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.
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
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
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.
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.
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.