Omic patterns of sensitivity and resistance to existing agents- exanded
Leiomyosarcoma (LMS) is a cancer defined by smooth muscle differentiation and is one of the most common sarcomas. Outcomes for LMS patients have not improved in decades: 50% of LMS patients develop metastases, for which there are no highly effective chemotherapies and which are associated with median overall survival of 18 – 24 months. The studies in this proposal seek to change this by developing innovative therapeutic approaches for LMS patients. Genomically, most LMS have complex and heterogeneous genomes, which result from abundant copy number and structural genomic aberrations and chromosomal instability. Chromosomal instability results from double-strand DNA breaks, which are toxic to cells. To limit genotoxic damage, cancer cells rely on DNA damage repair factors that sense and respond to DNA damage, maintaining chromosomal and genomic integrity. DNA damage can be repaired by two main mechanisms: homologous recombination and non-homologous end joining. If these repair mechanisms are deficient, the cells die. There is convincing evidence of DNA-damage repair dysfunction in LMS: most LMS cells have homologous recombination defects, which increases dependence on non-homologous end joining. These defects provide compelling therapeutic opportunities with compounds that block DDR pathways, such as PARPi and DNA-PKi. The overarching hypothesis driving this research proposal is that intrinsic chromosomal instability and DNA-damage repair defects in advanced LMS are vulnerabilities that can be maximized for therapeutic benefit, using combinations of DNA-damaging cytotoxic therapies coupled with targeted inhibitors that block DNA repair, particularly PARP and DNA-PK inhibitors. With the goal of improving the survival of LMS patients by exploiting prevalent DNA-damage repair defects, we propose the following research aims: Aim 1: To develop clinical-grade methods for identifying DNA-damage repair deficiency in LMS samples. Aim 2: To characterize DNA-PKi response and resistance mechanisms and synthetic lethal interactions in LMS using functional genomic in vivo screens (CRISPR screens). Completion of this project will deliver novel rational therapeutic approaches urgently needed to improve clinical outcomes for patients with LMS. These innovative approaches, bridging diagnostics and therapeutics, will fast-track patients with advanced LMS from outdated chemotherapy-based empiric treatment paradigms to rational molecularly driven precision therapeutics.