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in this issue
2 Message from the Director
3 Meet the Researchers
3 Discoveries
Science at the heart of medicine
4 Our Supporters
Is insulin a carcinogen?
– page 3
news
Einstein Cancer Center
Probing the
Transition
State
Newsletter for the
Albert Einstein Cancer Center
Issue 2 • Summer 2010
T
hey’re elusive and ephemeral: chemical states that exist
for just one billionth of a millionth of a second. But these
whispers of molecules may hold the key to treating a wide
variety of cancers.
“Transition states” form in every chemical change and whenever an enzyme
does its job of converting one chemical (the substrate) into another (the product). The fleeting transition-state molecule is neither substrate nor product, but
something in between—a ghostly intermediate to which the enzyme clings for
that vanishingly brief time.
While it doesn’t last long, the transition state of a chemical reaction can be
a powerful ally in the fight against cancer. The reason: Many types of cancer are
caused by overactive enzymes. If a drug could knock the offending enzyme out
of circulation, you’d have a powerful treatment—perhaps even a cancer cure.
In 1994, Einstein researchers started designing molecules, known as
transition-state analogs, that do just that. Vern Schramm, Ph.D., professor and
Ruth Merns Chair in Biochemistry at Einstein, leads this effort. The first cancer
target was the enzyme purine nucleoside phosphorylase, or PNP.
In 1975, scientists had identified an infant born with a genetically deficient
version of PNP. By age two, this infant lacking a functional PNP enzyme could
no longer make T cells, which are vital for a healthy immune system. Scientists
(continued on page 2)
message from
the director
I. David Goldman, M.D.
Director, Albert Einstein
Cancer Center
Professor, Departments of
Medicine and
Molecular Pharmacology
Susan Resnick Fisher
Professor
T
his July, the Albert Einstein
Cancer Center celebrates its 39th
year of continuous funding as a
National Cancer Institute–designated
Cancer Center. The Cancer Center
initially focused on basic research but
now has an active clinical research effort along with two population-science
programs: Cancer Epidemiology, and
Cancer Prevention and Control.
Our strong basic science programs
continue to flourish, and a steady stream
of important laboratory findings are
being translated into clinical initiatives.
As molecules that drive the growth of
tumors are identified, for example, Einstein scientists are developing drugs that
specifically target and deactivate those
molecules.
This issue of the newsletter focuses
on a new approach to cancer therapy:
transition-state inhibitors.
Dr. Vern Schramm, the Ruth Merns
Chair in Biochemistry, has pioneered
the development of transition-state
inhibitors and is a leading member of
the Albert Einstein Cancer Center’s
Experimental Therapeutics Program. As
“Probing the Transition State” describes,
these drugs are highly targeted, highly
potent and unique among cancer treatments in that they are nontoxic and can
be administered orally.
One of Dr. Schramm’s transition-state
inhibitors is now in advanced clinical trials for treating leukemia and lymphoma.
He is also working on a novel inhibitor
that can turn on the activity of genes
that suppress tumor growth. In recognition of his many scientific achievements, in particular the development of
transition-state inhibitors, Dr. Schramm
was recently inducted into the National
Academy of Sciences.
Probing the Transition State (continued from page1)
realized there was one situation in
which a lack of PNP—and therefore
no more T cells being formed—would
be a good thing: in treating T cell
cancers, conditions in which T cells
multiply uncontrollably. Yet inhibiting
PNP would not be easy.
“Seven companies had tried to
make drugs against PNP, and all seven
gave up,” says Dr. Schramm. “They
never found a compound that was
good enough.” Focusing on PNP’s
transition state might do the trick. But
how do you study something that appears and vanishes in almost the same
instant?
“There’s no way to actually observe a transition-state structure—
not by nuclear magnetic resonance,
crystallography or any other technique we have,” says Dr. Schramm. So
the research team deployed a series
of indirect strategies that combined
computer modeling and a novel use
of isotopes called kinetic isotope effects to gain insight into PNP’s transition state.
After figuring out that state, the
Schramm lab designed its analog—a
molecule closely resembling it but
with one big difference: the transitionstate analog would powerfully inhibit
PNP by binding to it and not letting
go.
It took three years of difficult
chemistry, including essential input
from Peter Tyler, Ph.D., and Richard
Furneaux, Ph.D., Dr. Schramm’s
chemistry collaborators from Industrial
Research Ltd., in New Zealand. “This
type of molecule had never been synthesized before,” Dr. Schramm recalls.
“But we constructed a drug that
bound to PNP more than 700,000
times more tightly than the normal
substrate did. It was a real eureka
moment.”
That inhibitor, Immucillin-H, was
licensed to BioCryst Pharmaceuticals
and is now in a pivotal phase 2B clinical trial for treating T cell cancers.
“The preliminary results look very
promising,” says Dr. Schramm. In less
than a year, he predicts, Immucillin-H
will be submitted to the FDA for
approval.
