Download Claudia Adams Barr Program in Innovative Cancer Research Dana

Claudia Adams Barr Program in Innovative Cancer Research
Dana-Farber Cancer Institute
BARR PROGRAM IMPACT STATEMENTS
Brain Cancer
New Treatment Opportunities - Discovery of new pathways in brain cancers leading directly to
promising new clinical trials for the nearly 23,000 patients who develop these diseases every year.
Brain cancers remain one of the most difficult cancers to treat and are responsible for more than
13,000 deaths annually. Barr Program support in 1998-2000 and 2002-‘04 enabled Rosalind Segal,
MD, PhD, to discover that a genetic pathway called “Notch” is consistently damaged in brain tumors.
Drugs already exist for other diseases to target Notch, and exciting new clinical trials are now
underway to explore opportunities to use these drugs for people with brain cancers. This has the
potential to significantly improve survival for these devastating cancers.
Breast Cancer
Discovering New Treatments - Explaining how drugs like Tamoxifen have improved breast cancer
survival rates by 33% in significant numbers of women, leading to the possible discovery of additional
treatments with even better outcomes for people with breast cancer.
Myles Brown, MD, used Barr funding in 2002-‘03 to make the first genome-wide map of all genes
that estrogen controls. This has enabled scientists for the first time to understand why certain
drugs have been so effective in treating breast cancer, including the marked improvement in
survival for women whose breast cancers respond to tamoxifen and other drugs that block
estrogen. Dr. Brown’s work is now expected to lead to new drugs and treatments for cancers that
target critical pathways in breast cancer. His team has used this information to discover new ways
to treat breast cancers that don’t respond to Tamoxifen.
Inhibiting Cancer Cell Growth - Discovery of a critically important biochemical pathway in breast
cancer cells leading to the development of inhibitors of this pathway and the potential to significantly
impact cancer growth.
Dr. Jean Zhao’s Barr funding in 2004 allowed her to systematically test a large number of proteins
for their effects on breast cancer growth. She identified a critically important role for the protein
PIK3CA in the behavior of breast cancer cells in the 36% of women whose breast cancers have this
mutation. Several drug companies have now developed PIK3CA inhibitors that are being tested in
clinical trials of breast and other cancers, and are showing great promise.
© 2015 Dana-Farber Cancer Institute
Cancer Genetics
Enabling Meaningful Analysis of Massive Databases - Identification of new methods for
controlling cancer cell growth, especially in breast and prostate cancers, by allowing scientists around
the world to interpret huge databases of gene expression data.
The Human Genome Project and DNA technology in general have provided the important tools
needed to uncover and treat the genetic abnormalities that cause cancer. Since there are three
billion units of DNA in the genome and an unknown number of ways that their functions are
controlled, the technologies used for research on the genetics of cancer are creating a tsunami of
data. Awarded Barr funding in 2005, Shirley (Xiaole) Liu, PhD, conducted groundbreaking research
to provide a way to manage that data. Scientists around the world are now using Dr. Liu’s “open
source” techniques, uncovering new pathways toward cancer development that can be targeted by
novel and effective therapies.
Enabling New Drug Development for Many Cancers - Discovery of abnormalities in cancer growth
proteins leading to the development of successful drugs including a 42% increase in survival for some
people with advanced lung cancer, and a 63% improvement in survival for certain types of metastatic
melanoma.
The Kinome Project, with initial Barr Program funding in 1997, discovered mutations in a family of
genes called “kinases” that prevent cell growth stimulators from being turned off, resulting in
cancer cells that replicate uncontrollably. These discoveries by William Sellers, MD, and his
colleagues led directly to the development of targeted drugs used by patients worldwide for the
treatment of multiple cancers including lung cancer, leukemia, and melanoma. Examples include
Tarceva and Vemurafenib, which improve survival in subsets of people with lung cancer and
melanoma, respectively. This work has become the model for personalized medicine in cancer
treatment and is widely credited for helping transform the approach that pharmaceutical
companies use for drug development.
Obesity and Cancer: Discovering Critical Linkages - Determining why obesity is a risk factor for
cancer, leading to the potential for major breakthroughs in the development of new ways to treat and
prevent cancer.
Bruce Spiegelman, PhD, supported by the Barr Program in 2005, has demonstrated that obesity
causes many body-wide alterations in metabolism, hormone levels, and inflammation, and that
these abnormalities may affect the development and progression of cancers. Determining the link
between obesity and these cancers could be instrumental to inhibiting cancer development in both
obese and non-obese people.
Immune Therapies
Enabling the Body to Fight Cancer - Enabling the discovery and successful use of vaccines to
enhance the ability of the human immune system to attack cancers, including an increase in survival
for men with prostate cancer.
Shannon Turley, PhD, discovered a new class of cells that suppress immune responses against
cancer. With Barr funding awarded in 2008, Dr. Turley used mouse models to understand how
© 2015 Dana-Farber Cancer Institute
some of the most difficult cancers to treat, such as pancreatic cancer, are able to suppress immune
responses. This growing understanding of the process is enabling development of new treatments,
such as the prostate cancer vaccine Provenge, which enhances the immune system’s ability to
attack prostate cancers.
