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Researchers to Explore Therapeutic Approaches to KRAS-Mutant Lung Tumors

Lung cancer researchers from Mount Sinai were awarded a 3-year, $500,000 grant from Stand Up To Cancer (SU2C) to explore therapeutic approaches to lung tumors with mutations in the KRAS gene. This undertaking could have a significant impact for a large population of cancer patients who currently lack effective treatment options.


KRAS mutations are among the most common observed in lung cancer and are found in approximately 30 percent of non-small cell lung cancers (NSCLC). NSCLCs with KRAS mutations are associated with a 35 percent higher risk of death than other NSCLCs. Although there has been marked improvement in treatment options for patients with these tumors, most patients either do not respond to these therapeutics or develop early resistance. Thus, there is still a need for curative therapeutic options.

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"Typically, when patients with advanced NSCLC with a KRAS mutation receive therapeutics, there is a period of regression and then the cancer recurs, which is the paradigm in lung cancer more generally," said principal investigator Fred R. Hirsch, MD, PhD, Executive Director of the Center for Thoracic Oncology and the Joe Lowe and Louis Price Professor of Medicine (Hematology and Medical Oncology) at the Icahn School of Medicine at Mount Sinai. "The idea behind our proposal is to explore whether we can use a targeted therapeutic agent called a RAF inhibitor to silence that pathway in these tumors and whether that creates a vulnerability that we can exploit to kill the cancer by using another therapeutic agent."


One reason for the higher risk of cancer-related death among patients with KRAS-mutant lung cancers is an inability to effectively silence tumor survival signaling through direct targeting of the mitogen-activated protein kinase (MAPK) pathway, which plays a key role in the development and growth of tumors.

Fred R. Hirsch, MD, ... - Click to enlarge in new windowFred R. Hirsch, MD, PhD. Fred R. Hirsch, MD, PhD

Through the SU2C Catalyst grant, Mount Sinai researchers will partner with Kwok-Kin Wong, MD, PhD, co-principal investigator, the Anne Murnick Cogan and David H. Cogan Professor of Oncology in the Department of Medicine, and Director of the Division of Hematology and Medical Oncology at NYU Langone's Perlmutter Cancer Center, to identify potential therapeutic combinations that build on the impact of JZP815, a novel pan-RAF inhibitor shown to enhance the effect of other therapeutic agents in treating KRAS-mutant NSCLC.


"With this collaborative grant, we have the impetus and ability to bring together Mount Sinai's diverse patient population and expertise in organoid modeling with NYU's extensive background in mouse modeling to explore questions we would not have been able to investigate independently," said co-lead investigator Benjamin D. Hopkins, PhD, Assistant Professor of Genetics and Genomic Sciences, and Oncological Sciences, at Icahn Mount Sinai, as well as co-leader of the Functional Genomics Pipeline at The Tisch Cancer Institute. "Together, we have the potential to develop new treatment strategies for KRAS-mutant lung cancer patients who are in critical need of improved clinical options. We are grateful to Stand Up To Cancer for making this undertaking possible."

Kwok-Kin Wong, MD, P... - Click to enlarge in new windowKwok-Kin Wong, MD, PhD. Kwok-Kin Wong, MD, PhD

Drawing on Mount Sinai's functional genomics pipeline, researchers will use genetically engineered KRAS-mutant mouse-derived cell lines to identify JZP815-related changes that result in vulnerabilities that can then be exploited with other therapeutic agents to effectively kill the tumor. The researchers will then validate these therapeutic combinations using both patient-derived organoids-3-D cultures of tumor cells-and mouse models to further assess their impact on tumor growth and development. They will also validate potential biomarkers that will help identify patients who are likely to respond favorably to a particular therapeutic combination, thus increasing the likelihood of positive outcomes.

Benjamin D. Hopkins,... - Click to enlarge in new windowBenjamin D. Hopkins, PhD. Benjamin D. Hopkins, PhD

"The goal for all cancer researchers is to improve patient care by identifying therapeutic agents that either are curative or deliver better results than the standard of care," Wong said. "We are excited to work toward this goal for a cancer that is more aggressive and is associated with a poorer prognosis than other lung cancers."


Allison Institute Announces Formation of Scientific Advisory Board

The James P. Allison Institute at The University of Texas MD Anderson Cancer Center established a scientific advisory board to provide strategic guidance and evaluation of its research portfolio and programs. The 11-person advisory board will bring together global leaders in immunotherapy and immunobiology. It will be co-chaired by Robert Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor of Pathology and Immunology at Washington University School of Medicine, and Elaine Mardis, PhD, Co-Executive Director of the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital and Professor of Pediatrics at The Ohio State University College of Medicine.


"As we work to make scientific breakthroughs that bring us a deeper understanding of immunobiology, it is critical that we engage with the world's leading experts," said Padmanee Sharma, MD, PhD, Director of Scientific Programs for the Allison Institute and Professor of Genitourinary Medical Oncology and Immunology at MD Anderson. "The experience and insight from this stellar group of physicians and scientists will be invaluable in steering us toward our ultimate goal of bringing the benefits of immunotherapy to all patients."


