Kristopher Sarosiek, PhD

2023 Collaborative Research Development Grant

Harvard T.H. Chan School of Public Health
Targeting Apoptotic Vulnerabilities in Ovarian Cancer

Project Summary
Ovarian cancer is among the most lethal cancers in women and over 60% of the patients diagnosed with this disease eventually succumb to it. In order to effectively treat aggressive ovarian cancers and have the potential for cure therapies must strongly induce cell death in cancer cells. Existing therapies, including the highly effective drugs carboplatin and paclitaxel, damage key components within cancer cells and can cure some patients. However, in most patients the ovarian cancer cells become resistant to therapy and the tumor typically regrows within a few months or years. Recently, new medicines have been developed that can enhance the ability of standard chemotherapies to activate tumor cell death, thus potentially providing an unprecedented opportunity to increase cure rates in many cancers, including ovarian. By combining standard therapies with cell death-promoting BH3 mimetics (medicines that inhibit pro-survival proteins that keep cancer cells alive), clinicians will be able to extend remissions or increase cure rates by delaying or preventing the development of treatment resistance in tumor cells. Importantly, BH3 mimetics have been already approved by the FDA for use in some cancers, with spectacular results observed even in patients that have been previously treated with multiple other therapies. The goal of our studies is to understand how to best use these new, highly effective drugs to improve treatment outcomes for women with ovarian cancers.

This grant was made possible in part by a generous donation from The Edmée Firth Fund for Research in Ovarian Cancer (EFFROC).

Bio

Kris pursued graduate training in Molecular and Cellular Pharmacology at the University of Miami School of Medicine under the mentorship of Izidore Lossos, MD. After receiving his PhD, Kris joined the laboratory of Anthony Letai, MD, PhD, at the Dana-Farber Cancer Institute/ Harvard Medical School for his postdoctoral fellowship.

In collaboration with others in the Letai laboratory, Kris found that some patients with cancers including ovarian cancer have tumors that are more highly primed to undergo programmed cell death (apoptosis) than others, as measured by a novel assay called BH3 Profiling (Ni Chonghaile & Sarosiek, et al., Science, 2011). Cancer cells and patient tumors that are more primed to undergo apoptosis are consequently more sensitive to chemotherapy treatment. This finding potentially explains why some patients respond favorably to chemotherapy while others do not. Kris has also utilized BH3 profiling to identify novel interaction preferences among the BCL-2 family of proteins, finding that BID preferentially activates BAK while BIM preferentially activates BAX to trigger apoptosis (Sarosiek, et al., Molecular Cell, 2013)

More recently, Kris has characterized how apoptosis is regulated in healthy tissues and how this impacts cell fate decisions in response to damage and stress (Sarosiek, et al., Cancer Cell, 2017). A key finding of this work is that developmental regulation of apoptosis is a major determinant of the treatment-associated toxicities observed in adult and pediatric cancer patients. The Sarosiek Laboratory at Harvard School of Public Health in Boston is building on these findings by characterizing how cell death is regulated in healthy and diseased cells in order to expose novel opportunities for therapeutic intervention. Our multidisciplinary research team utilizes computational, genetic, biochemical, cellular and molecular approaches to study cell death regulation in vitro and in vivo. Current areas of focus include the modulation of cell death for ovarian cancer therapy and the elucidation of genetic and environmental mechanisms that alter apoptotic homeostasis to drive tumorigenesis.