIP, the animals
lived longer, and showed reduced incidence
and severity of prostate neoplasms
(new, abnormal cell growth; particularly
of PIN, prostatic intraepithelial neoplasia
funny-looking cells that are linked to
prostate cancer), intestinal cancers, and
skin cancers as compared to rats fed PhIP
alone, says Nelson. This provides even
more evidence that eating vegetables
may protect against cancer-causing
agents like those in overcooked meats.

There is also a twist to the story: Food

safety pays off, as well. Nelson, along
with pathologist Angelo De Marzo, M.D.,
Ph.D., and scientist Karen Sfanos, Ph.D.

has also explored the idea that prostate

cancer may involve a combination of
environmental insults bad things in
the diet, plus something else that weakens
the body, like an infection. They wondered
whether chronic inflammation caused
by bacterial infection would make a
difference in rats that had consumed
PhIP. Using a specific strain of E.coli,
isolated from a patient with chronic
prostatitis/chronic pelvic pain syndrome
by urologist Anthony Schaeffer, M.D.,
and further studied by urologist Edward
Schaeffer, M.D., Ph.D., the R. Christian
B. Evensen Professor, they found, to
their surprise, that the charred food
plus the nasty bug (many people have
E.coli in their gut and it is harmless, but
some strains can get into meat when its
processed, and can survive if the meat is
undercooked) seemed to have a systemic
effect, causing an increase in the development and progression of cancer in the
skin and digestive tract. The rats that
received the double punch of E.coli plus
PhIP fared worse than rats that ate the
PhIP alone. In one study, the bacteriaand PhIP-consuming rats developed more
precancerous lesions within the prostate
and might have developed even more
problems except they also died sooner.
In further experiments, Nelson,
De Marzo and Sfanos found that when
we inoculated PhIP-fed rats with E.coli
in the prostate, the animals developed
acute and chronic prostate inflammation
out of proportion to that seen with PhIP
ingestion or E.coli inoculation alone, and
had more prostate neoplasms, intestinal
cancers, and skin cancers. This hints
that prostate infections and dietary
carcinogens might interact to promote
chronic prostate inflammation and prostate cancers, and that prostate infections
might augment carcinogen effects on
other tissues, as well, says Nelson.
Nelson, De Marzo, Sfanos, and
colleagues recently published two
papers on these striking new findings
in the journals PLoS ONE and Cancer
Prevention Research. n

Shorter Telomeres in
Normal Cells Can Point
to Prostate Cancer
Every time a cell divides, we
lose a minuscule portion of the
telomeres DNA, and become
more vulnerable to illness.
Brady scientist Alan Meeker, Ph.D., is
one of the foremost experts on a tiny but
very complicated subject: telomeres.
These are bits of specialized DNA found
at the ends of every chromosome. They
are like little shields, tips that protect
the chromosome from wear and tear
think of an aglet on a shoelace, keeping
the strings from fraying. Every time a
cell divides, we lose a minuscule portion
of the telomeres DNA; as we age, our
telomeres get progressively shorter.
Theyre a buffer between our chromosomes and the outside world, and as they
shrink, we become more vulnerable to
illness. Back in 2009, Discovery reported
on Meekers discovery with Brady scientist
Donald Coffey, Ph.D., The Catherine
Iola and J. Smith Michael Distinguished
Professor of Urology, that the shortening
of telomeres is an important contributing
factor to the development of prostate
cancer, and that men who inherit
short telomeres have a higher risk of
developing cancer.
Since then, Meeker has continued to
work with Hopkins scientists to learn
more about telomeres, and with
Christopher Heaphy, Ph.D., he found
that, in men who underwent radical
prostatectomy, those with telomere
abnormalities in both their prostate
cancer cells and in nearby cells that
otherwise appeared normal had a
14-fold increased risk of dying from
their disease.
Next, given these interesting results,
particularly the presence of short
telomeres in the nearby normal-appearing
cells, we hypothesized that the presence
of shorter telomeres in diagnostic
biopsies would also be associated with
risk of prostate cancer. In collaboration
with colleagues at the Johns Hopkins

Bloomberg School of Public Health,

Meeker and Heaphy studied telomeres
in normal cells in biopsies from men
who received a placebo in a national
prostate cancer prevention study, the
Prostate Cancer Prevention Trial.
We found that men with short telomere
lengths in their biopsies had a higher
likelihood of having prostate cancer
compared to men who had normal
telomere lengths, says Meeker. These
findings suggest that telomere shortening
in normal-appearing cells may help
predict the presence of prostate cancer.
In order to test this idea, we are validating
these findings, and also performing studies
to better understand the biology of this
subset of cells with short telomeres within the prostate tumor microenvironment.
This work was recently published in the
journal, The Prostate. n

A Double Whammy
for Detecting Prostate
Cancer in African
American Men
Because of the groundbreaking research
of urologist Ted Schaeffer, M.D., Ph.D.,
scientists know that prostate cancer
is more aggressive in men of African
descent than it is in Caucasian men.
They also know, thanks to Schaeffer, that
not only is cancer more aggressive in
these men; its harder to find. Schaeffer
discovered that African American men
are twice as likely as Caucasian men to
have aggressive cancers develop in the
anterior area of the prostate.

They discovered that not only

are the cancers different, but
the difference is potentially
dangerous.
If you think of the prostate as a house,
and the rectum as the basement, we
come up through the basement with the
biopsy needle, says Schaeffer. In most
Caucasian men, prostate cancer is located
in the posterior part of the prostate,

immediately adjacent to the rectum

so its basically on the first floor. But in
African American (AA) men, aggressive
cancers are hiding up in the attic, which
is much more difficult to sample on an
ordinary prostate biopsy. For this reason,
many AA men are misclassified as having
indolent disease they are falsely
reassured that their cancer is not the
kind to worry about and their diagnosis
of aggressive cancer is delayed.
Building on this work, Schaeffer has
explored whether these cancers themselves are different not just in location,
but in their molecular makeup. In other
words, are the fundamental building
blocks different in tumors that begin
in the posterior location? To find out,
Schaeffer and colleagues examined the
genetic codes of more than 100 prostate
cancers from both anterior and posterior
locations, in both AA and Caucasian
men. (Caucasian men can develop anterior
tumors that are aggressive, but they
are more common in AA men.) They
discovered that not only are the cancers
different, but the difference is potentially
dangerous.
We found that these anterior cancers
make less PSA than the posterior

tumors do, and that anterior cancers are

less dependent on male hormones for
their growth than posterior tumors are.
This was true in men of both races, but
had the strongest association in AA men.
The problem, Schaeffer says, is that we
use PSA levels as a screening tool to look
for cancers. So that this may be a double
whammy for men with anterior cancers:
First, anterior cancers are already harder
to detect with traditional prostate biopsies.
Second, if they make less PSA, men with
these tumors may not be offered a biopsy
at the earliest possible stage, because
a doctor might look at the PSA number
and think all is well.
We dont yet have a biomarker that is
capable of specifically picking up an
anterior tumor, but this is certainly a
dream of mine, Schaeffer adds. However,
the advent of MRI-ultrasound fusion
biopsies shows significant promise in
picking up these hard-to-find cancers.
Schaeffer believes that all men who have
had a negative prostate biopsy should
undergo an MRI scan, to make sure there
isnt an anterior tumor lurking in the
prostates attic. But men of African
descent with an elevated PSA may want to
consider getting an MRI as a first step. n

Congratulations
to Schaeffer
One of the things the Brady is most known for is
training the next generation of leaders in
Urology. In exciting news, urologist Edward
Schaeffer, M.D., Ph.D., has been appointed the
new Chair of Urology at the Northwestern Feinberg School of Medicine in Chicago. He will be
the Edmund Andrews Professor of Urology. This
is a great and well-deserved opportunity for Ted,
says Alan W. Partin, M.D., Ph.D., Jakurski Family
Director of the Brady Urological Institute. His
leadership, scholarship, mentorship and fellowship will be greatly missed. We congratulate him
on his contributions to the Brady and on this
outstanding recognition of his achievements.
Schaeffer: Schaeffer, left, is the R. Christian B.
Evensen Professor. Here he is with Evensen, one
of the charter founders of the Patrick C. Walsh
Prostate Cancer Research Fund. In his years at
the Brady, Schaeffer has seamlessly combined
surgical acumen and scientific discovery, says
urologist Patrick Walsh, M.D.

WINTER 2016 | DISCOVERY

found on T cells, white blood cells that

fend off infections and help fight cancer.
In melanoma, bladder, lung and kidney
cancer, these drugs have shown dramatic
results, causing long-term remission of
disease in some cases. In prostate cancer,
however, giving PD-1 blockade alone has
not had promising results.

Results of immunotherapy in prostate

cancer have been less impressive than in
other diseases, with immune checkpoint
(see side story) blockade showing little
evidence of response in several clinical
trials, Drake says. But based on our
published data, we hypothesized that
combining immunotherapy with
hormonal therapy earlier in the
course of disease before the cancer
stops responding to hormonal therapy
could lead to better outcomes.

Drake: We hope these promising results will drive

a translational clinical trial.

Immunotherapy
Plus Short-Term
Hormonal Therapy:
Promising Results
But when we gave immunotherapy just before hormonal
therapy, the results were
striking. A significant
proportion of animals never
developed castration-resistant
disease.
The bodys own immune system can
pack an amazing punch. When the body
decides to recognize something as an
enemy and the full power of its militia
kicks in, the effect can be powerful too
powerful in the case of an autoimmune
disease, and not powerful enough in cancer.
Although the idea of cancer-targeted
immunotherapy has been around for
decades, only recently has it begun
to show some stunning successes in
melanoma, lung cancer, kidney cancer,
and bladder cancer. In prostate cancer,
however, success has come more slowly.
Brady scientist Charles Drake, M.D.,
Ph.D., an immuno-oncologist and one
of the thought leaders in the field, is
taking a new tack.

Using an animal model that reliably

responds to castration, or androgen
ablation, the medical shutoff of testosterone, but later develops castrationresistant disease, we tested the relative
timing of hormonal therapy and
immunotherapy, Drake explains.
Immunotherapy alone, either early
or late in the diseases course, was
ineffective. But when we gave immunotherapy just before hormonal therapy,
the results were striking. A significant
proportion of animals never developed
castration-resistant disease.
There are different types of immune
checkpoint inhibitors. Drake and
colleagues tried PD-1 blockade, and
found that it was unimpressive.
Then they tried CTLA-4 blockade,
which was more promising, and a new
compound was better still. A CTLA-4
antibody that targets and depletes
regulatory T cells (which suppress
the immune system) was the most
efficacious immunotherapy we found,
Drake says. Taken together, we hope
that these promising results will drive
a translational clinical trial, in which
anti-CTLA-4 is administered in
combination with a short course of
hormonal therapy in men with high-risk
disease whose PSA has returned and
is on the rise.
Drake and colleagues presented these
results at the American Association
for Cancer Researchs annual meeting
in 2015. n

Ross: Freezing the prostate may make the tumor

more vulnerable to immunotherapy.

Cryotherapy Plus
Immunotherapy May
Equal New Hope for
Men with Metastatic
Prostate Cancer
Think about aggressive treatment for
metastatic prostate cancer, and what
comes to mind? Most likely, its not cryotherapy or immunotherapy or putting
these two therapies together. But that
may soon change, if a small trial at Johns
Hopkins is as promising as Brady scientists
Ashley Ross, M.D., Ph.D., and Charles
Drake, M.D., Ph.D., hope it will be.
One thing that advanced prostate cancer
does well is adapt to and overcome
therapy, says Ross. You give antiandrogens, and the cancer develops
castrate resistance. Give stronger
anti-androgens, and chemotherapy, it
figures out a way around them, too.
But recent success in treating other
forms of cancer particularly melanoma
with checkpoint-blocking drugs such
as PD-1 inhibitors (see side story), has
given rise to the hope that this new
approach to immunotherapy will work
in prostate cancer, too, allowing the
immune system to kill cancer cells and
adapt just as quickly as the cancer does
to continue to eradicate disease.
PD-1-blocking drugs target the
Programmed Death 1 (PD-1) molecule
a checkpoint for the immune system

The combination of a PD-1

blocker and cryotherapy may
provide the long-awaited kick
in the pants the body needs to
attack advanced prostate cancer.
The combination of a PD-1 blocker and
cryotherapy may provide the long-awaited
kick in the pants the body needs to attack
advanced prostate cancer. In the past,
immunotherapy has produced a much
more muted effect in prostate cancer:
slight decreases in PSA, a mild trend to
better survival, nothing huge, says Ross.
One reason is that with prostate cancer,
the body doesnt seem to mount a great

immune response; it needs some help.

