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 five-year survival rate after diagnosis is <50%. Newer classes of therapy, called immunotherapy, stimulate patients’ own immune systems to recognize and kill cancer cells. Unfortunately, immunotherapies in HGSOC have thus far proven ineffective. Both standard of care and immunotherapy, specific molecular mechanisms that determine response are generally unknown and poorly understood. Thus there is an urgent and critical unmet need to understand the nature of how and why cancer cells respond to treatments to improve clinical outcomes for HGSOC patients.
Our team has made important progress in uncovering 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 for two key reasons: i) they show differences treatment outcomes and ii) they show differences in immune system response to cancer cells. We also note 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. Cancer evolution itself is driven by mutations accruing in the genomes of malignant cells and is shaped by the nature and levels of immune system recognition and infiltration.
We have designed a new program of research that will link the properties of cancer evolution and immune system response to mutational processes as key factors driving HGSOC drug response. Our team is comprised of leading experts in ovarian cancer oncology, surgery, pathology; and cancer genomics, cancer evolution, immunology, 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 change as a result of therapy. Aim 1 will investigate how different mutational processes confer ‘capacity’ of HGSOC to evolve; Aim 2 will investigate how different mutational processes stimulate immune cells to recognize and infiltrate cancers; and Aim 3 will investigate how mutational processes induce differences in how malignant cells and immune cells change after receiving a) standard of care chemotherapy b) combination immuno- and chemo- therapy in a clinical trial setting.
Our work will advance the field providing a novel ‘cellular dynamics’ view linking cancer evolution with immune 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 chemo and immune therapeutic strategies, ultimately leading to improved outcomes for women diagnosed with HGSOC.
This grant was made possible in part by a generous donation from Ovarian Cycle New York.