Grant: Project Grant

Recent pan-cancer DNA sequencing efforts identified that mutations in members of a protein complex, called SWI/SNF complex, are highly prevalent across many tumor types. However, the understanding of how these genetic mutations drive cancer development is incomplete. In addition, the biologically informed therapeutic development for cancers bearing these mutations is still in its infant stage. We have recently discovered that gynecologic cancer cells bearing mutations in SMARCA4, the catalytic element of the SWI/SNF complex, have unique metabolic features. We propose that metabolic alterations act in concert to sustain the development of SMARCA4-deficient cancers and serve as promising targets for therapeutic development. We will take cancer cells derived from small cell carcinoma of the ovary hypercalcemic type (SCCOHT), a rare but unique ovarian cancer type that is driven solely by genetic inactivation of SMARCA4, as a key model to uncover metabolic changes accompanied with genetic perturbation of SWI/SNF-deficient cancer and develop therapeutic approaches for battling these lethal malignancies. This study will lead to new and unique insights into SMARCA4-dependent tumor biology and inform the care of other SWI/SNF-deficient cancers, such as lung cancer, pancreatic cancer, melanoma and brain cancer.