“Long-Range Tumor-Host Signaling Mechanisms Driving Paraneoplastic Syndromes”
Dr. Ong is utilizing a new genetic tumor model in Drosophila to uncover the molecular basis of paraneoplastic syndromes such as cachexia, immune dysfunction and early lethality.
Building on the MANAFEST project begun in December 2017 with support from both the Bloomberg-Kimmel Institute and The Mark Foundation for Cancer Research, the new center will expand its focus on platforms for identifying cancer immunotherapy biomarkers, leveraging innovative technologies in cancer genomics, immune cell profiling, and digital pathology. The overarching goal is to facilitate the development of biomarkers that can more accurately predict which patients will benefit from a given immunotherapy, a centerpiece of Kimmel Cancer Center’s precision therapy vision.
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Chordoma is a rare, difficult-to-treat bone tumor of the spine or base of the skull. The Mark Foundation has partnered with the Chordoma Foundation to support a team of researchers at three different institutions using rational drug design to identify small molecules that can inhibit brachyury, a protein thought to be the essential driver of chordoma. This project is an expansion of a successful pilot study supported by both foundations that mapped the 3-dimensional structure of brachyury, identified several pockets where chemical fragments can bind, and engineered chordoma cell lines and other reagents required for downstream validation studies. The goal of the project is the identification of several compounds that bind to brachyury and have the properties necessary for successful therapeutic development and, in the long term, to create a targeted small-molecule drug for treating chordoma.
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“Convergence of Machine Learning and Translational Genomics for Prostate Cancer Precision Medicine”
Dr. Van Allen is developing machine-learning algorithms to analyze genomic, imaging, and clinical data from over 3000 prostate cancer patients that can be used to predict clinical outcomes, inform care decisions, and accelerate new biological discoveries. This work will create a clinical and translational discovery engine in prostate cancer that will ultimately be translated into an open source platform that can be used by both clinicians and researchers. These efforts will also lay a foundation for innovative data science efforts across cancer types. Originally from Los Angeles, Dr. Van Allen studied Symbolic Systems at Stanford University, obtained his MD from UCLA, and completed a residency in internal medicine at UCSF before completing a medical oncology fellowship at the Dana-Farber/Partners CancerCare program.
“Drug Combinations to Preempt Resistance in AML”
Dr. Tyner is researching new drug combinations that can help avoid relapse in acute myeloid leukemia (AML) patients who have been treated with targeted therapeutic agents. Although response rates with targeted therapies are promising (ranging from 30% to 80%), most AML patients will relapse in less than one year. Researchers in the Tyner laboratory are using CRISPR/Cas9 genetic screens to uncover mechanisms of sensitivity or resistance to a panel of different drug combinations and to predict which combinations are most likely to have longer-lasting anti-cancer activity. Dr. Tyner attended Grinnell College and Washington University in St. Louis and is currently a Professor at the Knight Cancer Institute, Oregon Health & Science University. Dr. Tyner's research is focused on drug combinations to enhance therapeutic efficacy and circumvent drug resistance.
“Targeting Cellular States and Plasticity in Glioblastoma”
Dr. Suvà is working to better understand and treat the aggressive brain cancer glioblastoma multiforme (GBM). Researchers in his laboratory have recently found that GBM cells can exist in one of four biochemically distinct cellular states and that the ratio of cells in these states can vary in tumors. They are now working to characterize the genetics and tumor microenvironments that lead to each state, determine the relationship and transitions between them, and identify drugs that can best target each one. Dr. Suvà is an Assistant Professor in the Department of Pathology at Massachusetts General Hospital and an Institute Member at the Broad Institute of MIT and Harvard. His expertise is in neuro-oncology and in single-cell genomic technologies. He obtained his MD and PhD in Lausanne, Switzerland.
"Exploiting Lymphatic Transport for Early Detection"
Dr. Lund is developing a novel method for the early detection of tumor progression by focusing on biomarkers that are trafficked through the lymphatic system. Researchers in her laboratory are working to confirm that lymphatic vessels filter proteins secreted by tumors and that those secreted proteins are a rich source of cancer biomarkers. This research, initially focused on melanoma, will also determine whether proteins secreted into the lymph play a role in the early stages of tumor spreading and immune suppression. Dr. Lund earned a PhD from Rensselaer Polytechnic Institute and completed postdoctoral training at the Swiss Federal Institute of Technology Lausanne. Dr. Lund is an Associate Professor in the Ronald O. Perelman Department of Dermatology at NYU Langone Health.
“Mechanism of cGAS-STING Inactivation in Antitumor Immunity and Disease”
Dr. Kranzusch is investigating how the signaling molecule cGAMP is controlled within cells, research that is critical for the rational design of next-generation anti-cancer immunotherapies. cGAMP carries immunity-stimulating signals between the enzyme cGAS and the receptor STING, which can spread rapidly from cell to cell to activate a widespread antitumor immune response. Researchers in the Kranzusch laboratory are studying the mechanism and downstream immune effects of cGAMP regulation, including identifying the key biological factors involved in cGAMP degradation. Dr. Kranzusch earned his PhD from Harvard University and completed postdoctoral studies at University of California, Berkeley. In 2016 he started as an Assistant Professor of Microbiology at Harvard Medical School and the Dana-Farber Cancer Institute. The Kranzusch Lab uses a biochemical and structural biology approach to understand the immune response to cancer.
“Improving Cancer Immunotherapy through Metabolic Modulation”
Dr. Delgoffe is exploring ways to improve the metabolic function of T cells used in cell-based immunotherapies. The tumor microenvironment (TME) puts T cells under severe metabolic stress, limiting their ability to sustain a prolonged antitumor immune response. Researchers in the Delgoffe laboratory will enhance the quality and efficacy of therapeutic T cells either by making alterations to the cell production process that will increase metabolic health or by genetically engineering the cells to better adapt to and function in the metabolically challenging TME. Dr. Delgoffe received his BS from Western Michigan University before completing PhD training at Johns Hopkins University School of Medicine. After postdoctoral training at St. Jude Children’s Research Hospital, he began his own research group in 2014. His laboratory studies how T cells meet their energetic needs in metabolically challenging microenvironments, especially those found within solid tumors. Dr. Delgoffe works to understand the metabolic demands associated with cancer immunotherapy and develops strategies to bolster the immune system to combat malignancy.
Immune checkpoint inhibitors (ICIs) are a class of anti-cancer drugs that fight tumors by activating the body’s immune response. ICIs are remarkably successful at treating some patients while remaining wholly ineffective for others. Led by co-principal investigators Edison T. Liu, MD and Laura Reinholdt, Ph.D, researchers at the Jackson Laboratory are using mouse models to untangle the as yet unknown relationship between genetics and patient response to these immunotherapies. This research may one day allow doctors to use genetic sequencing to predict patient response to immunotherapy, as well as help scientists develop more effective next-generation ICIs.
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