Barr Program Impact Statements
Blocking Key Drivers of Cancer Cell Growth
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 Claudia Adams Barr Program in 2007, Cathy Wu, MD, used powerful DNA sequencing to identify five genes that are abnormal in CLL. The numerous genetic flaws uncovered by this study offered clues to the biological underpinnings of CLL, paving the way for novel targeted treatments that hone in on the unique genetic features of each tumor.
Identifying Novel Treatments
Although recent treatment advances benefit many patients with leukemia and lymphoma, some tumors develop resistance to treatment. Claudia Adams Barr Program funding in 2008 and 2013 has allowed David Weinstock, MD, (who has also been a runner/fundraiser on the Dana-Farber Marathon Challenge team) to use powerful new technologies to identify new potential targets and the alterations linked to resistance. His discovery of the mechanism through which an altered gene drives a form of leukemia has already led to clinical trials testing of a drug that may target this alteration.
Improving Diagnoses and Treatment Decisions
Brain cancers remain among the most difficult cancers to diagnose and treat, due in part to the challenges associated with acquiring tissue samples and conducting surgery in such a vulnerable region. Claudia Adams Barr Program support in 2013 enabled Mikael Rinne, MD, PhD, to develop a sensitive and specific test that can quickly determine whether a diffuse glioma brain tumor sample contains three key mutations. Since these mutations can help identify most gliomas, this knowledge will allow physicians to make conclusive diagnoses during surgery and may guide treatment decisions. Moving forward, Dr. Rinne plans to explore extending this strategy to other diseases.
New Treatment Opportunities
For six years during the 1998-2004 timeframe, Rosalind Segal, MD, PhD, parlayed Claudia Adams Barr Program funding into the discovery that a genetic pathway called “Notch” is consistently damaged in brain tumors. Drugs already existed for other diseases to target Notch, and exciting clinical trials are exploring opportunities to use these drugs for people with brain cancers. This has the potential to significantly improve survival for these devastating cancers.
Discovering New Treatments
Myles Brown, MD, used Claudia Adams Barr Program funding in 2002-2003 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. Building on this work, Dr. Brown continues to investigate the mechanistic underpinnings of hormone-positive cancers and how to expand treatment options for patients whose tumors do not respond to tamoxifen.
Inhibiting Cancer Cell Growth
Dr. Jean Zhao’s Claudia Adams Barr Program funding in 2004 allowed her to systematically test a large number of proteins for their effects on breast cancer growth. She identified the specific, cancer-driving roles of various alterations to the PI3K protein, including PI3KCA. Based on these findings, drug companies have developed PIK3CA inhibitors that are being tested in clinical trials of breast and other cancers. Dr. Zhao also continues to explore the use of PI3K inhibitors in combination with other breast cancer drugs.
New Drugs to Trigger Cancer Cell Death
All living cells contain “executioner proteins” that help to control the growth of normal cells. Cancer cells can sometimes prevent activation of these proteins, enabling them to replicate uncontrollably. Claudia Adams Barr Program in 2008 empowered Loren Walensky, MD, PhD, to generate 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.
Enabling Meaningful Analysis of Massive Databases
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 Claudia Adams Barr Program 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
The Kinome Project, with initial Claudia Adams 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.
Metabolism and Cancer
Bruce Spiegelman, PhD, supported by the Claudia Adams Barr Program in 2005 and again in 2009, has made critical discoveries about the links between obesity, metabolism, inflammation, and the development and progression of cancer. For instance, Dr. Spiegelman identified the proteins that control fat activation and may thereby play a role in driving cancer cachexia, a significant, involuntary weight loss that affects approximately half of all cancer patients and can negatively impact treatment.
Enabling the Body to Fight Cancer
Shannon Turley, PhD, discovered a new class of cells that suppress immune responses against cancer. With Claudia Adams Barr Program funding awarded in 2008, Dr. Turley used mouse models to better understand how some cancers suppress the body’s natural immune responses. Studies like this have propelled Dana-Farber’s leadership in developing immunotherapies, drugs that harness the power of the human immune system to treat cancers. These drugs have already shown tremendous promise in melanoma and prostate cancer and are being developed for use across many additional disease areas.