What it needs is a jump-start, and this is
where cryotherapy comes in.

system how to recognize prostate cancer

at distant metastatic sites, and not just
delay its progression but kill it.

Working with medical oncologist Drake

and post-doctoral fellow Benjamin Benzon,
Ross and scientists in his laboratory have
been testing ways that local therapies
applied right to the prostate can
augment the systemic immune
response against cancer. We needed a
way to help the prostate cancer expose
more of its tumor antigens so the
immune system will recognize it better.
To explore this, we generated mouse
models of metastatic disease and tested
surgery, radiation, cautery and cryotherapy.
Cryotherapy appeared to cause the
greatest anti-cancer response, allowing
T cells to attack tumors at distant sites,
as well, says Ross. The act of freezing
the prostate, while not enough to
eliminate cancer in distant metastatic
sites on its own, may just cause enough
chaos within the tumor denaturing
some of its proteins, disrupting its
cells that we could teach the immune

The trial, done in collaboration with

Drake at Hopkins and with Merck, is
open to men with fewer than five
metastases and an intact prostate. Its
a single-arm trial, says Ross. Everyone
will get cryoablation of the prostate,
an FDA-approved, minimally invasive
treatment. They will get hormone
deprivation for eight months, and a
course of immunotherapy with an
anti-PD-1 molecule called Pembrolizumab. At one year, we will look to see
what their PSA is and if their metastatic
lesions have disappeared. We are hoping
that we will see regression of their
metastases and very low PSAs in at least
50 percent of the men.
For more information on this and other
trials, please call Ross at 443-287-7225.
You can also read more about the trial
at Clinical Trials.Gov (trial number
NCT02489357, https://clinicaltrials.gov/
ct2/show/NCT02489357). n

What are Immune Checkpoints, and How Can We Block Them?

Immune Checkpoint Blockade to Treat Cancer:

The immune system is all about communication. For
an immune cell a foot soldier in the bodys effort to
protect itself against enemy invaders to be activated,
two signals need to be made. Signal 1 is controlled
by the T cell, a white blood cell, that recognizes a
tumor-specific protein, called an antigen, through its
receptor. Think of Radar OReilly in MASH, listening
to his headset and hearing something suspicious.
Signal 2 comes from B7 molecules. Heres where the
communication gets scrambled: In tumors, T cells
often pick up a checkpoint molecule called CTLA-4,
which sticks to B7 molecules like glue. This is bad,
because it effectively hijacks Signal 2 blocking the
communication back to the foot soldier and the
T cell never gets the signal to go fight the bad guy.
A second and maybe even more important checkpoint
is controlled by the interaction between PD-L1 on the
tumor cell and PD-1 on the T cell.

Recent advances in our understanding of the

immune system have resulted in a sea change in
the treatment of aggressive malignancies, says
Brady scientist Charles Drake, M.D., Ph.D. He
should know; he is doing groundbreaking work on
immunotherapy in prostate cancer. In particular,
we now know that in many patients, their immune
cells have already seen the tumor and are poised
to destroy tumor cells. However, those tumordestroying immune cells are often held back by
a series of molecules known as immune checkpoints. Normally, Drake explains, these checkpoints
function to protect the body from auto-immune
attack; but in cancer, tumors hijack those
pathways to protect themselves, instead.
The world of immunotherapy involves a lot of
alphabet soup-sounding names. For example, the
most important checkpoint pathway is controlled
by two molecules that act on two different kinds
of cells. The initials PD stand for Programmed
Death. PD-L1 is made by tumor cells, and PD-1
is on the corresponding immune cells called T
cells. When tumors are under attack, they crank
up the production of PD-L1, says Drake, and this
is a bad thing. PD-L1 protects the tumor cells by

binding to PD-1 on those invading white blood

cells called T cells effectively turning them off.
Imagine a smoke alarm going off, and the home
security system calls the fire department and
says, Dont worry, its just a false alarm, so the
house keeps on burning.
But scientists have figured out how to break this
cycle in other words, to call the fire department
back and say, Hurry up! We need you!
Drake is excited about blocking another immune
checkpoint that targets the molecule CTLA-4.
Interestingly, blocking both of these checkpoints,
CTLA-4 and PD-1, leads to a higher response
rate than blocking either one alone, notes Drake,
and a Johns Hopkins team led by Emmanuel
Antonarakis and Drake is planning a trial of
dual-checkpoint blockade in men with advanced
prostate cancer that expresses a mutated
androgen receptor called ARV7 which makes
them particularly resistant to androgen-targeting
therapies. Note: Not all men express AR-V7;
there is a brand-new blood test, only available
at Johns Hopkins, that can tell whether you are
in this group (see story on PAGE 13).
9

WINTER 2016 | DISCOVERY

The results of this study

indicate that not all men
with a family history
of prostate cancer have
equivalent risk.

Kathy Wiley and William Isaacs: This work

will help identify men who could benefit from
earlier and more frequent screening.

Will I Get Prostate

Cancer?
New Study Calculates
Genetic Risk
For more than a decade, investigators led
by William Isaacs, Ph.D., the William
Thomas Gerrard, Mario Anthony Duhon
and Jennifer and John Chalsty Professor of
Urology, have made tremendous progress
in discovering major genetic factors
linked to an inherited risk of prostate
cancer. In fact, a decade before that,
Brady investigators led by Isaacs
and urologist Patrick C. Walsh, M.D.,
showed that prostate cancer runs in
some families, and that men with a
family history of prostate cancer tend
to develop it at a younger age; before
this, prostate cancer was thought simply
to be a really common disease in men.
Some of the risk factors Isaacs and
colleagues at Hopkins and elsewhere
have discovered include common and rare
genetic variants, such as mutations in the
genetic sequence called single nucleotide
polymorphisms, or SNPs, and in the
genes, HOXB13 and BRCA2. In a new
study, Isaacs, along with Jianfeng Xu and
Brian Helfand at NorthShore Research
Institute in Chicago, have looked to see
which is more accurate at predicting a
mans risk of developing prostate cancer:
a family history of the disease, or specific
genetic risks, determined by looking at his
DNA (specifically, by measuring SNP
profiles found in blood cells or saliva).
10

It is well established that men who have

a first-degree relative with prostate
cancer are at increased risk for prostate
cancer, says Isaacs. What is not known
is the degree to which these men are at a
higher risk. In the past, each man with
a first-degree relative was assumed to
have the same increase in risk, depending
on how many affected first-degree
relatives he had. For example, a man
whose father had prostate cancer would
be at an elevated risk of developing
prostate cancer, but a man whose father,
brother, and grandfather had prostate
cancer would be at an even higher risk.
In the study, Isaacs, Xu and Helfand
examined DNA samples from men with
a family history of prostate cancer to
determine the number of risky SNPs
altered stretches of DNA these men
inherited. Interestingly, although most
of these men carried more genetic risk
factors than men without a family
history, some men carried less, says
Isaacs. These men were more likely
not to develop prostate cancer than
men without a positive family history.
Indeed, the results of this study indicate
that not all men with a family history
of prostate cancer have equivalent risk.
In fact, Isaacs continues, there is a wide
range of risk, and this can be estimated
through measuring prostate cancer risk
SNPs to calculate a genetic risk score.
This study has been submitted for
publication.
Additional studies are needed to validate
these findings, he adds, but this study

provides a strong basis for developing

a simple and inexpensive test to assess
differences in prostate cancer risk
among sons and brothers of men with
prostate cancer. Such an assessment
could be useful in identifying men who
would most likely benefit from earlier
and more frequent disease screening. n

Surviving Prostate
Cancer: Good News for
Radical Prostatectomy
Patients
So you had radical prostatectomy and
things have been going pretty well. You
feel good, and your PSA remains undetectable. Its been several years now; are
you out of the woods?

Overall, men are highly

unlikely to die from prostate
cancer after surgery
even men with high-risk
prostate cancer. If you do not
experience recurrence for
several years, your likelihood
of survival for 10 more years
is outstanding.

After radical prostatectomy, about a

third of men experience a return of PSA,
says urologist Misop Han, M.D. the David
Hall McConnell Professor in Urology.
However, only a very small number of
men who have had surgery ultimately
die from prostate cancer. So, men contemplating surgery or those who have
already had surgery may wonder, What
is my chance of surviving from prostate
cancer if I have not had PSA recurrence
for several years after surgery?
Han and Brady epidemiologist Bruce
Trock, Ph.D., recently set out to answer
that question, using the Bradys massive
database to track results from more than
14,000 men who had surgery at Johns
Hopkins between 1984 and 2013. They
divided men into three risk groups: low,
intermediate, and high. Then they
calculated what they call the Conditional
Survival probability the likelihood of
survival for 10 additional years.
They found that men in the low- and
intermediate-risk groups had a very high
probability at least 96 percent of not
dying from a return of prostate cancer at
10 years, regardless of the time duration
without recurrence, says Han. In
other words, these men are highly unlikely
to die from prostate cancer, regardless
of whether they experience recurrence
or not. In the high-risk men, the
probability of survival from prostate
cancer at 10 years was 91 percent for
those who experienced recurrence
within one year. However, if these
high-risk men do not have recurrence
for more than three years, their
probability of survival from prostate
cancer for 10 additional years is even
higher greater than than 99 percent.
These results give much hope for
men with prostate cancer, said Han.
Overall, men are highly unlikely to
die from prostate cancer after surgery
even men with high-risk prostate cancer.
If you do not experience recurrence for
several years, your likelihood of survival
for 10 more years is outstanding. n

MicroRNAs: Genes that

May Make Radiation
and Chemotherapy
More Effective
Your dishwasher is broken again. Youve
kept it going, but maybe youve fixed it
too often; maybe it needs to go. On the
molecular level, your body faces similar
dilemmas all the time when it comes to
fixing damaged DNA. DNA is a precious
thing, and the body works hard to keep
it in good shape, but theres a delicate
balance, explains Brady scientist Shawn
Lupold, Ph.D., the Frank Hinman Scholar:
Too little DNA repair can lead to an
accumulation of changes to uncontrolled cell growth, cancer development,
or even cancer progression. On the
other hand, too much DNA repair can
be detrimental, too, if it helps cancer
cells resist treatment like chemotherapy
or radiation.
Although cancer biologists know a
lot about how to work with and around
some of the bodys DNA-fixing mechanisms, theres a new repairman in town,
genetically speaking: A newly discovered
class of genes called microRNAs. Lupold
has been studying these genes and their
role in the development and progression
of prostate cancer with other Brady
scientists, including Theodore L. DeWeese,
M.D., Ph.D., the Sidney Kimmel Professor
and Director of Radiation Oncology and
Molecular Radiation Sciences. Although
what microRNAs do is very complicated
and is still not fully understood, basically
they send messages that produce action.
Each microRNA gene encodes a short
RNA transcript that results in selectively
turning off the synthesis of specific
proteins and enzymes, says Lupold.
In a recent study with DeWeese and Koji
Hatano, a visiting urologist and fellow
from Osaka University in Japan, Lupold
learned more about how microRNAs
regulate DNA repair pathways in cancer
cells. Using a novel and high-throughput
screening strategy, our team evaluated
more than 800 different human
microRNAs, says Lupold. They were
looking for microRNAs that seemed
especially adept at inhibiting DNA repair

and sensitizing prostate cancer cells to

radiation therapy for a new weapon
that would not only make radiation
therapy more powerful against prostate
cancer, but would also hinder the cancer
cells ability to recover from the attack.
This work was published in April in the
journal, Nucleic Acids Research. Hatano,
who was first author on the paper,
identified miR-890 as one of the most
potent radiation-sensitizing microRNAs
in the study, says Lupold. This particular
microRNA inhibited the ability of cancer
cells to repair the most lethal type of
DNA damage, double-stranded breaks.
This led to an over 50-percent increase in
prostate cancer cell sensitivity to ionizing
radiation. Most importantly, we demonstrated that miR-890 specifically targets
and inhibits the expression of multiple
DNA repair genes and pathways.

