2017 SWCRF Scientific Review and breakthroughs Highlights Progress and Innovation in Funded Research Programs

SWCRF scientific collaborators and guest presenters at the 2017 Scientific Review

Cancer researchers supported by the Samuel Waxman Cancer Research Foundation (SWCRF) shared encouraging progress in their funded projects at the 2017 SWCRF Scientific Review on April 30 and May 1. Coming together at the Icahn School of Medicine at Mount Sinai Medical Center, current SWCRF grantees and guest speakers presented key findings in their collaborative work in all forms of cancer, including several presentations relating to the new SWCRF Aging and Cancer Research program. 

Drs. Samuel Waxman, Steven J. Burakoff, Hua Yu, Lorraine Gudas and Jonathan Licht at the SWCRF Breakthroughs Symposium

SWCRF Chief Scientific Officer Jonathan Licht, MD, delivered a summary of the proceedings from the two-day session at the SWCRF Breakthroughs scientific update, both of which were sponsored by Syros Pharmaceuticals.  Hosted by SWCRF Founder and CEO Samuel Waxman, MD, the symposium was attended by donors and collaborators and featured welcoming remarks by SWCRF Chairman of the Board Michael Nierenberg and Dr. Steven J. Burakoff, Director of the Tisch Cancer Institute at Mount Sinai Medical Center. SWCRF Scientific Advisory Board (SAB) member Lorraine Gudas, PhD, shared highlights from the SAB’s report and updates in gioblastoma therapy and aging and cancer research were provided by SWCRF grantee Dr. William Weiss and guest presenter Dr. Maria Figueroa, respectively. SWCRF Board member Dena K. Weiner gave a stirring commentary on the importance of funding cancer research. Dr. Waxman closed the presentation with a report on the state of the SWCRF and its new Partnership for Aging and Cancer Research. The ceremony was followed by a reception showcasing poster presentations by SWCRF grantees. Wines for the reception were provided by longtime SWCRF supporter Palm Bay International

Highlights from the Scientific Review 

Presentations by the SWCRF grantees and guests were observed by members of the SWCRF Scientific Advisory Board, including Dr. Gudas, Robert Hromas, MD, FACP, Nancy Speck, PhD, and Hua Yu, PhD. 

Overview: Epigenetic Targets and Therapies 

A major focus of the Foundation has been to devise strategies to target transcription factors and epigenetic regulators that play a critical role in carcinogenesis through misexpression, mutation, or gene translocation. Collectively the groups have developed important new insights into the modes of action of mutant epigenetic regulators in cancer and developed potential therapeutic approaches to such tumors.

Examples of such research include:

  • Studies by Drs. Shai Izraeli, Tel Aviv University,  and John Crispino, Northwestern University, focus on understanding transcription factors, such as ERG and GATA, that affect normal and/or cancer stem cell self-renewal, differentiation, and survival. For more than a decade, these two scientists have studied basic mechanisms of the development of leukemia in children, particularly those associated with Down syndrome (DS); from this work they developed new therapies against a rare form of leukemia that develops in children with DS.

  • Drs. Margaret Goodell, Baylor College of Medicine, and Ross Levine, Memorial Sloan Kettering, study mutations in DNMT3A, which encodes a protein that places a methyl group on DNA. They and other investigators recently described a new clinical phenomenon, called clonal hematopoiesis of indeterminate prognosis (CHIP), in which mutations of DNMT3A (and other key genes) arise in older individuals and appear to drive the growth of blood cells derived from a single mutant stem cell. Leukemias and other blood malignancies appear to arise from this expanded set of aberrant cells.

  • Dr. Xiu Xiong, University of North Carolina, works on Tet enzymes, which remove methyl groups from DNA. He recently discovered that these enzymes form part of the body’s defense against viral infections, including cancer-causing viruses. 

  • Dr. Ari Melnick’s group at Weill Cornell Medical Center studies BCL6, a key regulator of the cellular response to physiologic stress. Increased expression of BCL6 is one cause of certain forms of lymphoma. His laboratory and collaborators are developing drugs that inhibit the BCL6 protein as potential novel therapeutic agents for lymphoma.

  • Dr. Christopher French, Brigham and Women’s Hospital, studies the rare and lethal disease, midline carcinoma. He and colleagues found that an abnormal form of the BRD4 protein, which binds to specific chemical modifications of chromatin, underlies this cancer. He has characterized the proteins that interact to cause abnormal gene expression in this cancer, and he and his collaborators are developing potential new drugs to block binding of BRD4 to chromatin as a treatment for this otherwise rapidly fatal disorder.

  • Drs. Wilson Miller, Jewish General Hospital, and Jonathan Licht, University Florida Health Cancer Center, are creating drug-resistant cell lines to study how drugs that inhibit histone deacetylase and histone methyltransferase may kill lymphoma and myeloma cancer cells. They found that flexibility (plasticity) of the cell’s state of differentiation may account for the resistance of cells to these drugs, and are working to overcome this phenotypic plasticity.

  • The Shanghai Institute of Hematology group found that patients whose tumors have mutations of the p53 tumor suppressor (the most commonly mutated gene in cancer) are more likely to response to therapy with azacytidine, an inhibitor of DNA methylation; they seek to discover the reason for this phenomenon. They also created scientifically valuable mouse models of leukemia caused by mutations of the DNMT3 gene.

