Maximizing responses to DNA damage-inducing therapies in Leiomyosarcoma (LMS)
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fast-track patients with advanced LMS from outdated chemotherapy-based empiric treatment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.