They were looking for a new

weapon that would not only
make radiation therapy more
powerful against prostate
cancer, but would also hinder
the cancer cells ability to
recover from the attack.
In laboratory studies, the team injected
the microRNA into established prostate
tumors in mice, and two days later treated
the animals with radiation therapy.
The tumors treated with miR-890 were
significantly reduced in size and growth
when compared to controls, says
Lupold. The next step, currently being
worked on by Lupold and DeWeese,
is to find the best way to deliver these
microRNAs to prostate cancers, with the
ultimate goals of selectively sensitizing
prostate cancer tumors to radiation and
chemotherapy, while sparing the healthy
tissues right next to the cancer. In
other studies of microRNAs, Lupolds
lab is exploring the role of these genes
in other aspects of prostate cancer, such
as androgen signaling. n

11

WINTER 2016 | DISCOVERY

PIN: Some high-grade PIN cells may be more dangerous than they look.

High-Grade PIN: Wolf

in Sheeps Clothing?
If it is high-grade PIN that is
found in multiple cores or is
present in tissue from both
sides of the prostate, then a
repeat biopsy is recommended.
PIN, short for prostatic intraepithelial
neoplasm is a condition in prostate biopsy
tissue that pathologists see under the
microscope. The cells are funny-looking;
pathologists consider them not to be
cancerous, but not normal-looking, either,
and for years, PIN has been considered a
sort of precursor for prostate cancer.
Although PIN shares many hallmarks
of prostate cancer, it does not appear to
invade the surrounding normal tissue,
says molecular pathologist Michael
Haffner, M.D. When PIN cells are
found in isolation, and no actual cancer
cells are found, its not always clear what
to make of the finding. As a matter of
precaution, urologists usually recommend
repeat biopsies if there are many cores
of tissue with this finding to make sure
that everythings okay that the PIN
itself is not progressing to become cancer,
or that cancer cells were not missed the
first time around.
12

But new findings by Haffner, molecular

pathologist Angelo De Marzo, genomics
expert Srinivasan Yegnasubramanian and
oncologist Bill Nelson may call for extra
precaution in some men. By way of a series
of genetic analyses, they were able to
trace the evolutionary ancestry to look
back in time, in effect of PIN lesions in
prostate tissue specimens. Surprisingly,
we found that many lesions that look like
a precursor lesion have identical genetic
fingerprints of invasive cancer cells,
says Haffner. Therefore, at least a subset
of PIN lesion likely represents cancer
cells that have invaded into normal
prostate glands a potentially dangerous
wolf in sheeps clothing. This study
provides important new insights into
how prostate cancer cells can grow and
spread, but also establishes new molecular
markers that can be used as helpful tools
in the future to discriminate less harmful
precursor lesions from invasive cancers.
Urologist Patrick C. Walsh, M.D., reassures
men who have PIN that it is most likely
just that precursor cells that are not
cancer. But if it is high-grade PIN that
is found in multiple cores or is bilateral
(in tissue from both sides of the prostate),
then a repeat biopsy is recommended. n

For Castrate-Resistant
Prostate Cancer:
High-Dose Testosterone
Hormonal therapy takes away a driving
force of prostate cancer testosterone.
It can work well for many years, but
eventually the prostate cancer cells figure
out how to adapt to the low-testosterone
environment, and they begin to grow.
But studies in the lab of Brady scientists
John Isaacs, Ph.D., and Samuel
Denmeade, M.D., have shown that these
testosterone-deprived prostate cancer
cells can be paradoxically killed by
treatment with something they didnt
expect high amounts of testosterone,
says Denmeade.
Based on this observation, Denmeade
and colleagues recently carried out a
pilot clinical trial that showed that a
monthly injection of high-dose testosterone

could be safely given to men with

castrate-resistant prostate cancer, and
that it produced a therapeutic benefit
in some men. These exciting findings
were published in the journal, Science
Translational Medicine. In addition,
Denmeade says, we observed that after
treatment with high-dose testosterone,
in most cases the prostate cancer cells
became re-sensitized and were no longer
resistant to treatments that lower or
block testosterone. In other words, the
treatment had a double impact: After
being bombarded with testosterone,
prostate cancer cells were once again
susceptible to hormonal therapy.

The treatment had a double

impact: After being bombarded
with testosterone, prostate
cancer cells were once again
susceptible to hormonal therapy.
These results were promising enough
for Denmeade to received funding
from both the National Institutes of
Health and the Department of Defenses
Prostate Cancer Research Program to
perform more clinical studies at Johns
Hopkins. He and colleagues will be testing
this concept in larger groups of men
with prostate cancer that has become
resistant to standard hormone deprivation
treatments. Our goal with these clinical
studies is to establish a role for high-dose
testosterone as an inexpensive treatment
that could improve quality of life, reduce
disease burden and potentially reverse
therapeutic resistance in men with
advanced prostate cancer, he says.
We hope to establish this as an effective
therapy that can improve survival,
overcome resistance to hormonal therapy,
and meaningfully improve quality of life,
functional activity, and sexual function in
men with castrate-resistant prostate cancer.
Denmeade was the principal investigator
on the pilot study. Co-authors on the paper
include Michael Schweizer, Emmanuel
Antonarakis, Hao Wang, Seun Ajiboye,
Avery Spitz, Haiyi Cao, Jun Luo, Michael
Haffner, Srinivasan Yegnasubramanian,
Michael Carducci, Mario Eisenberger,
and John Isaacs. n

Boosting Testosterone
Not Shown to Raise
Prostate Cancer Risk
Testosterone therapy was not
found to increase PSA levels,
or to promote the occurrence
of prostate cancer.
Does testosterone therapy raise your
risk of getting prostate cancer or having
a heart attack? For definitive answers,
large-scale, long-term controlled studies
are needed, says Arthur L. Burnett, M.D.,
the Patrick C. Walsh Distinguished
Professor of Urology. However, in the
meantime, results of a meta-analysis
study led by Burnett suggest that, for
prostate cancer at least, the risk is not
changed by taking extra testosterone.
Testosterone therapy boosting low
testosterone with supplemental medication
is often prescribed for men with low
blood levels of testosterone, for symptoms
including reduced libido and sexual
activity, fewer spontaneous erections,
decreased energy and depressed mood.
But controversies surround the role of
testosterone therapy, particularly with
respect to prostate cancer and cardiovascular health risks, and these concerns
have heightened recently, says Burnett.
In an effort to address the prostate cancer
side of these worries, Burnett collaborated
with Peter Boyle and colleagues of the
International Prevention Research
Institute in Lyon, France. They pored over
data from about 20,000 men who participated in 24 population-based studies
that evaluated the association between
blood testosterone levels and the risk of
prostate cancer. We found that the risk
of prostate cancer was neither increased
or decreased among men with high
levels of testosterone compared to lower
levels, says Burnett. Also, testosterone
therapy was not found to increase prostate
specific antigen (PSA) levels, or to promote
the occurrence of prostate cancer. The
meta-analysis was presented as a prize
abstract selection at the Press Program
of the American Urological Association
2015 Annual Meeting.

Burnett hopes that these findings will be

helpful to clinicians and patients who are
worried that boosting low testosterone
will cause prostate cancer to develop. n

test available are: Alison Mass Bommarito

and Salvatore J. Bommarito, R. Christian
B. Evensen, A.R. Deane Nesbitt, Jr.,
Joseph F. Rascoff, Harvey G. Sherzer,
Carolyn and William C. Stutt, F. Patrick
Hughes, and John C. Corckran , Jr.

For Men with Advanced

Prostate Cancer: New
Hopkins Test Can Tell if
Some Drugs Wont Work

The study that led to this new AR-V7

test began about one year ago and was
conducted in the Molecular Diagnostic
Laboratory, led by James Eshleman,
M.D., Ph.D., Professor of Pathology, in
conjunction with Luos laboratory. We
walked through every bit of detail of this
test, Eshleman says, a complex process,
and carried out a complete analysis
to justify using the test on men with
advanced prostate cancer. The Molecular Diagnostic Laboratory at Hopkins
is a CLIA-certified lab. (Any facility that
performs laboratory tests on human
specimens for the purpose of diagnosis
or treatment is required by Federal law
to have a CLIA certificate, and Medicare
requires the CLIA certificate number
before any claims can be processed.)

For the first time, a blood test is available

to help men with advanced prostate cancer
determine if certain medicines will work
or if they can avoid the trouble and cost
of taking expensive drugs that wont
fight their cancer.
This test, developed and tested at Johns
Hopkins, promises to predict treatment
response and resistance in men with
prostate cancer that no longer responds
to standard hormonal therapy.

This is a major milestone.

The test targets a faulty androgen receptor
(AR) molecule called AR-V7, discovered
in 2008 by Brady scientist Jun Luo,
Ph.D. This is a major milestone, says
Luo, who also pioneered the first AR-V7
blood test in his research laboratory.
Transforming a discovery and moving
a test from bench to bedside has been a
major challenge historically.
That the test is available now to patients
at the Brady represents several victories
of collaboration among scientists and
physicians in several disciplines, and of
Brady philanthropists who saw a need
and responded with what urologist
Patrick Walsh, M.D., calls an emergency
influx of generosity. Walsh, University
Distinguished Professor of Urology, notes
that the Brady Institute itself wouldnt
have been possible without private
philanthropy starting with a large
endowment from James Diamond Jim
Brady a century ago. Time after time,
friends of the Brady have stepped in and
their support has made it possible for us
to continue to do great things. In this case,
this gift helped get the test to the men who
need it most as soon as possible. The
philanthropists who helped make this

For men with advanced cancer that has

become resistant to hormonal therapy,
there are now six FDA-approved drugs
that have been shown to improve survival.
We ultimately hope that biomarker
tests such as AR-V7 will help clinicians
decide among these six drugs in a more
rational manner, says Emmanuel
Antonarakis, M.D., Ph.D., Associate
Professor of Oncology, who was the
clinical lead investigator on this project.
Having a robust clinical test for measuring AR-V7 in blood is only the first
step, however. Antonarakis cautions
that further prospective clinical trials
will be required before the AR-V7 test is
clinically validated and before information from the test can be used to guide
treatment decisions for all men with
advanced prostate cancer.
The AR-V7 blood test offered by the
Molecular Diagnostic Laboratory has
not yet been approved by the FDA and
is available only at Johns Hopkins. For
more information on how to request this
test, please contact: Katie Beierl, molecularpathresults@jhmi.edu. n

13

WINTER 2016 | DISCOVERY

He is a remarkable man,
who first had a dream
he believed he was meant to
do cancer research and
then came to Hopkins and
made it happen.

Don Coffey: Awarded the American

Association for Cancer Researchs highest honor.