Dr. Schramm and his chemistry
team recently designed a transitionstate analog against another enzyme
very different from PNP. This enzyme,
MTAP, helps synthesize polyamines,
chemicals needed by rapidly dividing
cells such as cancer cells.
Sure enough, this analog effectively inhibits MTAP. In animal
tests, the MTAP inhibitor has shown
promise against prostate cancer, lung
cancer and cancers of the head and
neck. It has been licensed to Pico
Pharmaceuticals; Dr. Schramm anticipates that clinical trials could begin
within the next year or two.
“Evidence so far suggests that
this drug may be especially useful for
preventing cancer from spreading, or
metastasizing,” says Chandan Guha,
M.B.B.S., Ph.D., professor and vice
chair of radiation oncology, who collaborates with Dr. Schramm in testing
the MTAP inhibitor in cancer cells in
culture and in mice. “As a result, the
progression of the cancer would be
retarded, and patients would be able
to live longer with their cancers.”
Cancer Q&A
Q: Are we winning the war on cancer?
A: Yes, but gradually. The cancer death rate has declined slightly
(by about 5 percent) over the last 5 decades—from 193.9 per 100,000
in 1950 to 183.8 per 100,000 in 2005. There are three reasons:
More screening. Tests such as mammography and colonoscopy are
picking up cancers at an earlier, more treatable stage.
Less smoking. Millions of people have gotten the message about the
dangers of tobacco smoke.
Better therapies. Surgery, radiation and chemotherapy are now more
effective than ever.
On the negative side, more Americans are becoming overweight or
obese, which increases their risk of developing several types of cancer,
including breast, colorectal, prostate and pancreatic cancer.
Meet the researchers
Claudia Gravekamp, Ph.D.
Xingxing Zang, Ph.D.
Assistant Professor, Department of
Microbiology & Immunology
Harriet O. Smith, M.D.
Associate Professor, Department of
Microbiology & Immunology
Cancer is much more common in older
than in younger people. Unfortunately,
cancer vaccines (which stimulate the immune system to fight cancer) don’t work
so well in older people, because they’ve
lost responsive immune cells known as
naïve T cells. Dr. Gravekamp is trying to
circumvent this problem in developing a
vaccine to treat metastatic breast cancer.
She and her colleagues have enlisted
the help of a bacterium, Listeria monocytogenes. They are using the versatile
microbe to combat breast cancer in three
ways: arouse other immune cells called
memory T cells (well preserved in older
people) to attack cancer cells; trigger
so-called innate immune responses (also
well preserved in older people); and kill
tumor cells directly by eliciting a sharp
rise in levels of toxic by-products within
the tumor cells.
Dr. Zang studies the immune system
and how to wield it against cancer. He
is focusing on mechanisms that stimulate and inhibit T cells. Dr. Zang came to
Einstein from Memorial Sloan-Kettering
Cancer Center, where he discovered new
members of a “family” of costimulatory
molecules that play an important role
in regulating T cell function. He is now
studying how these so-called B7 costimulatory molecules interact with T cells to
regulate immunity and inflammation.
Dr. Smith has found that the protein
GPR30, when present at high levels in
endometrial and ovarian cancers, predicts
a much lower chance of survival. She and
her colleagues are studying how GPR30
and other factors stimulate tumor growth,
with the goal of finding drugs to block
the spread of these cancers. Dr. Smith is
also working on strategies to make cancer
chemotherapy more effective.
Professor, Department of Obstetrics &
Gynecology and Women’s Health
(Gynecological Oncology)
ON T H E W E B
To learn more about the Albert Einstein Cancer Center, please visit
the center’s website at www.einstein.yu.edu/cancer.
discoveries
Interrupting the Colon Cancer
Conversation
How does colon cancer begin? “Crosstalk” between colon cells and immunesystem cells called macrophages may
contribute—and Lidija Klampfer, Ph.D., assistant professor of medicine (oncology),
is eavesdropping on the conversation.
Early in a cell’s evolution from normal
to cancerous, it signals nearby macrophages to produce a protein called
interleukin (IL)-1 beta; this protein, in turn,
activates a cancer-promoting signal.
In a 2009 study published in
Oncogene, Dr. Klampfer and colleagues
showed that vitamin D3 interrupted the
cancerous crosstalk by blocking IL-1 beta
production, which inhibited the growth of
tumor cells.
Is Insulin a Carcinogen?
Breast cancer is much more common
in postmenopausal women who are
obese than in those of normal weight—a
major concern in light of the U.S. obesity
epidemic. But what are the molecular
pathways through which obesity increases
the risk of breast cancer?
Einstein researchers Howard Strickler, M.D., Marc Gunter, Ph.D., Thomas
Rohan, M.D., Ph.D., and Geoffrey Kabat,
Ph.D., recently completed studies of two
large groups of women. They reported
that while estrogen levels are increased
in obese women, the elevated levels of
another hormone—insulin—explained the
obesity/breast cancer link. Their findings
were published recently in the Journal of
the National Cancer Institute.