The Allison Institute was launched to foster groundbreaking scientific research that will integrate immunobiology across disciplines. With exceptional discovery, translational, and clinical research, the institute will develop novel and synergetic therapies that enable cures for more patients. It is directed by James P. Allison, PhD, Regental Chair of Immunology and Director of the institute, together with Sharma and Raghu Kalluri, MD, PhD, Director of Operations and MD Anderson Chair of Cancer Biology. Members of the scientific advisory board include the following individuals.


Mark Dawson, MD, PhD, is a clinician-scientist and Associate Director of the Peter MacCallum Cancer Centre in Melbourne, Australia. He also is Professor at the University of Melbourne, the Sir Edward Dunlop Fellow for the Cancer Council of Victoria, and a Howard Hughes Medical Institute International Research Scholar. Dawson's research is focused on studying epigenetic regulation in normal development and cancer, which has helped identify several first-in-class epigenetic therapies resulting in various clinical trials around the world. Among several honors, Dawson was elected to the Australian Academy of Science and the Australian Academy of Health and Medical Sciences.


Philip Greenberg, MD, is Professor and Head of the Program in Immunology at Fred Hutchinson Cancer Center and holds the Rona Jaffe Foundation Endowed Chair. He is an internationally recognized expert in cancer immunotherapy and President-Elect of the American Association for Cancer Research. His early discoveries showed how to target diseases using T cells and developed the technology for generating antigen-specific T cells ex vivo for cell therapy, which helped drive the field forward. Greenberg continues to lead efforts to develop and test new strategies to genetically reprogram T cells and use synthetic biology to more effectively target many cancer types.


Marcia Haigis, PhD, is Professor of Cell Biology and Director of Gender Equity for Faculty in Science at Harvard Medical School. She is an active member of the Dana Farber/Harvard Cancer Center, the Paul F. Glenn Center for Biology of Aging Research, and the Ludwig Center at Harvard Medical School. Haigis' research has made fundamental contributions to the understanding of how mitochondria mediate metabolic reprogramming in cancer and contribute to tumor and immune interactions in the tumor microenvironment. She is a recipient of numerous awards and was chosen as a National Academy of Medicine Emerging Leader in Health and Medicine.


Elaine Mardis, PhD, is Co-Executive Director of the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital in Columbus, Ohio, and holds the Rasmussen Nationwide Foundation Endowed Chair of Genomic Medicine. She also is Professor of Pediatrics at The Ohio State University College of Medicine, a member of the National Academy of Medicine, and Past President of the American Association for Cancer Research. Mardis is an internationally recognized expert in cancer genomics and immunogenomics, with interests in the integrated characterization of cancer genomes, defining DNA-based interactions and RNA-based pathways and immune microenvironments that lead to cancer onset and progression, with a focus on pediatric cancers and precision oncology.


Diane Mathis, PhD, is Professor of Immunology at Harvard Medical School and holds the Morton Grove-Rasmussen Chair of Immunohematology. She is an active member of the Committee on Immunology at Harvard Medical School, the Broad Institute, the Dana-Farber/Harvard Cancer Center, and the Harvard Stem Cell Institute. Mathis' research on T-cell differentiation and tolerance/autoimmunity seeks to understand these processes at a mechanistic level and discover how they influence a variety of human diseases. She is a member of the National Academy of Sciences and the American Academy of Arts and Sciences.


Miriam Merad, MD, PhD, is Director of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai and Director of the Human Immune Monitoring Center at Mount Sinai in New York City. She is an internationally acclaimed physician-scientist and leader in the fields of dendritic cell and macrophage biology, focusing on their contributions to human disease. Merad has identified new subsets of both macrophages and dendritic cells, both with key roles in regulating the anti-tumor immune response. She is now working to develop therapies targeting these unique cell populations in cancer and other conditions. For her contributions to the field, Merad was elected to the National Academy of Sciences in 2020.


Kunle Odunsi, MD, PhD, is Director of the University of Chicago Medicine Comprehensive Cancer Center and Dean for Oncology, Biological Services Division at the University of Chicago. He is responsible for strategic oversight of all programmatic aspects of cancer at the University of Chicago, including the three primary missions of research, patient care, and education. His research in tumor immunology and immunotherapy focuses on the mechanisms of immune recognition in ovarian cancer and the development of therapies targeting tumor antigens. Odunsi is a member of the National Academy of Medicine.


Robert Schreiber, PhD, is the Andrew M. and Jane M. Bursky Distinguished Professor of Pathology and Immunology and Director of the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University School of Medicine in St. Louis. He is a tumor immunologist and cytokine biologist who has focused primarily on interferon-gamma biology, seeking to understand the mechanisms underlying natural and therapeutically induced immune responses to developing and established cancers. Schreiber demonstrated that the immune system can prevent tumor outgrowth, induce tumor dormancy, and sculpt tumor immunogenicity-a process he named cancer immunoediting. He is a member of the National Academy of Sciences and the American Academy of Arts and Sciences, along with many other honors.


