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 cancer remains one of the most difficult cancers to treat and is 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 now use these drugs for brain cancer patients. This has the potential to significantly improve survival for this devastating cancer.
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 breast cancer patients.
Myles Brown, MD, used Barr funding in 2002-‘03 to discover the way estrogen works in normal tissues and breast cancers, resulting in 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 33% improvement in survival for women whose breast cancers respond to 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.
Breast Cancer: 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 enzymes for their effects on breast cancer growth. She identified a specific protein known as PIK3CA and showed that it plays a critically important role in 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.
Breast Cancer: Optimizing Treatment for Early Stage Patients - 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, achieved early molecular classification of tumors, leading directly to customized treatments now used by oncologists around the world with significantly better outcomes for patients. For example, gene expression is now used routinely to help determine those breast cancer patients who are most likely to relapse after surgery and therefore need additional treatment, and Todd’s science provided the rationale for its development. This Barr research is also serving as the foundation for how many other diseases will be routinely treated as well.
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 inundation of 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.
Chemotherapy: Determining When to Use - 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, programmed cell death, or apoptosis, rapidly eliminates them 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 collaborating with drug companies who are interested in commercializing this test and making it available clinically.
Drug-Resistant Cancers: New Treatments - Development of new compounds, potentially the next “super drugs”, to treat some of the most resistant cancers, including lung and colon cancer.
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. Pharmaceutical companies are now rushing to develop new drugs based on the work initially funded by the Barr Program and to schedule these drugs for clinical trials. These could provide exciting treatment options for some of the most difficult cancers, including lung and colon.
The Human Immune System: Enabling the Body to Fight Cancer - Enabling the discovery and successful use of vaccines to enhance the ability of the human immune system to reject cancers, including a 22% increase in survival for prostate cancer.
Shannon Turley, PhD, is determining the fundamental reasons why human immune systems do not reject cancers and has discovered a new class of cells that suppress immune responses against cancer. With Barr funding awarded in 2008, Dr. Turley is using mouse models to understand how some of the most difficult cancers to treat, such as pancreatic, are able to suppress immune rejection. 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 reject cancers and improves survival by 22%.
Innovative Treatments: 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 patients with advanced lung cancer, and a 63% improvement in survival for certain metastatic melanoma patients.
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 leading to a 42% improvement in lung cancer survival, and Vemurafenib, producing a 63% improvement in survival for metastatic melanoma when the mutations are present. 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.
Leukemia: Blocking Key Drivers of Cancer Cell Growth - Discovery of mutations in genes that controls the way RNA is made, leading to trials for new treatments for 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.
Leukemia and Lymphoma: Improving Treatment Potency - Identifying genes in leukemias and lymphomas that cause resistance to treatment by producing genetic alterations.
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 has allowed David Weinstock, MD, to use a powerful new technology called next-generation sequencing 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.
Lung Cancer: Major Improvements in Survival Rates - Discovery of mutations in lung cancer tumors leading to a 42% increase in survival for patients with these mutations worldwide.
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 genetic abnormalities in certain lung cancer tumors. This discovery defined the patients who benefit from two drugs, Iressa and Tarceva, which have proven effective in treating the 15% of lung cancer patients whose tumors contain the specific mutations that were discovered from this Barr research. Today, these drugs are being used successfully with lung cancer patients across the world whose cancers were previously untreatable and have produced a 42% improvement in survival in those patients.
Lung Cancer: 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. Drug companies from around the world are now asking Dr. Wong to develop similar “co-clinical” trials to test their drugs.
Lymphoma: New Drugs to Trigger Cancer Cell Death - Development of new therapies with the potential to reactivate the “executioner” function of cancer cells and prevent their uncontrollable growth.
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.
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.
Obesity and Cancer: Discovering Critical Linkages - Determining why obesity is a risk factor in 10-15% of human cancers, 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.
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 pain treatment drugs.
Managing the pain that cancer patients 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 the underlying genes expressed in neurons critical for pain perception. Eventually, this will enable drug companies to develop novel therapeutic targets for pain treatment.
Pancreatic Cancer: Enabling More Effective Diagnosis and Treatment - Creation of the first complete mouse model that faithfully replicates the genetic profile of human pancreatic cancer, one of the most lethal cancers and afflicting 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. Dr. Nabeel Bardeesy, PhD, used Barr funding in 2003 to develop the world’s most authentic mouse model that will now enable detailed study of the 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.
Pancreatic Cancer: 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 all 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 plans to move to human trials soon.
Prostate and Other Cancers: Discovering Vaccines - Enabling the development of new vaccines for multiple types of cancer including Provenge which increased survival by 22% for prostate cancer, and Ipilimumab which improved survival by 56% for melanoma.
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 multiple other vaccines and immune modulators for melanoma, ovarian cancer, and prostate cancer that are now in advanced clinical trials across the world. If these trials are successful, an exciting and entirely new option for treating certain types of cancer will become available. 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.