  • Dr. Robert Weinberg of the Whitehead Institute for Biomedical Research is studying the epigenetic regulation of the so-called epithelial-mesenchymal transition, which can block the effects of immune therapy against breast tumors, a finding with great clinical importance

  • Drs. Stephen Baylin, Robert Casero and Cynthia Zahnow at Johns Hopkins used drugs that alter epigenetic gene expression to boost anti-tumor immunity, an approach that has led to innovative clinical trials in ovarian cancer.

  • Dr. Samuel Waxman is developing at Mount Sinai a new therapeutic approach to the treatment of triple-negative breast cancer (TNBC) based on a SID decoy, a small peptide that mimics a key region (SID domain) of the MAD1 protein. He is combining the SID decoy with derivatives of retinoic acid as potential adjuvant therapy for TNBC.

  • Dr. Gregory David, NYU Langone Medical Center, is studying the Sin3A protein in pancreatic cancer, and showed how Sin3a mediates inflammation that can provoke the development of pancreatic cancer.  

  • Guest presenter Dr. Emmanuelle DiTomaso, VP, Head of Translational Medicine at Syros Pharmaceuticals, delivered a talk on the company’s work in cancer super-enhancers.

Overview: Tumorigenesis, Cancer Stem Cell Renewal and Dormancy

The nature of the cancer stem cell, cancer cell proliferation and tumor dormancy is another major scientific theme of SWCRF-supported researchers.

Examples of such research include:

  • Dr. Julio Aguirre-Ghiso of the Icahn School of Medicine at Mount Sinai discovered that the transcription factor, NRF2, is key to programming the cancer cell into a “dormant” state.  He has now identified compounds that can activate NRF2 and induce the dormant state as potential anti-cancer agents. 

  • Dr. Jayanta Debnath,  University of California San Francisco, studies the autophagy pathway in cancer and found that tumor cells generate proteins through the process of autodigestion, which are then released from the cell in small lipid-coated bubbles called exosomes; he will define the cancer-promoting potential of the molecules in such particles.  

  • Dr. Doris Germain, Icahn School of Medicine at Mount Sinai, has investigated the unfolded protein response and the re-programming of the mitochondria (the energy “powerhouse” of the cell) in cancer cells. Cancer development may be influenced by the diminished ability of mitochondria in aging cells to handle misfolded proteins, coupled with exposure to certain excess oxygen products.

  • Dr. Ronald Evans, Salk Institute, studied the intersection of cancer and metabolism by examining effects on colon cancer development of certain nuclear receptors that respond to high fat diets, effects of altered production of bile components, and varying composition of microorganisms in the gut.

  • Drs. Duane Compton, Dartmouth, and Ethan Dmitrovsky, MD Anderson, are using drug combinations that target chromosome instability in lung cancer, and their studies have led to a successful series of clinical trials in lung cancer. They have also used a high-throughput chemical screening process to identify potential inhibitors of this pathway as a means to developing novel cancer therapeutics.

  • Dr. Josep Llovet’s program in liver cancer at Mount Sinai has won international awards (eg, American Association of Cancer Research team science award) as he categorized subtypes of liver and gall bladder cancer, with the goal of developing new therapies. He found that certain subtypes of liver cancer are invaded by immune cells, and such patients may preferentially benefit from immunotherapy approaches. His group is also developing mouse models of liver cancer in which immune therapies can be tested. 

  • Drs. Albert Baldwin, University of North Carolina Chapel Hill, Kevan Shokat, and William Weiss, both of the University of California San Francisco, continued to develop new targeted therapy against brain tumors. They found that the cancer cells find ways to rewire themselves to become resistant to inhibitors of cellular signaling.  These studies led to new ideas on how to target brain tumors with advanced chemical techniques and new inhibitors of the AKT/mTOR pathways.  

Aging and Cancer 

Following the very successful Aging and Blood Cancer Symposium in 2016, several other scientists were invited to the annual SWCRF meeting: 

·  Dr. Maria Figueroa, University of Miami, discussed how methylation of the genome and gene expression change with age, and described a program of inflammation and altered gene splicing that develops as the blood system ages. 

·  Dr. Emmanuelle Passegué, Columbia University, reviewed how the ability to handle cellular stress and DNA damage changes as blood stem cells age. 

·  Dr. Andre Nussensweig, National Cancer Institute, showed how genetic instability develops over time and may lead to cancer-causing mutations. 

·  Dr. James DiGregori, University of Colorado, discussed how the aging of tissues causes an inflammatory environment that can stimulate cancer development. 

·  Drs. Saghi Ghaffari, Icahn School of Medicine at Mount Sinai, and Hans-Willem Snoeck, Columbia University, discussed aging of mitochondria and how this affects blood cell function. 

·  Dr. Jason Butler, Weill Cornell Medical School, showed how the aging bone marrow has a negative influence on blood cells, and hypothesized that leukemia development may occur because of changes in both the blood stem cell and in the cells that support and nourish them. 

The ideas of these investigators will form the basis of the new SWCRF Aging and Cancer Grant Program to be jointly sponsored by the National Cancer Institute and American Foundation for Aging Research. 

 

Click here to donate to our research programs. 

Click here for a gallery of photos from the SWCRF Breakthroughs