Exploiting genomic vulnerabilities in leiomyosarcoma

• Applicant: Jan Philipp Novotny, Ph.D.
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442654483

Leiomyosarcomas (LMS) are one of the most common soft tissue sarcomas in Germany. In the majority of cases, treatment with curative intent is only possible in early stages and with complete microscopic removal of the tumor. In the advanced setting, palliative chemotherapy has only limited efficacy in most patients and no targeted treatments are available to date, highlighting the need for new treatment approaches. Genetically, Leiomyosarcomas display a low mutational burden, but are characterized by striking karyotypic heterogeneity that is expressive of chromosomal instability (CIN). It is now recognized that a critical threshold for maximum tolerable CIN exists in cancer cells and, thus, treatments that will exacerbate intrinsic CIN to intolerable levels are of particular interest in advanced LMS. Within this project I will (a) quantitatively assess the impact of various DNA damaging agents on chromosomal instability and cell viability, (b) test a compelling hypothesis, which is that DNA-repair inhibitor drugs can boost intrinsic CIN to extremely genotoxic levels and (c) identify escape mechanisms conferring resistance to CIN inducing agents in advanced LMS. I will do this using well-established methods, as well as by utilizing state-of-the-art technology, such as single cell whole genome sequencing (sc-WGS) and CRISPR/Cas9 knockdown (CRISPRi) screens. The proposed work will form the basis for much needed translational clinical trials to advance treatment of this aggressive cancer.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Jonathan Alfred Fletcher