New Ways to Activate the Immune System
An important area of cancer research asks why the human body’s defense systems do not always attack and destroy tumors as they form. Funded by the Claudia Adams 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 research has also enabled the development of immune-activating drugs such as ipilimumab, which showed striking effects in melanoma in a trial led by Dana-Farber scientists and is now approved by the Food and Drug Administration for treatment.
Discovery of an Important Mutation
The Claudia Adams Barr Program provided initial funding in 2002 to Matthew Meyerson, MD, PhD, who discovered mutations in the EGFR protein in certain lung cancer tumors. This critical finding helped lead to the development of an array of drugs that target EGFR, changing the landscape of lung cancer care. 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
One of the difficult problems facing researchers is that tumors often become resistant to therapies. One promising area of cancer therapeutics is using chemistry 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 Claudia Adams Barr Program 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. For example, they identified ways to overcome resistance to 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 developed resistance to older EGFR inhibitors.
Speeding New Drug Development
Kwok-Kin Wong, MD, PhD, received Claudia Adams Barr Program support in 2008-2009 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.
Enabling More Effective Diagnosis and Treatment
Pancreatic cancer remains one of the most difficult cancers to treat, due in part to the lack of an accurate early diagnostic test for the disease. Nabeel Bardeesy, PhD, used Claudia Adams Barr Program funding in 2003 to develop the world’s first authentic mouse model of pancreatic cancer. This enabled investigators to conduct studies to determine which genes were most likely to drive the progression of pancreatic cancer in humans. Building on this work, Dana-Farber’s pancreatic cancer researchers are now developing a collection of pancreatic cell lines and animal models to bolster preclinical research and expedite the identification of the most promising therapeutic options.
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 survive in the presence of cancer therapies. Alec Kimmelman, MD, PhD, with Claudia Adams Barr Program support in 2009, 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. These treatments were found to be very effective in mouse models, and Dr. Kimmelman is testing this strategy in current clinical trials.
Neuroblastoma in Children: New Treatment
While recent advances have improved survival for children with neuroblastoma, some forms of this disease continue to present serious treatment challenges. With Claudia Adams Barr Program support in 2007, Rani George, MD, PhD, was the first to discover that neuroblastoma tumors often contain a mutation in the ALK gene. Since then, Dr. George and her team have initiated preclinical studies and clinical trials to test ALK inhibitors in combination with other therapies, which could ultimately result in new treatments for children with neuroblastoma.
Changing the Discovery Paradigm
Through Claudia Adams Barr Program support, Charles W. M. Roberts, MD, PhD, studied malignant rhabdoid tumors and the role of the SWI/SNF chromatin remodeling complex—a group of proteins that regulate gene expression. His studies revealed that subunits of this complex are mutated in 20 percent of all pediatric and adult cancers, demonstrating their potential as important therapeutic targets. This ongoing research is providing new insights into what drives both pediatric and adult cancers, unleashing new opportunities to discover more effective therapies.
Optimizing Treatment of Early Stage Cancers
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 site where tumors originate. Funded by the Claudia Adams 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 and deliver targeted therapies 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
Typically, if cells become sufficiently damaged or abnormal, they self-destruct in a process known as apoptosis before they can cause any harm. Cancer cells, which bear many abnormalities, have ways to escape this death sentence through “antideath” proteins. Anthony Letai, MD, PhD, used Claudia Adams Barr Program funds in 2005 to develop a powerful test to determine whether a patient’s specific cancer cells will be destroyed by chemotherapy, thereby enabling the selection of the most appropriate cancer treatment. Dr. Letai is currently working to confirm the efficacy of this test, with the ultimate goal of making it available for a range of different types of cancer.
Pain Management: New Treatment Opportunities
Many patients with cancer experience pain and other side effects during the course of their disease treatment. With Claudia Adams Barr Program support in 2007, Quifu Ma, PhD, revolutionized the understanding of this problem by identifying genes expressed in neurons that are critical for pain perception. His work may someday enable drug companies to develop novel therapeutic targets for pain treatment.