Memorial Sloan Kettering Cancer Center
I believe that transformative research emerges from an interdisciplinary space in which innovative approaches are used to address existing questions as well as uncover new scientific problems. My lab is particularly interested in developing chemical tools which we apply to unravel molecular mechanisms that govern genome organization and transcriptional regulation. Recently, we identified a new link between cancer cell formation and environmental stress, including the western diet, pollution and smoking. We expect that understanding these details will expose new cancer vulnerabilities and lead to better cancer prevention and treatment.
Yael David, PhD is an Assistant Member in the Chemical Biology Program at Memorial Sloan Kettering Cancer Center and an Assistant Professor at Weill Cornell Medical College. Dr. David received her BSc in Biology from SUNY Stony Brook and PhD in Biochemistry from The Weizmann Institute of Science in Israel. Realizing the power of interdisciplinary research, Dr. David then moved to the Chemistry department at Princeton University where she combined her expertise in cell biology and protein biochemistry with Prof. Tom Muir’s expertise in peptide and protein chemistry. She pioneered several novel approaches that opened the door to performing research with chemical precision at a biochemical resolution and in a physiological context. In 2016 Dr. David was recruited to MSKCC, where she studies fundamental epigenetic events and their misregulation in cancer. In the two and a half years since it was established, her lab has made tremendous progress developing innovative methodologies to address the causal role of histone modifications in determining cell fate. They harnessed these and other methods to reveal a new class of histone modifications, which provide a mechanistic link between metabolic stress and cancer. Importantly, they identified key regulators of this cascade, to which they are developing small molecule inhibitors. Their fearless approach to complex biological questions fuels their overarching goal to unravel pathophysiological pathways and develop new therapies.
Targeting histone glycation as a new cancer-metabolism pathway
Despite a known epidemiological correlation between diabetes and cancer, there is a major knowledge gap in the molecular mechanism linking these two conditions. Understanding the contribution of underlying metabolic abrogation to cancer pathogenesis is critical for its prevention, detection and treatment. Glycation, the chemical reaction of sugars with proteins, is the hallmark of diabetes (e.g. A1C test) and correlates with various disease complications. We recently found that histone proteins, which spool the DNA and act as an integrative platform for regulating cellular fate (as part of epigenetic regulation of cellular transcription), undergo significant glycation in cancer. Moreover, we found that these adducts change chromatin architecture by directly perturbing histone-DNA interactions as well as competing with other regulatory marks that are key in maintaining normal cellular transcription and which perturbation were shown to drive cancer.
“I am committed to pushing the boundaries of science by asking provocative biological questions and applying powerful chemical tools to address them. As a young scientist with limited access to higher levels of funding necessary for such research, the generous support of the Pershing Square Sohn Prize will allow my lab to continue developing transformative technologies and shorten the path from our innovative basic research to the patients’ bedside.”
In an effort to uncover a cellular response, we identified DJ-1 as an enzyme capable of reversing histone glycation and protecting cells from metabolic damage. Since DJ-1 is an oncogene highly expresses in many cancers, we hypothesized that cancer cells overexpress DJ-1 in order to evade glycation damage while maintaining a high metabolic state (“Warburg effect”). Indeed, depletion of DJ-1 from cells increased their sensitivity to sugar and decreased their survival. Here we propose to interrogate histone glycations as a new link between metabolic stress and cancer. Importantly, we propose to develop and apply small molecule inhibitors for DJ-1 as a new therapeutic route. Together, these will provide crucial information of a newly identified pathway with far reaching implications in cancer treatment.
“Innovation is never to doubt yourself but doubt everything else.”