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Through funding basic cancer research, Dana-Farber’s Claudia Adams Barr Program in Innovative Basic Cancer Research has led to a range of breakthroughs in our understanding of the causes and treatments of cancer.
Claudia Adams Barr 1910-1957
Dana-Farber’s Claudia Adams Barr Program in Innovative Basic Cancer Research selects the brightest scientists and funds their most innovative ideas to propel basic research discoveries that transform cancer treatment. Program investigators have made tremendous advances and spearheaded breakthroughs that are improving care, quality of life, and survival for patients everywhere.
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B-cell malignancies are cancers that originate in B cells. Supported by the Claudia Adams Barr Program in 2018, Baochun Zhang, MD, PhD, is exploring a new approach that leverages the unique biology of these cancers. He had previously identified the signaling protein LMP1 as an important driver of immune response against the Epstein-Barr virus (EBV), a virus that can trigger B-cell malignancy when the immune system is compromised. Further, he found that LMP1 spurred the death of infected B cells. In the laboratory, Dr. Zhang introduced LMP1 into B-cell malignant cells, hypothesizing it would similarly fight the disease. The study confirmed his hypothesis, making LMP1 a powerful drug candidate. Dr. Zhang’s work studying LMP1 is ongoing.
Shwachman-Diamond Syndrome (SDS) is a rare, inherited type of bone marrow failure characterized by a low number of white blood cells. With support from the Claudia Adams Barr Program in 2018, Cailin Joyce, PhD, performed single-cell RNA sequencing on SDS cells. This approach has the potential to yield a high-resolution snapshot of individual cells and the differences between them. Using this technique, she found that the TGF-β pathway was more active in certain stem cells. Dr. Joyce then treated SDS cells with a TGF-β inhibitor and found that the intervention improved the growth of bone marrow cells. These findings indicate that blocking the function of TGF-β might represent a promising treatment approach for patients.
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.
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.
With support from the Claudia Adams Barr Program in 2015, Julia Etchin, PhD, is studying a protein called exportin1, or XPO1, as an attractive, new target for acute myeloid leukemia (AML) therapy. Selinexor (KPT-330), an investigational drug that targets XPO1, has produced promising results in patients with AML in early clinical testing. Dr. Etchin found that selinexor destroys both rapidly-dividing AML cells and treatment-resistant leukemia stem cells, while sparing normal blood cells.
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.
Breast cancer is a heterogeneous disease and does not always respond to immunotherapy. In 2018, the Claudia Adams Barr Program funded the work of Carlos Gil del Alcazar, PhD, who is studying breast cancer’s tumor microenvironment to better understand how certain subtypes evade immunotherapy. He treated research models with the combination of an immunotherapy and a TGF-β inhibitor, a drug that has been shown to counteract immune evasion. He observed a striking dichotomy in response rates across the different models. Building on this work, Dr. Gil del Alcazar plans to identify which tumors respond best to which interventions. This could ultimately help physicians identify patients who should receive certain therapies based on their tumor’s molecular makeup.
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.
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.
Since they were first identified in the early 1990s, genes in the BRCA family have been the focus of intense research because of the increased risk of breast cancer they cause when abnormal. With support from the Claudia Adams Barr Program in 2015, Elodie Hatchi, PhD, has shed new light on one of the ways that BRCA1 functions at a molecular level. Dr. Hatchi’s unprecedented work is the first to identify and outline the relationship between BRCA1 and unusual DNA structures, as well as the role this interaction may play in driving the formation of breast cancer cells.
The most frequently mutated gene in breast cancer is PIK3CA which controls cell growth. A type of targeted therapy called a PI3K inhibitor should treat cancer cells that have PIK3CA mutations, yet these drugs have not yet proven to be clinically successful. With support from the Claudia Adams Barr Program in 2015, Xiuning Le, MD, PhD, is conducting research to determine which mutations may cause resistance to PI3K inhibitors and is generating data to determine if and how targeted therapies can be combined with PI3K inhibitors to boost their overall effect. Dr. Le and her colleagues completed a large genomic screen, which identified several abnormalities most likely to be involved in resistance to PI3K inhibitors. Some of these abnormalities may be manipulated to restore sensitivity of breast cancers to PI3K inhibitors.
Haribabu Arthanari, PhD, supported by the Claudia Adams Barr Program in 2018, studies cancer-driving interactions between proteins. He focuses on the eIF4E protein, which is implicated in 90 percent of human cancers. This master regulator orchestrates a process called translation, which refers to how a cell converts the genetic information in its DNA to create proteins. Dr. Arthanari is exploring the underlying mechanisms driving eIF4E and its translation collaborator, the amino acid S209, to fuel tumor cell proliferation. His preliminary findings suggest that S209 could serve as a powerful drug target for a broad range of cancers.
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 created groundbreaking new therapies for multiple types of cancer, many of which no longer respond to conventional therapies. One of these is now in clinical trials at Dana-Farber and elsewhere.
