Overall: Project Summary / Abstract
This SPORE entitled, Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer
biology and new approaches to diagnosis and treatment, represents a collaborative initiative with strong
expertise in sarcoma investigation, epidemiology, and cancer genetics. Our primary goals include advancing
knowledge regarding the impact of somatic and germline mutation of TP53 and other DNA repair genes on the
pathogenesis of leiomyosarcoma as well as translational and clinical research studies to facilitate significant and
tangible improvements in the survival and quality of life of sarcoma patients. Although sarcomas are a diverse
group of malignant tumors, we focus on leiomyosarcoma, a common soft tissue sarcoma, that is more frequent
in women (uterine LMS), Black Americans and older adults. LMS because of its chromosomal instability, has a
clinical behavior similar to other soft tissue sarcomas including undifferentiated pleomorphic sarcoma,
dedifferentiated liposarcoma, myxofibrosarcoma and MPNST. LMS is most often aggressive, and treatments are
generally lacking. Sarcomas like leukemias and lymphomas, are mesodermal malignancies and carry biological
significance disproportionate to their clinical prevalence.
The diverse histotypes of sarcoma, and its relative rarity, demand that translational and clinical sarcoma research
be conducted in the context of multi-disciplinary, multi-institutional initiatives. The projects are: (1) Genomic
Vulnerabilities in Leiomyosarcoma; (2) Understanding the role of TP53 in LMS development; and (3)
Applying liquid biopsy technologies to detect clinical response and mechanisms of resistance in the
treatment of LMS. The projects are integrated with high functioning cores and programs for career enhancement
and developmental projects.
This multi-institutional SPORE will investigate contemporary and fundamental issues in sarcoma research, with
its major focus on translational research including the development of new therapies and relevant clinical
biomarkers. Project 1 identified an important new target in DNA repair which is so potent it permits combination
with low dose doxorubicin and introduces this new therapy in advanced drug development studies and a Phase
1/2 trial. Project 3 pursues detection of LMS ultra-rare tumor fragments found in peripheral blood. Quantification
of this ctDNA permits accurate assessment of tumor burden and accelerates exploration of tumor evolution.
Project 2 is a genetic epidemiology study focusing on risk for sporadic LMS as well as secondary to Li-Fraumeni
syndrome. The emphasis will be on TP53 gene, which is somatically mutated in almost (92%) all LMS patients
and other genes affecting DNA repair. Patients with Li-Fraumeni have germline mutation of this gene.