Dissecting the Impact of Mutational Processes on Therapeutic Response in Ovarian Cancer
Abstract
Women with high-grade serous ovarian cancer (HGSOC) represent 70% of all ovarian cancers and suffer high morbidities and poor response to standard-of-care treatment. The 5-year survival rate after diagnosis is <50%. Thus, there is an urgent and critical unmet need to understand the nature of how and why cancer cells respond to treatments in order to improve clinical outcomes for HGSOC patients. Our team has made important progress in uncovering new features of HGSOC biology. We found that HGSOC patients can be grouped into four biologically distinct subtypes by the specific nature of how mutations accumulate in their genomes. The subtypes are meaningful, as they show differences in treatment outcomes in a standard-of-care setting. Yet, the mechanisms behind these differences are poorly understood, limiting implementation of the subtypes into clinical management. Our objective is to establish the mechanistic evidence to support implementing mutational processes as a new tool to guide treatment options for HGSOC patients. This will aid in clinical management, potentially increasing the eligibility of patients for treatment with a new and effective class of drugs called PARP inhibitors and also sparing patients from unnecessary toxicity due to futile therapeutic intervention. For cancers with mutational processes that portend poor response to therapy, mutational processes can be implemented to enroll patients into clinical trials for novel therapeutic strategies. We have also reported that HGSOC cancer cells evolve extensively prior to treatment, leading to profound diversity between cancer cells in the same patient. This is thought to be a major determinant of treatment resistance; however, studies linking mutational processes to cancer evolution have not been undertaken. We have designed a new program of research that will link the properties of cancer evolution and treatment response to mutational processes as key factors driving HGSOC progression. Our team is comprised of leading experts in ovarian cancer oncology, surgery, pathology, cancer genomics, cancer evolution, single-cell measurements, and computational biology. We will bring to bear leading edge technology, measuring the genomes of thousands of individual single cells per cancer, leading to an ultra-high-resolution view of how HGSOC changes as a result of distinct mutational processes and newer classes of drugs. Aim 1 will investigate how different mutational processes confer the “capacity” of HGSOC to evolve; Aim 2 will investigate how different mutational processes activate specific biological pathways; and Aim 3 will investigate how mutational processes link to response to four classes of drugs – two that are in use today and two that are promising new compounds. Our work will advance the field providing a novel “cellular dynamics” view linking mutational processes with cancer evolution, phenotypic states, and drug response. We anticipate improved mechanistic knowledge of therapeutic response will lay the groundwork for novel therapeutic approaches and development biomarkers to optimally demarcate which patients are best suited to which class of therapeutic strategies, ultimately leading to improved outcomes for women diagnosed with HGSOC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010565
Entities
People
- Sohrab Shah
Organizations
- Sloan-Kettering Institute
- United States Army