Don Coffey: the Man, the Movie

Youve seen him many times on the
pages of Discovery. Hes a scientific
legend, here at the Brady, throughout
Hopkins, and beyond, as the scientists
he has trained and inspired begin
mentoring their own postdoctoral fellows
and students. Now you can see him on
the big screen or someday soon on the
little screen, if you want to watch The
Donald Coffey Story in the comfort of
your own home. (It will be available on
our website: urology.jhu.edu)
Don Coffey is an internationally
renowned scientist and also a powerful
driving force in the careers of dozens of
scientists who are trying to understand
cancer, says Alan W. Partin, M.D., Ph.D.,
the Jakurski Family Professor and Director
of Urology. He ignites the imagination
and creativity of people who are asking
good scientific questions, and helps
them figure out what they need to do
to find the answers. In addition, he is a
remarkable man, who first had a dream
he believed he was meant to do cancer
research and then came to Hopkins
and made it happen. We hope that
his life story will be inspiring to new
generations of future scientists, and to
our patients.
In April 2015, Coffey received the American
Association for Cancer Researchs
highest honor, the Margaret Foti Award
for Leadership and Extraordinary
Achievements in Cancer Research.
Coffeys work on the nuclear matrix
established a new paradigm for
understanding the biology of normal and
cancer cells, while his prostate cancer
research helped change the face of that
14

deadly disease, said Margaret Foti, M.D.,

Ph.D., the AACRs chief executive officer.
But his impact extends far beyond his
scientific achievements. His outstanding
leadership skills, dedication to mentoring
young investigators, passionate advocacy
for sustained increases in funding for
cancer research, and remarkable ability to
translate complex scientific concepts into
lay language make him an icon in the field
and a true champion of cancer research.
In accepting the award, Coffey said that
it fulfills my lifetime dream. Sixty years
ago, my wife, Eula, and I accepted our
joint calling to serve this mission. Johns
Hopkins University, the AACR, and
hundreds of colleagues, supported by
private and public donors, have all made
this possible. We thank all of you.
Coffey is a former president of the AACR,
the largest cancer research society, with
35,000 members from 110 countries.
In other Coffey news from 2015:
At the American Urological Associations
yearly meeting, the Coffey-Crain Award
was presented by the British Journal of
Urology International, and the Society
of Basic Urology presented the Coffey
lecture. The Prostate Cancer Foundation
held its second meeting of the Coffey
Holden Academy in La Jolla, California.
Coffey delivered the 16th Biennial
Science Creativity and Human Destiny
lecture at The Johns Hopkins University,
and he was invited to provide the very
first paper to launch the Asian Journal
of Urology. n

Potential New Pathway

to Kill Prostate Cancer
This pathway has been
considered untouchable, and
efforts have not been invested
to exploit it as an avenue to
deactivate cancer cells. But our
research has proven otherwise.
There is a brand new way to target cancers,
and cancer biologist Marikki Laiho, M.D.,
Ph.D., the Willard and Lillian Hackerman
Professor in Radiation Oncology, is one
of only two scientists in the country
funded by the National Institutes of
Health to work on it. Its called RNA
polymerase I transcription.
This adventure in new science began
when Laihos group discovered a small
synthetic chemical molecule, called
BMH-21, and showed that it has a unique
way of killing cancer cells. We learned
that the molecule is a novel inhibitor of
RNA polymerase I, she says. RNA polymerase I transcription is an intricately
coordinated transcriptional program.
It is highly activated and insufficiently
controlled in cancers, but despite its
ability to support cancer growth, it has
received little attention as a possible
new target for therapy.
Transcription in this case means reading
the DNA into RNA, that is, converting
the universal genetic code into a new
biomolecule, RNA, says Laiho. RNA
polymerase I drives a fundamental process
that synthesizes the RNA component for
the ribosomes (tiny factories inside cells
where proteins are made), and hence, is
essential for making cellular proteins.
These building blocks are necessary for
the life and health of cells. For this reason,
this pathway has been considered
untouchable, and efforts have not been
invested to exploit it as an avenue to
deactivate cancer cells. But our research
has proven otherwise.
Laihos findings suggest the promise of
inhibiting RNA polymerase I transcription
in a potential new class of cancer-fighting
drugs. We have shown that it has
therapeutic benefit, and it is well-tolerated
in preclinical models. We hope that our

findings will invigorate basic science efforts

on RNA polymerase I transcription. We
still lack basic knowledge of the factors
associated with this fundamental process
and their regulation.
Laiho believes BMH-21 has particular
relevance for the treatment of prostate
cancers, and is turning her work toward
developing this molecule into a clinical
drug. Her team has received the Harrington
Discovery Institutes Harrington-Scholar
Innovator Award and the Prostate Cancer
Foundation Global Challenge Award
for this work. Laiho and colleagues are
now exploring the role of BMH-21 in
advanced prostate cancer. n

Two Non-Cancerous
Causes for Higher PSA
The greater the amount of
inflammation in the prostate,
the higher the PSA level.
How can prostate cancer screening be
improved? Brady epidemiologist Elizabeth
Platz Sc.D., M.P.H., the Martin D. Abeloff,
M.D., Scholar in Cancer Prevention and
colleagues are studying a group of men
you might not expect to be helpful here
men who dont have prostate cancer.
We are looking at factors that can affect
blood levels of PSA other than prostate
cancer, she says.

the Prostate Cancer Prevention Trial,

a large investigation in which men who
were not diagnosed with prostate cancer
during the trial itself were asked to have
a biopsy when the study ended, even if
they did not appear to need one. We
only included men who had a PSA lower
than 4 ng/ml and a normal digital rectal
exam, and who did not have prostate
cancer found in their biopsies. Platz
and colleagues found that the men with
more inflammation in their biopsied
tissue had higher PSA levels, and the
greater the amount of inflammation,
the higher the PSA level.
Although the scientists do not know
exactly how inflammation raises PSA,
they think that the inflammation disrupts
the PSA-producing cells in the prostate
and also makes the blood vessels within
the prostate more permeable, causing
PSA to leak into the bloodstream. Platz
and colleagues hope that information
from this study will one day help reduce
unnecessary biopsies, both for men
who have never been screened, and men
who have been screened and biopsied,
but cancer was not found.
In another study, led by biostatistician
Sarah Peskoe, Platz and colleagues
looked to see whether testosterone
affects PSA levels in the blood. While
we know that testosterone helps signal
to prostate cells to make PSA, no one
had quantified the association between

testosterone and PSA in the blood in a

general population of men who havent
been diagnosed with prostate cancer,
says Platz. In this study, the investigators
looked at data from 378 men, between
the ages of 40 and 85, who participated
in the National Health and Nutrition
Examination Survey, which ran from
2001 to 2004. We only included men
who did not have a prostate cancer
diagnosis and had not had a recent
biopsy, rectal examination, cystoscopy,
or known prostate infection or
inflammation, says Platz. The scientists
found that men who had higher testosterone levels also had higher PSA levels.
We also found that the odds of having
a clinically elevated PSA were greater
among men with higher testosterone
levels. Our findings may indicate that in
prostate cancer screening, American men
who have higher testosterone levels may
be more likely to undergo unnecessary
prostate biopsy, flagged by their higher
PSA. While we are not advocating that
men should have their testosterone
measured at this time, we expect that
knowledge of the testosterone-PSA
association may help refine tools for
clinical decision-making in men who
have an elevated PSA. Platz and
colleagues published the results of
these two studies in Prostate Cancer
and Prostatic Diseases, and Prostate,
respectively. n

This is happening in two different studies.

In one, led by urologist Martin Umbehr,
M.D., a postdoctoral fellow studying
with Platz, we evaluated the extent
to which inflammation in the prostate,
which is very common, affects PSA
levels, explains Platz. With Angelo De
Marzo, she was one of the first to conduct
studies linking inflammation and prostate
cancer. Although urologists have long
known that prostate inflammation may
cause PSA to be elevated, previous
studies looked at men who underwent
prostate biopsies because they had an
elevated PSA. Our analysis included data
from 224 men from the placebo arm of
Platz and De Marzo: Learning about prostate
cancer by studying men who dont have it.

15

DISCOVERY | WINTER 2016

New Tests Show

Genetic Changes Linked
to Aggressive Prostate
Cancer
ERG is a troublemaker, a gene
that may promote the growth
of cancer. With PTEN out of
the picture, it stars in its own
episode of genes gone wild.
When the cats away, the mice will play.
Thats whats happening, on a very tiny
scale, in aggressive prostate cancer, and
its being demonstrated in important
work by urologic pathologists Tamara
Lotan, M.D., Angelo M. De Marzo, M.D.,
Ph.D., and colleagues. Two of the most
common genetic changes that we see in
aggressive prostate cancer are the loss of
the PTEN gene and rearrangements that
lead to over-expression of an oncogene
called ERG, says Lotan.
In this case, the cat the keeper of the
peace is a gene called PTEN. PTEN is
a tumor suppressor. Its job is to put the
brakes on the out-of-control growth that
leads to cancer. Without the restraint
of PTEN the gene is knocked out in
about half of lethal prostate tumors
cancer cells start behaving badly. Previously in Discovery, we reported that
PTEN is one of the few genes whose
loss has been consistently associated
with aggressive prostate cancer. Two
years ago, Lotan, De Marzo, and others
at Hopkins found a strong correlation
between the loss of PTEN and the signs
of aggressive prostate cancer, including
the Gleason grade of the tumor as well
as the stage of the tumor and the time
it took for metastases to develop; this
work was published in Clinical Cancer
Research. In a larger follow-up study just
published in European Urology Focus by
Lotans team, the scientists found that
PTEN loss correlated with faster
recurrences after radical prostatectomy.
ERG, on the other hand, is a troublemaker,
a gene that may promote the growth of
cancer. With PTEN out of the picture, it
16

stars in its own episode of genes gone

wild. Lotans team has worked with
De Marzo and other Johns Hopkins
investigators to develop and test simple,
inexpensive assays that show the status
of PTEN and ERG in prostate tumors.
In work recently published in Modern
Pathology, Lotan and colleagues showed
that men who have Gleason 6 tumors with
PTEN loss are about three times more
likely to be upgraded to Gleason 7 or
higher at radical prostatectomy. Further,
Lotans team showed that prostate
tumors with PTEN loss are two to three
times more likely to be lethal compared
to tumors without PTEN loss, even
after adjusting for the usual clinical
and pathologic signs we currently use
to predict prognosis, Lotan says.
Interestingly, PTEN loss is more tightly
associated with lethal disease when
the tumor does not have ERG gene
rearrangement suggesting a significant
interaction between these important
genes in the progression of prostate
cancer. Lotan recently presented these
findings at meetings of the United States
and Canadian Academy of Pathology,
and of the American Association for
Cancer Research.
Validated tests developed by Lotan,
De Marzo and colleagues are now
being offered in the clinical lab at Johns
Hopkins, and Lotans team is working
with investigators from several other
academic centers to develop these
tests into FDA-cleared prognostic and
predictive biomarkers. n

Could Nerve-Sparing
Brachytherapy Help
Preserve Sexual Function?
The neurovascular bundles of Walsh,
discovered by Patrick C. Walsh, M.D.,
are tiny, delicate, and important: they
contain the nerves that control erection.
An unfortunate risk of any treatment for
prostate cancer is that many men who
undergo curative surgery or radiation
will subsequently develop erectile
problems, explains radiation oncologist
Danny Song, M.D. For men who undergo

At Last, a Desperately
Needed Mouse
Model of Aggressive
Prostate Cancer

surgery, the nerve-sparing techniques

discovered by Walsh have been shown
to help preserve sexual function.
But until now, there has been no clear
understanding of what exactly leads to
this side effect in patients undergoing
radiation, says Song, who recently set
out to change this. Prior studies have
attempted to answer this question by
evaluating the dose of radiation received
by the neurovascular bundles, which are
tiny cables of blood vessels and nerves
that run along the sides of the prostate.
However, these studies have not shown
a difference in erectile function when
comparing patients who received high
vs. low doses to these structures. So
Song took a different approach. In a
recent study of 366 men who underwent
brachytherapy (the implantation of
radioactive seeds at precise points to kill
prostate cancer), Song and colleagues
measured radiation doses to various
anatomic structures around the prostate.

