2020 Mentored Investigator Grant Recipient — Ignacio Vázquez-García, PhD
Cancers typically develop from a single cell that proliferates and expands in space and time. Modeling the process of clonal evolution in cancer may enable the prediction of progression and response to therapy. To quantify cancer evolutionary dynamics, we must first gather evidence of the spatio-temporal determinants of tumor evolution. One specific disease of interest is high-grade serous ovarian cancer (HGSOC), which represents the most lethal gynecologic malignancy. The dynamics of the disease in HGSOC brings about significant intra-tumor heterogeneity, which is a major impediment to improve outcomes for women who are diagnosed with the disease. This is likely due to several factors, including the natural history of disease prior and to and after treatment, the sources of mutations which differ across patients, and the interaction of the tumor with the immune system as a “non-self” tissue. Investigating the fundamental biology of HGSOC will address a fundamental gap in knowledge around the molecular mechanisms of response to chemotherapy and immunotherapy, as specific determinants of response are generally unknown or poorly understood. Ultimately, our hope is that this knowledge will open new avenues for the management of HGSOC patients, for which there is an unmet clinical need.
To investigate these factors, we have initiated a multi-modal prospective study of spatio-temporal determinants of HGSOC evolution, treatment and response (MSK SPECTRUM) at Memorial Sloan Kettering Cancer Center. This project will address two major aims based on the collection, integration, computational analysis and interpretation of patient samples and datasets from MSK SPECTRUM. Firstly, we will study the extent of intra-tumor heterogeneity in HGSOC. Intra-tumor heterogeneity provides the genetic and epigenetic “tapestry” upon which the evolution of the tumor unfolds, and is profoundly constrained by the local environment surrounding the tumor. Secondly, we will study the evolution of tumour cells during therapy as a dynamic process. Both of these aims will utilise state-of-the-art technologies in genomics and imaging, to measure the genomes of thousands of individual single cells per cancer. This will provide a high resolution view of the cellular dynamics of HGSOC during the progression of the disease and as a result of therapy. We ultimately hope MSK SPECTRUM will drive innovation in the prevention, diagnosis, and treatment of ovarian, and all, human cancers.