In addition to its well-known role in
sugar metabolism, insulin is a growth
factor that can induce cells to multiply.
Insulin’s growth-factor activity probably
explains how this hormone promotes
postmenopausal breast cancer, the Einstein scientists concluded.
“Research must focus on ways to
reduce insulin’s effects on cell replication,
while preserving its effects on sugar metabolism, and to determine insulin’s role
in other obesity-related cancers,” says
Dr. Strickler, professor of epidemiology
& population health, who along with Dr.
Rohan developed the studies. “By understanding insulin’s role,” he adds, “we may
have an opportunity to prevent breast
cancer in obese and high-risk women and
reduce its recurrence in women being
treated for the disease.”
our supporters
Notable Gifts and Grants
Albert Einstein Cancer Center gratefully acknowledges the generosity of the following individuals and organizations whose
support is critical to advancing its mission.
Einstein’s National Women’s Division
has launched a $3 million fundraising initiative in support of research in women’s
health and cancers. It will benefit basic
and translational research studies at the
Einstein Cancer Center aimed at developing new prevention strategies and
innovative treatments for breast, ovarian,
uterine and cervical cancers.
The Breast Cancer Research Foundation
has made a commitment of $600,000
to support research studies by Rachel
Hazan, Ph.D.; Susan Band Horwitz, Ph.D.,
the Rose C. Falkenstein Chair in Cancer
Research, and Haley McDaid, Ph.D.; and
Thomas Rohan, M.D., Ph.D.
Jane and Myles P. Dempsey have made
a $500,000 gift to fund innovative pilot
projects as well as specialized technical facilities in support of the Breast
Cancer Working Group, led by Joseph
A. Sparano, M.D., at the Einstein Cancer
Center. Dr. Sparano is professor in the
departments of medicine (oncology) and
of obstetrics & gynecology and women’s
health. This research focuses on developing new approaches to diagnosing and
treating breast cancer. Mr. Dempsey is
founder and chairman of Tech Air, a leading provider of industrial, medical, and
specialty gases.
Stand Up to Cancer and the American
Association for Cancer Research have
awarded a grant of $712,866 to Matthew
Levy, Ph.D., assistant professor of biochemistry, for developing novel molecules
that deliver anticancer drugs directly to
their cancer-cell targets. Dr. Levy is one
of 13 young scientists nationwide whose
research is supported by a Stand Up to
Cancer–American Association for Cancer
Research Innovative Research Grant.
events
Einstein’s Cancer Research Advisory
Board hosts events during the year that
bring together people interested in supporting the work of the Albert Einstein
Cancer Center with distinguished
Einstein faculty members who share the
latest developments in cancer research.
Allen M. Spiegel, M.D., the Marilyn
and Stanley M. Katz Dean, and I. David
Goldman, M.D., director of the Albert
Einstein Cancer Center and the Susan
Resnick Fisher Professor, were the featured speakers at two Einstein Lunch &
Learn seminars in Palm Beach, FL. They
spoke about new developments in cancer research and treatment at Einstein.
Lively question-and-answer sessions
followed. We are grateful to Roni and
Stuart Doppelt and David J. Klein, who
hosted the luncheon on March 8 at High
Ridge Country Club, and to Einstein
Overseers Marilyn and Stanley M. Katz,
who hosted the luncheon on March 9 at
Palm Beach Country Club.
Alb e r t E i n s t e i n
cancer center
Our mission: to promote and carry out
research that will yield insights into the
origins of cancer and lead to effective new
approaches for preventing, diagnosing and
treating malignant diseases
Left, David J. Klein; right, Roni Doppelt
and Marilyn Katz, chair, Cancer Research
Advisory Board
Terri and Michael Goldberg hosted
a cocktail reception on behalf of the
Cancer Research Advisory Board at their
home in New Jersey in October 2009.
Dr. I. David Goldman described current studies at the Cancer Center, and
Joseph A. Sparano, M.D., discussed the
current status of breast cancer treatment
and research. Thanks to the Goldbergs
and to all the Einstein friends and supporters who attended.
ADMINISTRATION
Director
I. David Goldman, M.D.
Deputy Director
Jeffrey Pollard, Ph.D.
Terri Goldberg, left, and Michael Goldberg
with Einstein Overseer Betty Feinberg
To learn more about supporting the work
of the Cancer Center, please contact:
Ira Lipson
Director of Institutional Advancement
Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue, Mazer 725
Bronx, NY 10461
718.430.2371
[email protected]
Associate Directors
Leonard Augenlicht, Ph.D.
Susan Horwitz, Ph.D.
Steven Libutti, M.D.
Roman Perez-Soler, M.D.
Michael Prystowsky, M.D., Ph.D.
Thomas Rohan, M.D., Ph.D.
Richard Seither, Ph.D., M.S., M.B.A.
Pamela Stanley, Ph.D.
ADVISORY BOARD
Chairperson
Marilyn R. Katz