Patients who received

lower doses to the cavernosal
nerves had less risk of erectile
problems.
We also looked at the area where the
nerves converge at the apex of the
prostate, the place where the urethra
joins the prostate, Song says. These
nerves are essentially the combined
neurovascular bundles from both sides
of the prostate, which join on their way
down to the penis. One could consider
this to be the main hub where the
nerves meet on their way down to the
penis. Song and colleagues discovered
that the risk of erectile dysfunction was
high in men who received higher doses
to the cavernosal nerves, but patients
who received lower doses to the
cavernosal nerves had less risk of erectile
problems. We are excited by these results
and hope that, armed with a better
understanding of the area that needs to
be avoided when placing seeds, radiation
oncologists will be able to use this
knowledge to improve sexual function
and quality of life for their patients. n

From left, An, Yegnasubramanian, and Haffner: Figuring out how cancer cells move through tissue and bone.

Pro st ate Can ce r Me t astasis: Ne w D isco ve rie s

Taking AIMat
Invasive Cancer
To invade other tissue and
migrate far distances, cancer
cells need to alter their
cytoskeletal properties.
In other words, they need to
become tiny shape-shifters.
One of prostate cancers worst features
is its ability to spread to distant sites,
particularly bone, and to start new,
malignant outposts. How do they do it?
Research by scientists Srinivasan
Yegnasubramanian, M.D., Ph.D., Michael
Haffner, M.D., Ph.D., Steven An, Ph.D.,
and colleagues has turned up an important
clue and a potential new avenue for
treatment.
In order to invade other tissue and
migrate far distances, cancer cells need
to alter their cytoskeletal properties,
says Yegnasubramanian. In other words,
they need to become tiny shape-shifters.
But exactly how they become malleable
enough to move through tissue and bone
has been poorly understood.
With support from the Patrick C. Walsh
Prostate Cancer Research Fund and
the David H. Koch Foundation,
Yegnasubramanian, Haffner, An, and

colleagues have identified a protein

that appears to suppress the ability of
normal cells to invade. This protein,
called AIM1, binds and modulates the
major component of the cytoskeleton
in normal prostate epithelial cells,
Yegnasubramanian adds. They found
that AIM1 seemed to have an out-ofbody experience in invasive primary
prostate cancer, separating itself
from the cancer cells cytoskeleton.
Additionally, AIM1 was often deleted
and/or reduced in expression in
metastatic prostate cancer. In laboratory
models of prostate cells, when the
scientists cut the expression of AIM1,
the cancer cells began to remodel themselves, and this increased their invasive
and migratory potential. Taken together,
these findings implicate the loss of AIM1
function in conferring prostate cancer
cells with the ability to invade and
produce invasive cancer and metastases.
This work continues, and now the
investigators are working to identify
the molecular mechanisms through
which AIM1 can do its sleight-of-hand,
allowing cancer cells to become invasive.
When we understand this, we may be
able to prevent or treat prostate cancer
metastases the major cause of prostate
cancer morbidity and mortality,
says Yegnasubramanian. We are also
evaluating whether AIM1-mediated
changes can be used as a biomarker to
identify aggressive prostate cancers
with metastatic potential. n

How do scientists develop a new treatment

for prostate cancer? First, they need a safe
way to test it before they even think about
trying it in humans. Unfortunately, the tools
available to researchers make it difficult to
develop and test targeted immunotherapy
and treatments for bone metastases,
two areas of great need in prostate cancer
therapy, explains Brian Simons, D.V.M.,
Ph.D. New drugs are currently tested
primarily on xenografts -- human cells
growing in mice without a functioning
immune system. But if mice dont have an
immune system, they cant very well serve
as models for any treatment that requires
the bodys own ability to fight disease.
Another problem: Very few of these models
develop metastatic tumors, which limits
the development of treatments for bone
metastasis.

If mice dont have an

immune system, they cant
very well serve as models
for any treatment that
requires the bodys own
ability to fight disease.
Simons has developed a new laboratory
model that has the potential to do a lot
of good for men desperately in need of
treatment for advanced prostate cancer.
Working with Edward M. Schaeffer, M.D.,
Ph.D., the R. Christian B. Evensen Professor
of Urology, and a team of investigators, he
has come up with a mouse model of bone
metastatic prostate cancer that has many
features of very aggressive human prostate
cancer. When injected into mice, these
cells frequently form bone metastases that
initially respond to anti-androgen therapy,
but then become castration-resistant
tumors, he says. Already, this model is
being used to test new immunotherapy
treatment strategies and imaging systems
to detect bone metastasis.

17

A New Way to Attack Early Metastatic Disease

There are bits of cancer that
have spread, or metastasized,
beyond the prostate, but not
that many, and not at very
many locations in the body.
Cancer in this state is still
vulnerable, and still responds
to treatment.
In the blockbuster movie, Independence
Day, terrifying space aliens invade
earth. From one mother ship, dozens of
equally deadly, smaller ships spread out
around the planet. But these evil aliens
are beaten by a tiny home force. The
secret? They attack the mother ship, and
without its protection, the smaller ships
are vulnerable.
This is a pretty good model for what radiation oncologist Phuoc T. Tran, M.D., Ph.D.,
wants to do with metastatic prostate
cancer in its earliest stages. He believes that
by eliminating the bigger sites of cancer,
tiny new ones wont be able to flourish.
Its an idea that has shown success in
the treatment of breast cancer, where
improved local control decreases metastatic
as well as local relapse, Tran says. This
local treatment model is true for prostate
cancer, too. Better control of localized
cancer by adjuvant radiation to the area
around the prostate (called the prostatic
bed) lowers the risk of other metastases
and improves overall survival. We believe
that sites of macroscopic disease visible
on MRI or other images support the
maturation of microscopic spots of cancer
into future metastases. Going after the
cancer that can be seen has substantial
clinical implications for the cancer too
small to be seen, he adds. This is hardly
ever performed in prostate cancer.
In the spectrum of cancer, from localized
to advanced metastatic disease, is a kind
of midpoint called an oligometastatic
state. There are bits of cancer that have
spread, or metastasized, beyond the
prostate, but not that many, and not at very
many locations in the body. Cancer in this
18

state is still vulnerable, and still

responds to treatment. For example, in
patients with oligometastatic sarcomas
or colorectal cancer, local radiation to
the primary tumor combinedwith chemotherapy, can result in long term diseasefree survival in between 25 and 40
percent of patients, says Tran. Our
own clinical experience suggests an
oligometastatic state exists in a subset of
prostate cancer patients who may benefit
from local radiation treatment to all
sites of macroscopic metastatic disease.
Picture, if you will, the bloodstream. It
goes throughout the body, flowing in one
direction. Cancer cells that make their
way into the blood, like seeds floating on
a river, leave the original tumor the
mother ship and drift for a while,
eventually coming to rest at a distant site,
where they may start to grow. This is the
generally accepted model of how cancer
spreads. But Tran suspects that these
circulating tumor cells (CTCs) get homesick that they pay an occasional visit
back to the original tumor, or maybe visit
one of their siblings that has struck out
on its own and built a home. These visits
are invigorating: The CTCs become
more robust, he says, and this cyclical
process of CTCs interacting with more
established cancer results in the release
of signals that foster tumor growth.
Like a domino effect, then, tumor growth
leads to angiogenesis the paving of new
roads, made of blood vessels, to supply
the tumor; angiogenesis is followed by
immune evasion the cancer mutates to
dodge the bodys militia of immune cells
and ultimately, the formation of new,
macroscopic metastases. This theory of
macroscopic metastases being self-seeding
communal sanctuaries is supported by
recent genomic data from studies of
human prostate cancer cells, Tran says.
Whats the best way to target these little
blots of cancer? Tran believes the key is
stereotactic ablative radiation (SABR),
a highly focused, localized, high-dose
radiation delivered in a hypofractionated
course, meaning in several large doses,
spread out over several days. Its ideally
suited for treatment of oligometastatic

patients, and has shown high local control

rates with minimal toxicity, he says.
SABR effectively targets the microenvironment of tumors, and in melanoma
patients, has been shown to have antitumor
effects on the irradiated tumor and an
abscopal effect think of a shock wave,
affecting areas not part of the original
blast on distant metastases when
combined with other immune systemstimulating agents.
Tran is starting a multi-institutional study
aimed at killing oligometastatic cancer
through SABR and immune systemtargeting agents. This program is partly
funded by an award from the National
Cancer Institute to radiation oncologist
Ted DeWeese and Director of Nuclear
Medicine Martin Pomper, and by
a Movember-Prostate Cancer Foundation
Challenge award to Tran, who is the
principal investigator, and to urologist
Ashley Ross, DeWeese, Pomper, Adam
Dicker (from Thomas Jefferson University),
Max Diehn (from Stanford University),
Charles Drake, Hao Wang, Kenneth
Pienta and Mario Eisenberger.
In 2015, among other honors and
awards, Tran was appointed Clinical
Director of Radiation Oncology and
was named Associate Editor for the
journal, Cancer Research. n

Capturing Cancer Cells

in the Bone, Years Before
They Cause Trouble
Brady surgeons and scientists are working
together, using a surgical technique
pioneered by three of our urologists, to
target potentially lethal prostate cancer
before it has a chance to spread. The key
here involves what we call disseminated
tumor cells, or DTCs, explains Ken
Pienta, M.D., the Don Coffey Professor
of Urology. We can detect them at
the time of radical prostatectomy

these tiny prostate cancer cells that

have escaped the prostate and taken up
residence in the bone marrow.
Important note: DTCs are not the same
thing as bone metastases. Just because

a man has these cancer cells in his bone

marrow doesnt mean that he has cancer
growing in his bone, Pienta hastens to
point out. The purpose of this story is
not to scare anybody, but to tell you about
exciting work that has the potential to
allow doctors to see into the future,
through a microscope, and identify troublemaking cells years before they are able to
cause a problem.
At the moment, Pienta and colleagues
dont know exactly what to make of these
DTCs. They remain poorly defined, he
says, but we think they are a mixture of
passively sloughed, nonlethal cells that
are going to die anyway which means
theyre nothing to worry about but in
some cases they could also be actively migrating, cancer cells that could eventually
develop into clinical metastases. It is very
important to study these DTCs so we can
determine how to stop the lethal ones.
Previously, it was reported that nearly
all men have these cancer cells in their
bone marrow at the time of surgery. Now
we have the know-how to prove how
many men have these cancer cells in their
bones, so we can go after that cancer.
In laboratory research, Brady resident
Michael Gorin has developed sensitive new
methods to detect and capture these cells
for analysis, Pienta says. And three Brady
surgeons Ashley Ross, Ted Schaeffer,
and Alan Partin have pioneered a
painless technique to sample the marrow
from the pubic bone just before radical
prostatectomy, when the patient is asleep.
This has never been done before and
represents an exciting new advance for
the field, says Pienta. The team has
already obtained samples from more than
50 men and we are busy characterizing
these cells. We expect to study 500 men
in the coming year; this will be the largest
study ever performed to characterize
DTCs in men at the time of surgery.
Pienta and colleagues believe this
research will identify the early steps by
which lethal prostate cancer develops
and metastasizes to the bone marrow
microenvironment, opening the door
for early therapeutic intervention to
decrease deaths from prostate cancer. n

Long days, short weekends, unparalleled research experience: Mentor Sarah Amend, a
postdoctoral fellow in Kenneth Pientas lab, with student Sounak Roy.

Summer Urological Research Experience (SURE)

It may not be a particularly restful summer vacation, but it SURE is a one-ofa-kind chance for students who are interested in urological and cancer research to learn from some of top scientists in the field, in the laboratory and at
lectures and seminars. Its a wonderful opportunity for young investigators to
see how research done at the bench can be translated into patient care, says
Ken Pienta, M.D., the Donald S. Coffey Professor of Urology and Director of
Research. The 10-week program offers a stipend of $3,000. Housing is provided
near the Johns Hopkins University, and shuttle transportation to the medical
campus is free.
This summer internship requires a full-time commitment, says Pienta.
Interns should be prepared for long days and short weekends. But the
experience is unparalleled.

