Identifying DNA damage repair-related vulnerabilities in leiomyosarcoma
Leiomyosarcoma (LMS) is one of the most common subtypes of soft tissue sarcoma. Classically, LMSs are characterized by an aggressive clinical course, a heterogeneous genetic profile and a very poor response to cytotoxic chemotherapy. Currently, not one single genetic abnormality is known to be responsible for the development of LMS. The gold standard of LMS treatment are chemotherapeutic regimens, however, with limited response; moreover, preliminary observations from PARP inhibitors clinical trials show mixed results. Given that, there is a need for sustained efforts to define effective targeted therapies and the discovery of novel and more effective therapeutic options for LMS is an area of high unmet clinical need. Compelling evidence is starting to ascribe a key role to the DNA repair systems in LMS biology and their prompt characterization could provide a map for future studies of additional genetic alterations or deregulated cellular processes as entry points for molecularly targeted intervention. So far, the function of the key players of DNA repair pathways has not been explored in LMS, leaving many potential therapeutic targets unexplored. Indeed, molecular mechanisms of DNA repair systems in LMS are unknown, which are a roadblock for exploiting genome repair-targeted therapies. The main goal of my research will be to identify novel DNA repair-targeted therapeutic strategies to extend the survival of LMS patients. Recently, to identify novel biological vulnerabilities in LMS, we carried out a genome-wide loss of function pooled screening in three patient-derived LMS cell line models. Preliminary results showed that several genes involved in DNA repair pathways have roles in LMS cell growth or survival. Based on my preliminary data, the present project aims to expand current knowledge on DNA damage and repair pathways in LMS, through: i) Identifying essential genes involved in DNA damage repair pathways in LMS cells; and, ii) In vitro analysis of anti-cancer drugs which specifically target dysregulated repair pathways in LMS, through a massive screening of about 500 drug compounds. Innovation: These studies will provide a mechanistic understanding of DNA repair systems in LMS based on state-of-the-art unbiased, high-throughput structural and functional genomic evaluations. Integrative analyses with orthogonal, mechanism-based drug screens will maximize the chances of rapid translation of our findings to the clinic. Insights provided by these studies will enable improved understanding of the mechanisms of action and other DNA-damage repair related therapeutics in LMS. Significance: These studies will identify DNA repair-related biologic vulnerabilities and biologically rational drugs with inhibitory activity against this aggressive sarcoma type. The successful completion of this project will yield novel insights into LMS biology and will lay the foundation to develop novel therapeutic approaches to improve LMS patients’ outcomes.