New Ways to Activate the Immune System - Enabling the development of new vaccines and other
approaches that enhance the immune system’s response to cancers.
An important area of cancer research asks why humans don’t reject tumors in their own bodies.
Funded by the Barr Program in 1998, Glenn Dranoff, MD, discovered complex regulatory pathways
in the human immune system that cancers exploit in order to escape destruction. Reversal of these
effects can lead to the development of vaccines against cancer, like Provenge for prostate cancer.
This Barr research has also enabled the development of immune activators for melanoma and other
cancers. A recent example is Ipilimumab, which showed striking effects in melanoma in a trial led
by Dana-Farber scientists and is now approved by the FDA.
Leukemia and Lymphoma
Blocking Key Drivers of Cancer Cell Growth - Discovery of mutations in genes that modify RNA,
leading to a new understanding of Chronic Lymphocytic Leukemia (CLL), the most common of adult
leukemias.
Chronic lymphocytic leukemia (CLL) causes a slow increase in white blood cells called B
lymphocytes, or B cells. Cancer cells spread through the blood and bone marrow, and can also affect
the lymph nodes or other organs such as the liver and spleen. CLL eventually causes the bone
marrow to fail. Funded by the Barr Program in 2007-’08, Cathy Wu, MD, used powerful “next
generation” DNA sequencing to identify five genes that are abnormal in CLL. The numerous genetic
flaws uncovered by the search could not only aid in the prediction of disease course but also offer
clues to the biological underpinnings of CLL, paving the way for novel targeted treatments.
Improving Treatment Potency - Identifying genes in leukemias and lymphomas that cause
resistance to treatment.
Although our current therapies cure about half of all patients with leukemia and lymphoma, the
other half fail treatment because their diseases become resistant to treatment. This often happens
as a result of genetic alterations in their leukemia and lymphoma cells. Barr funding in 2008-‘09
and 2013-‘14 has allowed David Weinstock, MD, (a DFMC runner/fundraiser in 2013 and 2014) to
use powerful new technologies to identify the genes that can cause this kind of resistance. Drugs
that inactivate these genes could prevent resistance and lead to cures in many more patients.
New Drugs to Trigger Cancer Cell Death - Development of new therapies that reactivate the ability
of cancer cells to die.
All living cells contain “executioner proteins” that help control the growth of normal cells. Cancer
cells find a way to prevent activation of these proteins, enabling them to replicate uncontrollably.
The 2008 Barr research project of Loren Walensky, MD, PhD, generated novel compounds that bind
to these proteins in cancer cells, reactivating their “executioner” function and triggering cell death.
By integrating chemistry, biology, and cancer medicine, this work has the potential to create
© 2015 Dana-Farber Cancer Institute
groundbreaking new therapies for multiple types of cancer, many of which no longer respond to
conventional therapies.
Lung Cancer
Discovery of an Important Mutation - Discovery of mutations in the protein EGFR leading to a 42%
increase worldwide in survival for patients with these mutations.
Lung cancer claims more lives than any other cancer, and is extremely difficult to treat. The Barr
Program provided the initial funding in 2002 to Matthew Meyerson, MD, PhD, who discovered
mutations in the protein EGFR in certain lung cancer tumors. This discovery defined the patients
who benefit from Tarceva and other drugs that target EGFR in the 15% of lung cancer patients
whose tumors contain these mutations. Today, these drugs are being used successfully across the
world to help people with cancers that were previously untreatable. Dr. Meyerson ran the Boston
Marathon® in 2011 as a member of the Dana-Farber Marathon Challenge fundraising team.
New Treatments for Drug-Resistant Cancers - Development of new compounds, potentially the
next “superdrugs,” to treat some of the most resistant cancers.
One of the difficult problems facing cancer physicians is the ability of tumors to become resistant to
therapies that are initially effective. A most promising area of cancer therapeutics is using
chemistry for basic research to design and create new classes of compounds that bind to and inhibit
the growth of cancer cells that have become drug-resistant. In 2006, Michael Eck, MD, PhD, and
Nathanael Gray, PhD, received Barr funding to uncover structural characteristics of cancer cells and
to develop compounds that attach themselves to these structures in a way that inhibits their
growth. This work is leading to the development of new drugs that are effective against resistant
cancers. Recently, they identified ways to overcome resistance to a new class of lung cancer drugs,
known as EGFR inhibitors. Pharmaceutical companies quickly developed new drugs based on their
work, and one of these drugs was shown to improve the survival of people with lung cancer who
have resistance to older EGFR inhibitors.
Speeding New Drug Development - Discovery of a new clinical trial approach, called “co-clinical”
trials, enabling the use of animal models to much more accurately predict behavior of treatments in
humans for lung cancers.