If you would like to support this wonderful program

or even sponsor a student, please see the envelope in this
issue of Discovery.

Want to learn more? To find earlier issues of Discovery and much more
check out our website: urology.jhu.edu
If you do not wish to receive this newsletter, please write to us at The James
Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions,
Baltimore MD 21287-2101.

19

THE PATRICK C. WALSH PROSTATE CANCER RESEARCH FUND AWARDEES 2016

THE PATRICK C. WALSH

PROSTATE CANCER RESEARCH FUND

Read About the Research You have Helped Make Possible.

the patrick c. walsh prostate cancer research fund
Its been going strong for a decade

2 0 1 5 A WA R D EES

now. Since its inception in 2005,

H. Ballentine Carter, M.D.,

The Carolyn and Bill Stutt Scholar,
Departments of Urology and Oncology

the Patrick C. Walsh Prostate

Cancer Research Fund has awarded
millions of dollars to Johns Hopkins
scientists in every discipline with
good ideas worth pursuing that
can help us understand more about
prostate cancer and help us
save lives with better ways to treat
and prevent it. Applications are
reviewed by a Scientific Advisory
Board composed of noted Hopkins
scientists and lay members.
These awards wouldnt have been
possible without the tremendous
and amazing generosity of our
patients and friends. On these
pages youll find some of the
exciting work this years award
winners are doing, which wouldnt
be possible without your help.

Misop Han, M.D.,

The Nancy and Jim ONeal Scholar,
Departments of Urology and Oncology
Sushant Kachhap, Ph.D.,
Department of Oncology
Anthony K.L. Leung, Ph.D.,
The Irene and Bernard L. Schwartz
Scholar, Departments of Biochemistry
& Molecular Biology and Oncology
Sangeeta Ray, Ph.D.,
The Dr. and Mrs. Peter S. Bing Scholar,
Department of Radiology and
Radiological Science
Linda Resar, M.D.,
The Peter Jay Sharp Foundation Scholar,
Departments of Medicine, Oncology,
and Institute for Cellular Engineering
Ashley Ross, M.D., Ph.D.,
The R. Christian B. Evensen Scholar,
Departments of Urology, Oncology
and Pathology
Daniel Thorek, Ph.D.,
Department of Radiology
Raphael Viscidi, M.D.,
The Beth W. and A. Ross Myers Scholar,
Departments of Pediatrics and Oncology
Hui Zhang, Ph.D.,
The Virginia and Warren Schwerin
Scholar, Department of Pathology

Understanding Prostate
Cancer Progression During
Active Surveillance

Did the low-grade cancer

somehow morph into highgrade disease, or did both
low- and high-grade disease just
happen to spring up together?
Urologist H. Ballentine Carter has done
pioneering research in prostate cancer
for decades, but hes never talked about it
like this: Think of low-risk prostate cancer
as a turtle, intermediate-risk cancer as
a rabbit, and high-risk cancer as a bird,
he says. The classification depends in
large part on the cancer grade. If turtles,
rabbits and birds were put into a fenced
area (the prostate), the turtles would
never leave, or spread to other parts of
the body. The rabbits would sometimes
leave, and the birds would often leave.
Carter has been thinking about the
different risk levels of prostate cancer
particularly as it has to do with low-risk
cancer the men who qualify for the
Active Surveillance program, which he
began 15 years ago and continues to lead.
With funding from the Patrick C. Walsh
Prostate Cancer Research Fund, Carter
has teamed up with some impressive
Hopkins co-investigators geneticist
William Isaacs, pathologists Angelo De
Marzo, Srinivasan Yegnasubramanian,
Jonathan Epstein and Michael Haffner,
and mathematical analyst and scientist
Sarah Wheelan. The purpose of this
project is to determine whether turtles can
evolve into rabbits and birds, says Carter.
The scientists have identified men in
the Active Surveillance program who
were initially diagnosed with low-grade
disease, but during the close follow-up
turned out to have high-grade cancer
found on a repeat biopsy, which resulted
in radical prostatectomy. Using those
pathology specimens, the low-grade

20

and high-grade components of the

cancer within the same prostate will be
genetically sequenced to determine how
these cancer cells are related, says Carter.
The scientists hope that by making a
genetic fingerprint of these tumors,
they can answer some key questions,
including: Did the low-grade cancer
somehow morph into high-grade disease,
or did both low- and high-grade disease
just happen to spring up together?
Do these high-grade cancers leave some
sort of calling card a genetic marker
that could be used to predict whether
men have cancers that are actually birds
in turtle clothing? The investigators will
also look at a control group low-grade
cancer that has remained low-grade,
to determine if there are high-grade
markers within these low-grade cancers,
Carter continues. Lastly, if we find
definitive markers of high-grade cancer
within low-grade cancer, we will
sequence prostate biopsies to determine
if disease that we diagnosed as low-grade
actually contained high-grade markers.
This information could help men
with a diagnosis of low-grade cancer
know whether they will eventually
need treatment. n

Prostate Biopsy: Can a Robot

Make it Better?
Misop Han, M.D., the David Hall
McConnell Professor of Urology,
believes that prostate biopsies dont
provide enough information. A typical
transrectal ultrasound (TRUS)-guided
biopsy has significant limitations, he
explains, because the probe is handled
by human hand. In new research funded
by the Patrick C. Walsh Prostate Cancer
Research Fund, he and his co-investigators,
robotics expert Dan Stoianovici and
epidemiologist Bruce Trock, plan to
improve TRUS-guided prostate biopsy
with a novel robotic TRUS manipulator
(called a TRUS Robot), which was

developed in our laboratory.

With robotic guidance, Han believes, the
TRUS-guided biopsy will not only be
able to provide important information
about the precise location of the biopsy
cores, but about the stiffness of the
prostate. As urologist Patrick Walsh
explains, the prostate should feel soft in
a digital rectal exam, like the pad of your
thumb. But if there is cancer, it feels
harder, more like a knuckle. The biopsy
needle cant feel; but Han hopes to fix
this: With the TRUS Robot, we are
incorporating a new imaging modality,
ultrasound elastography, which can detect
the relative stiffness of the prostate.
With elastography guidance, regions of
elevated relative stiffness will also be
included in the biopsy plan, to make the
urologist aware of any trouble spots
that may need further investigation. n

Targeting Prostate Cancer Cells

That Hibernate
When cancer escapes the prostate, some
cells go to the bone marrow, where they
are alive but dormant. These sleeping
cells are resistant to conventional therapy,
says scientist Sushant Kachhap, Ph.D.,
which means that if they wake up and
cancer begins to grow outside the prostate,
there are very few therapeutic options.

The dormancy seems to have

a protective effect think of
Sleeping Beauty, who managed
to sleep for 100 years and
hadnt aged a day when the
prince woke her up.
Kachhap is intrigued by these hibernating
prostate cancer cells. What makes them
sleep? What wakes them wake up?
While we know a great deal about how
cancer grows, very little is known about

the biology of prostate cancer dormancy,

he says. This makes targeting these
dormant cells a challenge, but also
extremely important. Kachhap believes
that the ability to become dormant is
acquired very early in the process of metastasis, when prostate cancer cells leave
the prostate and enter the bloodstream.
The dormancy seems to have a protective
effect think of Sleeping Beauty, who
managed to sleep for 100 years and
hadnt aged a day when the prince woke
her up. Normally, when cells break off
from the parent organ, they die due to a
mechanism called anoikis. But detached
prostate cancer cells survive by signaling
a process called autophagy, where parts
of the cell are broken down and the
energy is used for survival. In research
supported by the Patrick C. Walsh Prostate
Cancer Research Fund, Kachhap will use
cell and animal models to investigate
what triggers dormancy in prostate
cancer cells whether its caused by
breaking off from the main tumor, or by
autophagy, or something else. Moving
forward, we will test whether inhibiting
autophagy can lead to death of dormant
prostate cancer cells. We believe this
work can lead to new strategies for
targeting dormant prostate cancer cells,
and inhibiting metastatic cancer. n

Who Can Benefit from Drugs

That Stop Cancer Cells from
Repairing Themselves?
Anthony Leung, Ph.D., an RNA biologist,
is interested in drugs that inhibit PARP.
PARP which stands for poly (ADPribose) polymerase inhibitors have
shown promise in treating ovarian,
breast, and prostate cancers. These
drugs are designed to target cancers that
already have defects in their ability to
repair DNA, and rely on remnant repair
pathways for survival, he says. These
remnant pathways are mediated by
21

THE PATRICK C. WALSH

PROSTATE CANCER RESEARCH FUND

Read About the Research You have Helped Make Possible.

the patrick c. walsh prostate cancer research fund
Massachusetts Institute of Technology.
PARP; so by blocking these pathways,
As its name implies, a PARP inhibitor
scientists can kill cancer cells but spare
healthy cells with functional DNA repair. stops the PARP enzyme from working,
explains Leung. PARP works by putting
PARP-inhibiting drugs have been shown
a specific mark on proteins. In cancer
to extend life and even cause tumors
cells,
the abnormal activity of PARP
to go into remission in patients with
even
adds
marks to proteins that are
mutations in the DNA repair genes
normally unmarked. To scientists
BRCA 1 and 2. PARP inhibitors have
looking at proteins, such marks are
also shown survival benefits for other
the equivalent of signposts, and we
patients with difficult-to-treat, castrapredict
that people who will respond to
tion-resistant prostate cancers, says
these
drugs
will have a distinctive set
Leung. In an ongoing Phase II trial
of
protein
marks.
Thus, the ability to
of Olaparib, men with advanced,
identify
these
protein
marks may likely
castration-resistant prostate cancer
be
the
key
to
predict
which
patients will
have shown impressive responses, he
respond
well
to
PARP-inhibiting
drugs.
adds. This trial includes patients who
Recently,
our
lab
published
a
highly
have not inherited BRCA mutations, but
sensitive method to identify such protein
do carry mutations to DNA repair genes
marks.
We are now geared to apply our
within their tumors. These encouraging
method
to a panel of prostate cancer cell
data suggest the possibility of expanding
lines.
Some
of these cancer cells are
access to PARP inhibitors to patients with
killed
by
PARP
inhibitors, and some are
other defects in DNA repair pathways.
not.
Using
these
data, we will be able to
But will they respond? So far, scientists
identify which protein marks can distinhave not been able to predict who will
guish
responders from non-responders.
benefit from this drug, says Leung. At
Leung
hopes this work will identify a
the same time, it is equally important to
biomarker
that can be used in a blood
find out which patients are not responding,
test
to
help
determine which men will
so as to avoid unneeded treatments
benefit
from
PARP-blocking drugs. n
and, more importantly, false hope in
patients. Therefore, we urgently need a
sensitive tool that is able to distinguish
responders from non-responders.

22

Ultra-Precise Targeting
and Killing of Metastatic
Prostate Cancer

To scientists, these marks are

the equivalent of signposts,
and we predict that people
who will respond to these
drugs will have a distinctive
set of protein marks.

Radiopharmaceutical therapy is an ultraprecise way of targeting and treating

cancer cells. Scientist Sangeeta Ray,
Ph.D., is integrating molecular PET and
CT imaging, with the ultimate goal of
tumor-specific treatment of castrateresistant prostate cancer.

With support from the Patrick C. Walsh

Prostate Cancer Research Fund, Leung
hopes to develop such a tool, along with
Hopkins co-investigators Ken Pienta,
H. Ballentine Carter, and Robert Cole;
and Phillip Sharp, of the Koch Institute
for Integrative Cancer Research at the

What will happen next in

cancer cells is akin to lighting
up a guns target with a laser
sight making them much
easier to see and kill.