Phillip Sharp, PhD, is Institute Professor at the Massachusetts Institute of Technology and member of the Department of Biology at the Koch Institute for Integrative Cancer Research at MIT. His research interests have centered on the molecular biology of gene expression relevant to cancer and the mechanisms of RNA splicing. His landmark discoveries provided the first indications of "discontinuous genes" in mammalian cells, changing the understanding of gene structure and earning Sharp the 1993 Nobel Prize in Physiology or Medicine. Sharp also is a member of the National Academy of Sciences, National Academy of Medicine, and American Academy of Arts and Sciences, in addition to many other honors.


Karen Vousden, PhD, is a group leader at the Francis Crick Institute in London and former Chief Scientist for Cancer Research UK. Her research has made contributions to the understanding of how the tumor suppressor p53 is regulated and how it functions to control cancer progression. Vousden revealed an unexpected ability of p53 to help cells adapt and survive under transient periods of serine starvation, leading her to focus on cancer cell metabolism, as well as the role of oxidative stress and one carbon metabolism in cancer development and metastatic progression. Among numerous honors, Vousden is an international member of the National Academy of Sciences and American Academy of Arts and Sciences.


Catherine J. Wu, MD, leads the Division of Stem Cell Transplantation and Cellular Therapies at Dana-Farber Cancer Institute. She has initiated an integrated program of research and clinical activities that focuses on dissecting the basis of effective anti-tumor immunity. Her laboratory has focused on the use of genomics-based approaches to discover immunogenic antigen targets and understand the molecular basis of therapeutic response and resistance. Wu is a member of the National Academy of Medicine and has received numerous other awards.


Researchers to Study Rare Blood Cancers for Drug Development, Clinical Trial Access

A gift of more than $5.75 million from anonymous donors will allow researchers at the UVA Cancer Center to speed the development of new treatments for rare blood cancers and provide more patients with these cancers access to cutting-edge clinical trials. Researchers at the center will use the donation to establish a new Translational Orphan Blood Cancer Research Initiative Fund.


The initiative already has several projects in the pipeline that will help doctors better understand and treat rare blood cancers. These cancers are considered "orphans" or "neglected" because doctors and scientists often struggle to obtain funding for potentially life-saving research.


"Individually, these cancers affect relatively small numbers of people when compared with other cancers, but collectively they touch the lives of countless patients and families," said K. Craig Kent, MD, Chief Executive Officer of UVA Health and Executive Vice President for Health Affairs at the University of Virginia. "We are deeply grateful for this generous gift that will allow us to conduct important, groundbreaking cancer research and develop new treatments that will benefit patients around the world."


The new fund will be overseen by Thomas P. Loughran Jr., MD, Director of UVA Cancer Center, and Owen A. O'Connor, MD, PhD, an international authority on lymphoma. The fund will support far-reaching efforts in the battle against rare blood cancers, including research, drug development, and a special training fellowship in orphan blood cancers. In addition, the fund will allow UVA to help subsidize patients' travel costs to participate in clinical trials, allowing more people to do so.

K. Craig Kent, MD. K... - Click to enlarge in new windowK. Craig Kent, MD. K. Craig Kent, MD

"This extraordinarily generous gift will accelerate innovative research in such rare blood diseases," said Loughran, who discovered a rare form of blood cancer called large-granular lymphocytic (LGL) leukemia and is a leading expert in its treatment. The donation will help support Loughran's research into LGL leukemia with collaborator David J. Feith, PhD. They aim to identify new treatment targets and develop new approaches to improve outcomes for patients with the cancer and other malignancies in T cells. O'Connor, meanwhile, will work with Enrica Marchi, MD, PhD, to develop innovative therapeutics for peripheral T-cell lymphoma and cutaneous T-cell lymphoma. Other projects planned include the following:

Thomas P. Loughran J... - Click to enlarge in new windowThomas P. Loughran Jr., MD. Thomas P. Loughran Jr., MD

* Michael E. Williams, MD, and Craig A. Portell, MD, will develop a clinical study to enhance a treatment approach for mantle cell lymphoma developed by Loughran's team. In addition, they plan to identify combinations of non-chemotherapy drugs that work better together than individually.


* The cancer center will launch a new effort to increase collaborations with top researchers outside UVA. This will include awarding three $250,000 grants to foster these collaborations.


* The cancer center will provide patients with financial assistance to help cover the cost of traveling to participate in clinical trials. For many patients, the lack of access to an academic medical center such as UVA is a major barrier to accessing clinical trials that are the testing ground for the latest treatments.


* UVA will launch a monthly lecture series for faculty and staff to keep them abreast of state-of-the-art treatments and the latest developments in the battle against rare blood cancers.