Kwok-Kin Wong, MD, PhD, used Barr funding in 2008-‘09 to “turbocharge” the process of cancer
drug testing. Clinical trials of anti-cancer drugs usually show that they are effective in only a subset
of tested patients. Identifying which patients can benefit from a drug is difficult to achieve but can
spare those who won’t benefit from treatment. This saves time in drug development and health
care dollars. Dr. Wong conducted a clinical trial of two drugs in patients while simultaneously
testing the drugs in genetically modified mice he had developed. The responses in mice allowed Dr.
Wong to develop a genetic profile that perfectly predicted who would respond in the clinical trial.
Dr. Wong is developing similar “co-clinical” trials to test drugs with pharmaceutical companies
around the world.
© 2015 Dana-Farber Cancer Institute
Pancreatic Cancer
Enabling More Effective Diagnosis and Treatment - Creation of the first mouse model that
faithfully replicates the genetic profile of human pancreatic cancer, one of the most lethal cancers that
affects nearly 44,000 people annually.
Pancreatic cancer remains one of the most difficult cancers to treat. There is no early diagnostic test
for pancreatic cancer, and genetic research has done little to improve patient outcomes. Nabeel
Bardeesy, PhD, used Barr funding in 2003 to develop the world’s first authentic mouse model of
pancreatic cancer. This enabled the detailed study of genes most likely to drive the progression of
pancreatic cancer in humans. Dr. Bardeesy’s work is now being leveraged by other cancer institutes
and drug companies to identify and test new treatments.
New Treatments - Discovery that hydroxychloroquine, currently used for treating malaria, is
effective in shrinking or slowing the growth of pancreatic cancers.
Hydroxychloroquine is a drug that inhibits “autophagy,” a process that enables cells to break down
and eliminate structures such as damaged cell membranes. Cancer cells use autophagy to outwit
chemotherapy treatment: by activating this process they survive the stress of therapy. Alec
Kimmelman, MD, PhD, with Barr Program support in 2009-’10, discovered that autophagy is turned
on at all times in pancreatic cancer cells, suggesting that pancreas tumors are highly dependent on
autophagy and therefore good candidates for autophagy-inhibiting treatments. Testing with mice
treated with the drug, the treatments were found to be very effective, and Dr. Kimmelman is
advancing this discovery into human trials.
Pediatric Cancers
Neuroblastoma in Children: New Treatment - Discovery that about 10% of pediatric
neuroblastoma tumors contain a specific mutation, leading to the possible use of drugs that have
already proven successful in treating other cancers that have the same mutation.
Neuroblastoma has historically been a very difficult cancer to treat in children, and, although
chemotherapy and stem cell transplants have improved survival, relapse is common and nearly
almost always fatal. With Barr support in 2007, Rani George, MD, PhD, discovered that a significant
number of neuroblastoma tumors contain a mutation in the gene ALK. Several successful drugs
already exist to treat other types of cancer that demonstrate these same ALK mutations, and Dr.
George and her team have initiated clinical trials that could result in new treatments that will
improve survival for children with neuroblastoma.
Personalized Medicine
Optimizing Treatment of Early Stage Cancers - Determining which of the 35% of early-stage
breast cancer patients should receive chemotherapy and sparing the other 65% from unnecessary
treatments.
We now know that not all tumors are alike, and that treatment strategies need to be based on the
unique molecular characteristics of each cancer—not just the organs where tumors originate.
© 2015 Dana-Farber Cancer Institute
Funded by the Barr Program in 1996, Todd Golub, MD, performed one of the first molecular
classifications of tumors, which are now used by oncologists around the world to personalize
treatment decisions for people with cancer. For example, gene expression is now used routinely to
help determine which people with breast cancer are most likely to relapse after surgery and
therefore need additional treatment.
Determining When to Use Chemotherapy - Discovery of a new test to determine whether specific
cancer cells will die from chemotherapy, enabling a better way to determine which patients will
benefit from chemotherapy.
Normal cells of the body are constructed so that if they become sufficiently damaged or abnormal,
they rapidly die through a process known as apoptosis before they can cause any harm. Cancer
cells, which bear many abnormalities, apparently have found ways to escape this death sentence
through “antideath” proteins. Anthony Letai, MD, PhD, used Barr Program funds in 2005 to develop
a test to determine whether a patient’s specific cancer cells will be killed by chemotherapy, thereby
enabling the selection of the most appropriate treatment. Dr. Letai is currently commercializing this
test to make it available for a range of different types of cancer.
Supportive Care
Pain Management: New Treatment Opportunities - Discovery of the underlying genes responsible
for the crippling neuropathic pain experienced by more than 30% of all cancer patients, leading to
new approaches for the development of drugs that treat pain.
Managing the pain that some people with cancer experience as a result of their disease and from the
side effects of treatments is an area in which little progress has been made. With Barr support in
2007, Quifu Ma, PhD, revolutionized the understanding of this problem by identifying genes
expressed in neurons that are critical for pain perception. Eventually, this will enable drug
companies to develop novel therapeutic targets for pain treatment.
© 2015 Dana-Farber Cancer Institute