With support from the Patrick C. Walsh

Prostate Cancer Research Fund, Ray
and co-investigator Martin Pomper are
developing a very specific, low-molecularweight theranostic agent. Theranostic
is another new word you may be seeing
more of; its a combination of therapeutics
and diagnostics, and its a key term in the
growing field of personalized medicine.
Rays goal is to treat multiple sites of
disease simultaneously, minimizing
damage to adjacent normal tissue, and
to treat metastases at an earlier point,
when the volume of disease is lower,
she says. Currently, this is challenging
to achieve with standard external-beam
therapy. Ray is aiming to develop an
imaging agent that targets a molecule
on the surface of prostate cancer cells,
PSMA (prostate-specific membrane
antigen). What will happen next in
cancer cells is akin to lighting up a guns
target with a laser sight making them
much easier to see and kill.
Based on our preliminary studies, the
underlying hypothesis is that the lowmolecular-weight agents can be optimized
to demonstrate superior tumor penetration
and lower toxicity to normal tissues,
particularly the kidneys, and to provide
greater therapeutic efficacy than
currently available treatments. n

Studying the Molecular

Switches for Metastasis
You may soon be hearing more about a
protein called HMGA1. A tiny thing, it
is nonetheless critical for rapid growth
and development before birth. Normally,
it is switched off or silenced in our cells
after birth, but becomes abnormally
flipped back on in aggressive cancer
cells. During fetal development, it helps
to maintain the structure and function
of the cells nucleus, its command post
that houses our genetic material and
directs the behavior and function of
cells throughout our bodies. Much like

a quarterback on a football team, the

nucleus tells the cell either to remain in
place or move, or to progress into a more
specialized position, explains molecular
biologist Linda Resar, M.D. The nucleus
also dictates whether a cell will grow
and divide, or remain quiescent.
In work supported by the Patrick C.
Walsh Prostate Cancer Research Fund,
Resar and co-investigators Robert Veltri
and Karen Reddy are studying HMGA1
in prostate cancer. Resars laboratory
discovered that HMGA1 transforms
normal cells into aggressive cancer cells.
Moreover, HMGA1 is a marker of poor
outcomes for patients with diverse
tumors, she says. HMGA1 is present in
high levels in aggressive prostate cancers,
and it drives tumor cell invasion and
aggressive behavior in animal models of
cancer. Resar discovered that HMGA1
functions as a key molecular switch that
cancer cells need to grow rapidly and
spread. Our preliminary studies suggest
that HMGA1 alters nuclear shape and
function to flip on genes that enable
prostate cancer cells to leave their
primary site, invade and metastasize.

Resars laboratory discovered

that HMGA1 transforms
normal cells into aggressive
cancer cells.
Resar and colleagues are conducting
innovative studies to determine precisely
how HMGA1 causes changes to the
shape and function of the nucleus, and
whether we can use these alterations
to predict which tumors will behave
aggressively in men with prostate cancer.
We will also uncover the genes and pathways that are turned on by the HMGA1
switch to transform normal prostate
cells into invasive cancer cells. If the
investigators can crack the code of how
HMGA1 works, they will determine
whether these changes can predict tumors

that are likely to behave aggressively and

move to distant sites. They also hope to
develop approaches to target or block
these changes in therapy. Together,
our team will define the role of HMGA1
in nuclear structure and function in
prostate cancer, she says. Results
generated here will lay down the
groundwork to determine whether
HMGA1 and its role in nuclear
reprogramming can be used to predict
outcomes and optimize therapy for
men with prostate cancer. n

Prostate Cancer Screening:

Is There a Better Way?

Half of the men will, like

millions of American men,
undergo standard PSA testing
and receive a biopsy if the PSA
is elevated. The other men
will get the same PSA testing,
and then will undergo mpMRI,
a painless, noninvasive
procedure, before biopsy.
Prostate cancer screening is not specific
enough even though there are new
tools today that might reduce the risk
of over-diagnosis, says urologist Ashley
Ross, M.D., Ph.D. He believes that one
diagnostic test, in particular, shows
great promise: Multi-parametric
MRI (mpMRI), which can show
clinically significant cancer. Though
mpMRI is being integrated into
clinical practice, it has not been
rigorously compared to standard
prostate cancer screening, he says. How
good is it? Ross, with co-investigators
H. Ballentine Carter and Craig Pollack,
aims to find out. Our hypothesis is that
using mpMRI in men with elevated PSA
may decrease unnecessary biopsies and

the diagnosis of clinically insignificant

prostate cancer which doesnt need
to be treated with minimal underdiagnosis of clinically significant cancer.
To do this, Ross and colleagues will
design and perform a randomized trial.
Half of the men will be those who, like
millions of American men, undergo standard PSA testing and receive a
transrectal ultrasound biopsy if the
PSA is elevated. The other group of men
will get the same PSA testing, and then
will undergo mpMRI, a painless, noninvasive procedure, before biopsy. For
those undergoing MRI and then biopsy,
biopsy will be performed with MRIultrasound fusion technology. In
addition, the group will assess the
usefulness of biomarkers that recently
have come into clinical practice, and
determine the cost-effectiveness of the
two screening strategies. The results
of this trial will have immediate implications as to how we screen men for
prostate cancer. n

Improving Control of Cancer

in the Bones
One of the worst features of advanced
prostate cancer is bone metastasis.
A new agent called Radium-223
dichloride has shown success here; it is
an alpha particle-emitting radionuclide
that is incorporated in the bone material.
It emits highly toxic alpha particles that
kill cancer in the bone; however, it has a
very short range. In fact, it only kills the
cells directly next to it in the bone. In
research supported by the Patrick C.
Walsh Prostate Cancer Research Fund,
nuclear medicine scientist Daniel Thorek,
Ph.D., with co-investigator Ryan Riddle,
hopes to find out exactly how Radium-223
works at sites of bone metastasis.
In initial studies, we have developed
small animal models of prostate cancer
metastasis in the bone, and we are
23

WINTER 2016 | DISCOVERY

more brady urology cancer news

Read About the Research You have Helped Make Possible.

the patrick c. walsh prostate cancer research fund
performing high-resolution imaging
to evaluate the magnitude and microdistribution of the agent, says Thorek.
The investigators are evaluating the
effect of the Radium-223 on the bone
and prostate cancer cells at the sites
where the radionuclide is deposited.
This may provide insight into improving
dosing, in order to achieve an optimal
therapeutic effect on the prostate
cancer cells, with minimal surrounding
bone cell damage. They also plan to
use high-resolution, noninvasive nuclear
imaging to show how Radium-223
is distributed. This may provide a
means to personalize the application
of this radionuclide in men with
prostate cancer. n

Creating a Vaccine Against

Prostate Cancer

Trying to work around

prostate cancers impressive
ability to defend itself is like
a molecular game of chess.
The technology is there;
now the key is to figure out
the best strategy.
Can a man be inoculated against his
own prostate cancer? Scientist Raphael
Viscidi, M.D., along with co-investigators
Brian Simons and Ashley Ross, hopes
to find out. Because the disease can
be diagnosed early and the prostate
expresses tissue-specific proteins that
can be the target of vaccines, we are
investigating the value of a novel vaccine
for prostate cancer in an animal model,
says Viscidi. To make the vaccine, they
are using a virus actually, part of a
virus, a protein that has the ability to
form a large particle. The outer surface
of the particle can be decorated with
short proteins, think of sprinkles on
24

a cupcake and these will be derived

from tissue-specific proteins made by
prostate cancers. We have shown that
these novel particles can induce immune
cells, enlisting the body in the fight
against prostate cancer.
The physical properties of the particles
make them very potent inducers of cellular immune responses, Viscidi explains.
Unlike most other vaccines,
they can be administered on their
own to induce immune responses. We
are using three tissue-specific proteins
made by prostate cancers: prostatic
acid phosphatase, prostate stem cell
antigen, and stimulator of prostate
adenocarcinoma-specific T cells.
In work supported by the Patrick C.
Walsh Prostate Cancer Research Fund,
the investigators will dot the surface
of the vaccine particles with small
proteins known to specifically stimulate
the immune system of mice.
What the team is doing, trying to work
around prostate cancers impressive ability to defend itself, is like a molecular
game of chess. The technology is there;
now the key is to figure out the best
strategy. For example, Viscidi says,
cancers have recently been shown to
block immune responses by expressing
inhibitory proteins. Two of these
proteins are CTLA4 and TIM-3. But
in a counter move, scientists have
developed antibodies that block these
proteins. Will it strengthen the immune
response if the investigators combine
their vaccine with these anti-CTLA4
and anti-TIM-3 antibodies? They
plan to find out, using a model known
as the TRAMP mouse. The advantage
is that these spontaneously develop
cancer in the prostate gland. We will
treat mice of various ages, representing
stages of prostate cancer from small
lesions to metastatic disease, with our
vaccine alone or in combination with
anti-CTLA4 and anti-TIM-3 antibodies.
If the vaccine proves successful in

treating cancers in the mouse model, we

plan to construct a similar vaccine using
human prostate-specific proteins, and
test it in men with prostate cancer. n

Looking For a Smart Urine

Test for Prostate Cancer
As helpful as PSA testing has been for
millions of men, it does not always tell
doctors which mans cancer is lethal,
which mans cancer is indolent, and
which man doesnt have cancer at all,
but another prostate problem that is
causing his PSA to rise. In work funded
by the Patrick C. Walsh Prostate Cancer
Research Fund, scientist Hui Zhang,
Ph.D., along with co-investigators Robert
Veltri and Bruce Trock, believes these
answers may be found in specific
proteins in the urine.
Glycoproteins are proteins that
have carbohydrates attached to them.
We hypothesize that glycoproteins
specifically altered in aggressive prostate
cancer cells can be released to urine and
used as biomarkers, says Zhang, to
distinguish men with lethal cancer from
those with indolent prostate cancer.
The scientists hope to identify these
using quantitative analysis, looking at
urine glycoproteins from lethal and
indolent prostate cancer, and then
testing these potential biomarkers using
glycoproteomic analysis. The end result,
they hope, will be a noninvasive urinary
test. Urine biomarkers capable of
distinguishing lethal from indolent
prostate cancer will help men with
lethal prostate cancer to receive
appropriate treatment earlier, and
help prevent overtreatment in men who
have indolent disease. n

Bivalacqua: Radical cystectomy is not the ideal

treatment for everyone.

D IS COV E RY IN BL A D D E R CA NCE R

Bladder Cancer Surgery:

Who is Likely to Have
Complications?
We know that age alone
does not tell us how a patient
will do after surgery. Some
patients are young but frail,
while others are older with
great physical reserve.
The standard of care for patients with
muscle-invasive bladder cancer is
radical cystectomy, the surgical removal
of the bladder. However, this is a major
operation, with a significant risk of
complications and potentially, even
death. Radical cystectomy is not the ideal
treatment for everyone, especially for
higher-risk elderly patients with multiple
medical problems, says Trinity Bivalacqua,
M.D. Ph.D., Director of Urologic Oncology.
Who would do well with this procedure,
and who is a poor candidate? Its sometimes tough to predict. Assessing
surgical risk is a complicated task, and
the surgeon must take several factors
into account to determine how well
someone will do in the operating room
and in the immediate recovery period.

The key is frailty, he says. We know that

age alone does not tell us how a patient
will do after surgery. Some patients are
young but frail, while others are older
with great physical reserve. Bivalacqua
is the senior author of a study that can
help identify patients who are more
likely to have complications. This work
was recently published in Urologic
Oncology. In the study, Hopkins investigators led by medical student Meera
Chappidi and urologist Max Kates, M.D.,
validated a modified frailty index or
score. This is an objective measure that
is calculated using a set of 11 questions
that any patient can easily answer in
a couple of minutes during an office
visit, says Bivalacqua. Patients with
high frailty scores may have risk factors
that can be optimized before surgery
to decrease their chance of having a
complication, or they may benefit from
bladder-sparing therapies.

