Dissecting DNA damage and repair pathways in leiomyosarcomas: Improving therapy by understanding biology
Leiomyosarcomas (LMS) are aggressive tumors of the smooth muscle with no available effective treatments and a 2-year survival rate of 20%. They represent up to 25% of all soft tissue sarcomas (STS) and are the most common form of STS in the U.S. next to gastrointestinal stromal tumors (GISTs). Not one single genetic abnormality is known to be responsible for the development of LMS. Although a subset of tumors shows activation of the PI3K/AKT/mTOR axis, targeting this signaling pathway with small molecule kinase inhibitors has only led to minimal improvement in outcome. Therefore, new therapy options are urgently needed. The mainstay of LMS treatment are empirically determined anthracyclin-based chemotherapeutic regimens. However, not much is known about the regulation of DNA damage and repair pathways in LMS. We hypothesize that a better knowledge of DNA damage and repair signaling will lead to the identification of more effective therapies for LMS patients. Hence, our Specific Aims are to (1) Profile expression and activation of the main DNA damage and repair pathways in LMS, (2) Determine functionality of DNA damage and repair pathways in LMS and to (3) Identify and test anti-cancer drugs that specifically target dysregulated DNA damage and repair pathways in LMS. Our proposed studies focus on systematically mapping dysregulated DDR pathway signaling in LMS followed by targeted drug selection and hence immediate implications to improve standard therapies. This precision oncology approach is particularly imperative in a tumor entity that is not known to harbor any recurrent actionable targets, like LMS.