Some cancers are caused when a piece of one chromosome breaks off and joins another. The resulting molecules are called chromosomal rearrangements and they occur very frequently in childhood cancers. With funding from the Claudia Adams Barr Program in 2015, Tovah Day, PhD, is studying how chromosomal rearrangements form. She conducted a screen of several hundred genes to determine which are involved in the formation of chromosomal rearrangements. She identified a handful of genes and focused on one, PARP3, which promotes the formation of these rearrangements. Dr. Day and her colleagues have shown that drug-like small molecules can inhibit PARP3 activity and prevent the formation of chromosomal rearrangements.
Gastroesophageal cancers (GEC) are a group of genetically complex diseases that affect the stomach and esophagus. A primary barrier to the development of effective treatments for GEC is the lack of robust research models—such as cell lines and mouse models—in which to study these cancers. With funding from the Claudia Adams Barr Program in 2015, Eirini Pectasides, MD, PhD, is using a revolutionary new technology called CRISPR to generate mouse models that more faithfully represent human GEC tumor biology.
Liver cancer is extremely difficult to treat. One approach to liver cancer might be to prevent it from occurring in the first place. With support from the Claudia Adams Barr Program in 2015, Wolfram Goessling, MD, PhD, is studying how cirrhotic liver tissue activates signals that cause liver cells to make nutrients, particularly nitrogen and glucose, that can fuel tumor growth. This process occurs before detectable cancer even arises, offering an opportunity to prevent liver cells from ever becoming cancerous.
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.
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.
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.
Certain cancers ensure their survival by hiding from the immune system. With the support of the Claudia Adams Barr Program in 2018, Judith Agudo, PhD, focuses on overcoming immune evasion in cancer stem cells, which are thought to promote tumor metastasis. She is deciphering the regulation of MHC class I proteins, which play a critical role in immunosurveillance and, when defective, can help cancer stem cells elude the immune system. She aims to identify target proteins that aberrantly eliminate MHC class I proteins in cancer stem cells, with the ultimate goal of inhibiting these targets with drugs.
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.
The recent development of immunotherapies—drugs that leverage the power of the immune system to fight cancer—has opened up an array of promising new treatment approaches. With the support of the Claudia Adams Barr Program in 2015, Kai Wucherpfennig, MD, PhD, is using the latest technology to study neoantigen-specific T-cells. Neoantigens are substances that the immune system has never seen before and identifies as foreign, triggering the T-cells to attack. Dr. Wucherpfennig and his colleagues are studying how neoantigen-specific T-cell response changes in response to immunotherapy.
With funding from the Claudia Adams Barr Program in 2015, Wayne Marasco, MD, PhD, is studying an emerging immunotherapy in which disease-fighting T-cells are genetically engineered to carry chimeric antigen receptors (CARs) on their surface, enabling T-cells to recognize specific targets on cancer cells. Called CAR T-cells, these modified immune cells attack and destroy cancer cells. This treatment has demonstrated success in leukemia and lymphoma, but has not yet proven to be effective in solid tumors. Dr. Marasco is applying this therapy to renal cell carcinoma (kidney cancer).
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.
One of the difficult problems facing oncologists 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.
With few early symptoms, ovarian cancer is often caught at a late stage when treatment options are limited. With support from Claudia Adams Barr Program in 2018, Dipanjan Chowdhury, PhD, is leveraging microRNAs to identify the presence of early ovarian cancer using a blood test. Previous work by Dr. Chowdhury has shown that ovarian cancer cells and normal cells have different microRNA profiles, so if a blood sample contains a specific pattern of microRNAs, that indicates that ovarian cancer cells are present. Preliminary results suggest that patients whose tumors harbor BRCA mutations have different microRNA profiles than healthy patients, meaning that microRNA blood tests could be a tool for early detection.
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 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.
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.
Recent progress in genetic technologies has allowed researchers to learn more about the mutations that are specific to pediatric brain tumors. Mutations that affect histones, the spools around which DNA winds, are not common in adult tumors but are often found in pediatric brain tumors. This suggests that drugs that target these genetic abnormalities in histones could present a more effective approach to treating pediatric brain tumors. With support from the Claudia Adams Barr Program in 2015, Brendan Price, PhD, is leading research to develop cell lines that contain the specific histone mutations found in pediatric high grade gliomas.
Myeloproliferative neoplasms (MPN) are a group of blood cancers in which the bone marrow makes too many blood cells. Though previous research has established the genetic basis of the disease—a mutation in the JAK2 gene—there are currently no therapies that selectively target this mutation. With funding from the Claudia Adams Barr Program in 2018, Ann Mullally, MD, and Sahand Hormoz, PhD, are leveraging their funding to characterize the earliest changes that occur within the bone marrow following the acquisition of the JAK2 mutation. Their aim is to identify unique vulnerabilities in JAK2-mutated cells to target therapeutically.
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.
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 goal of making it available for a range of different types of cancer.
Metformin, a standard drug for type 2 diabetes, has shown some potential to prevent cancer. To maximize metformin’s advantages, researchers must first learn more about how this drug functions at the molecular level. Supported by the Claudia Adams Barr Program in 2005, 2009, and 2018, Bruce Spiegelman, PhD, is using a technology called mass spectrometry to test metformin against thousands of proteins to identify which ones can bind to the drug. He has identified several promising candidates. Should a target protein be validated, he aims to partner with a team of chemists to develop a more potent form of metformin.