Who Could Benefit

From Platinum-Based
Chemotherapy?
Some people with muscle-invasive
bladder cancer can benefit from systemic
chemotherapy before they undergo
radical cystectomy. Chemotherapy
administered before the operation is
called neoadjuvant chemotherapy, and
its proven benefits include improved
overall survival and a lower risk of
having a recurrence of bladder cancer.
However, it still is not widely administered, says Trinity Bivalacqua, M.D.
Ph.D., Director of Urologic Oncology.
There are several reasons why, including
concerns about delaying surgery, risk of
potential side effects, and the uncertainty
that it will be effective.
Two new studies by Hopkins investigators
in Urology, Pathology, and Oncology,
provide insight based on clinical and
molecular data; this work was published
in Urologic Oncology and PLOS ONE.
The researchers identified novel
biomarkers easily detected from
routine bladder biopsies, that can

predict patients whose cancer is most

likely to respond to this treatment,
Bivalacqua says. This new molecularbased test will help us identify bladder
cancer patients who will benefit the
most from chemotherapy before
radical cystectomy. n

D ISCOVER Y IN KIDNEY CANCER

For Small Kidney

Tumors: Active
Surveillance is a
Safe Option
How big is the kidney tumor? If its small,
less than 4 centimeters, upwards of
30 percent are benign, not even cancer,
says Phillip Pierorazio, M.D. Of the 70
percent left, half are low-grade, indolent
tumors that are not ever going to cause a
problem. That only leaves about a third
that are potentially aggressive. This is
good news: many of these people can
safely avoid surgery.
Who can safely avoid surgery? Although
several institutions have studied
surveillance, these studies have mainly
been retrospective, after-the-fact. Few
institutions have followed their patients
to make sure that active surveillance is
a safe option for them, says Pierorazio.
Six years ago, he and urologist Mohamad
Allaf, M.D., the Mohamad E. Allaf
Director in Minimally Invasive Urology
and Buerger Family Scholar, set out to
change this. They started the Delayed
Intervention and Surveillance for Small
Renal Masses (DISSRM, pronounced
disarm) Registry for patients with small
kidney tumors, and their groundbreaking
work is paving the way for people
with small kidney cancers to be treated
worldwide. Since 2009, they have
followed more than 200 patients;
Pierorazio and Allaf recently published
their results in European Urology.
Our DISSRM Registry follows not only
patients on active surveillance, but those
who have undergone surgery, as well,
25

WINTER 2016 | DISCOVERY

says Pierorazio. In general, he says, the
people who undergo active surveillance
are older, sicker and have smaller
tumors. However, these patients have
done incredibly well. No patient undergoing active surveillance has had kidney
cancer spread from the kidney, and none
has died of kidney cancer. These early
results demonstrate that active surveillance is a safe option for patients with
small kidney tumors and, at least, not
inferior to surgery in the short term.
About 10 percent of those who undergo
active surveillance end up having
surgery, either because of changes in
the tumor or their health status, making
surgery a more attractive option.
The next step for the Registry, he says,
is to continue to refine selection criteria
for active surveillance, to learn more
about the significance of growth rates,
and to measure quality of life for people
in the program. n

Is a Kidney Tumor
Benign? This Not-SoNew Test Can Tell
More cases of kidney cancer are being
diagnosed now than ever before, in
large part due to an increase in the use
of cross-sectional imaging techniques
such as CT and MRI. But many of these
cancers are slow-growing and benign,
and may not ever need to be treated,
says urologist Michael Gorin, M.D. The

problem, he adds, is that in standard

imaging, its hard to tell whether a
tumor is aggressive or not. Some tumors,
particularly benign oncocytomas and
hybrid oncocytic/chromophobe tumors
(HOCTs) are unique in that they are
composed of cells with numerous
densely-packed mitochondria, the
battery that makes the cells energy.

This test offers the potential

of sparing a significant number of patients an unneeded
invasive surgical procedure.
In the field of nuclear medicine, radioactive substances that are administered
intravenously can be detected on a scan
to measure how well or poorly an organ
is functioning. One such imaging agent
has a difficult name: 99mTc-sestamibi.
It is widely available, often used for
heart imaging and to show parathyroid
adenomas. 99mTc-sestamibi targets
the mitochondria, and clearly shows
mitochondria-packed tumors.
Gorin, Mohamad Allaf, M.D., Phillip
Pierorazio, M.D. and colleagues recently
found 99mTc-sestamibi to be effective
in diagnosing oncocytomas and HOCTs.
Their preliminary study of six patients
was published in Clinical Nuclear
Medicine. In a follow-up study, 50
patients who had a newly diagnosed
renal tumor were imaged prior to surgery.
This allowed us to compare the results
of the imaging test to the gold standard

of surgical pathology, says Gorin. In this

study, eight of 50 patients were diagnosed
with either oncocytoma or HOCT at the
time of surgery. 99mTc-sestamibi and
SPECT/CT imaging correctly identified
five of six oncocytomas and two out
of two HOCTs, resulting in an overall
sensitivity of nearly 88 percent. Using
this technology, we can be very certain
that patients with a hot tumor have a
benign mass, states Allaf. In addition,
only two tumors were falsely positive on
the imaging test.
Based on these findings, 99mTc-sestamibi
SPECT/CT appears to be an excellent
test for the preoperative identification
of benign renal tumors and offers the
potential of sparing a significant number
of patients an unneeded invasive surgical
procedure, says Pierorazio. The investigators plan on confirming this with a
larger study. Besides Gorin, Allaf, and
Pierorazio, authors included Mark Ball,
Christian Pavlovich Jonathan Epstein
and Alex Baras.
In related news:

Better Diagnosis
of Kidney Tumors

all three risk factors had an 89-percent

chance of having cancer, says urologist
Mohamad Allaf, M.D., the studys senior
author, while patients with none of
these risk factors have only a 64-percent
chance of having cancer. Ball adds: This
nomogram can help us do a better job
of predicting which patients are more
likely to have cancer, but its not enough
yet. Better tests are still needed to predict
which patients can forego surgery, and
who needs aggressive treatment.
In other recent findings, published in
The Journal of Urology, the team studied
how areas of a kidney tumor may look
different (or heterogeneous) under the
microscope. We found that even the
most aggressive tumors have areas that
look less aggressive under the microscope, says Ball, who was the studys
lead author. This may mean that biopsies
are not that helpful. Renal mass biopsy
is sometimes used before surgery to confirm the diagnosis, but its not a perfect
test, and our study shows that it can
sometimes give false reassurance, says
urologist Phillip Pierorazio, a coauthor
of the study. n

Risk-stratification is like picking out

the bad apples and leaving the good
behind, says Brady chief resident Mark
Ball, M.D. Because so many tumors
as many as 30 percent of small kidney
tumors that are surgically removed
are found to be benign, Ball and colleagues
have been working on ways to help
predict the risks of kidney tumors.
In a study led by Ball and recently published in the journal, Urologic Oncology:
Seminars and Original Investigations, the
investigators studied more than 1,000
patients from five different hospitals
and identified factors associated with a
higher risk of being cancer. Men were at
higher risk of having cancer than women;
other risk factors include a tumor size
greater than 3 centimeters, and a high
nephrometry score (a measure of tumor
complexity on CT scan). Patients with
Gorin: Many kidney tumors are slow-growing
and may not ever need to be treated.

Ball: We need better tests to predict who needs

surgery, and who doesnt.

D IS COV E RY IN T E S T IS CA NCE R

Early-Stage Testiscular
Cancer: A Laparoscopic
Improvement in Treatment
When a man is diagnosed with
early-stage testicular cancer (specifically,

From left, Allaf, Harris, and Pierorazio: New procedure is technically challenging, but is a better, minimally
invasive cancer operation. Note: Pierorazio sports a mustache grown in Movember to support testicular cancer
research and treatment.

a nonseminomatous germ cell tumor),

his treatment choices include active
surveillance, chemotherapy,
or a procedure called primary
retroperitoneal lymph node dissection
(RPLND), removal of the lymph nodes
to make sure the cancer has not spread.
But RPLND is major abdominal surgery.
Thus, more recently, active surveillance
has become the most favored management
strategy, says urologist Phillip Pierorazio,
M.D., given the uncertain, long-term
side effects of chemotherapy and the
short-term side effects of RPLND.
However, men who fail active surveillance
are often restricted to chemotherapy as
their only option for treatment.

In a disease that is 99 percent

curable and with patients
who have little surgical
risk due to their young age
and good general health,
the argument could be made
for aggressively treating men
with low-stage disease with a
minimally-invasive procedure.
Testis cancer generally affects young,
otherwise healthy men, and if it
werent such an arduous procedure
RPLND could eliminate the need for a
prolonged course of cancer surveillance
or the long-term side effects of chemotherapy. In a disease that is 99 percent

curable and with patients who have

little surgical risk due to their young age
and good general health, the argument
could be made for aggressively treating
men with low-stage disease with a
minimally-invasive RPLND, Pierorazio
continues.
There is a more minimally invasive
choice: Robot-assisted laparoscopic
RPLND. This procedure has been
shown to offer better perioperative
(during and immediately after surgery)
outcomes when compared to the open
operation, with the same degree of
cancer control. However, it is a technically
challenging procedure. Urologists
Mohamad Allaf, M.D., and Pierorazio,
who perform this operation, recently
published the results of the Johns
Hopkins experience and a comparison
of laparoscopic and robot-assisted
laparoscopic RPLND in the British
Journal of Urology International.
Kelly Harris, a medical student, future
urologist, and the lead author of the
study summarizes, Our group has
shown that robotic is comparable to
laparoscopic, with the added benefits of
better three-dimensional visualization
and degrees of freedom to afford a better,
minimally invasive cancer operation. n

27

THE BRADY: 100 YEARS

A History of the James Buchanan Brady Urological
Institute at Johns Hopkins
By Patrick C. Walsh and Janet Farrar Worthington
Featuring 380 Richly Illustrated Pages
2015 The James Buchanan Brady Urological Institute
and Johns Hopkins Medicine
For a century, the Brady has been the worlds leading urological
institute. Read about our past, meet our scientists and faculty
members, and join us as we look ahead to the next 100 years!
In this richly illustrated book, packed with stories that bring some
of the greatest names in Urology to life, youll learn:
How James Diamond Jim Brady was cured of BPH and donated
the money to start this institution.

A triumph of storytelling
and design.
Keith Reinhard,

Chairman Emeritus, DDB Worldwide

Download the e-book FREE at:

urology.jhu.edu/about/history/Brady100years
Currently available to the public in e-book format only,

How Hugh Hampton Young, a brilliant innovator who designed and

built many of his own surgical devices, became the Father of Modern Urology, transforming the field into a major surgical specialty.
How William Scott transformed the urology residency, allowing the
Brady to produce some of the worlds best surgeon-scientists.
How Patrick Walsh revolutionized the surgical treatment of
prostate cancer, changing the field of prostate cancer treatment
and research forever.
How Alan Partin continues the Bradys tradition of excellence
today, as we look forward to our next 100 years!

abridged Kindle edition coming soon.

The Bestselling Book on Prostate Cancer

Comprehensive, reassuring and full of hope. Now available
as an eBook and on Kindle!
COMPLETELY UPDATED 3RD EDITION

With this book you will learn answers to

these and other important questions:
Why do I need to have a baseline PSA at
age 40? I thought it was age 50!
If there is no magic PSA cutoff point, how
can my cancer be diagnosed?

Discovery is published by

THE JAMES BUCHANAN BRADY

UROLOGICAL INSTITUTE
Johns Hopkins Medical Institutions
Baltimore, Maryland 21287-2101

What is the most up-to-date information

on surgery and radiation therapy?

410.955.8434 | urology.jhu.edu

Have there been any breakthrough tratments in

the management of advanced disease?

University Distinguished Service

Professor of Urology

Patrick Walsh, M.D.,

Janet Farrar Worthington Writer/Editor

Hatcher Design Office Art Direction

Available from Warner Wellness: www.hgbusa.com or call 800.759.0190

Kieth Weller Principal Photography