Abstract B133: ROCK2 inhibition alters pancreatic cancer fibrosis and decreases metastasis

Abstract

Pancreatic cancer (PC) is a genetically complex, highly fibrotic, and treatment-refractory malignancy. At the time of clinical diagnosis most patients present with locally advanced, or metastatic disease, which renders them ineligible for surgery and leaves standard-of-care chemotherapy as the predominant treatment. However, chemotherapy has been shown to lead to chemo-induced fibrosis. The dense, stiff, and fibrotic stroma is a well-known driver of PC progression, metastasis, and chemo-resistance. Subcutaneous studies of high/low fibrosis patient-derived tumors from the APGI/APMA cohorts, showed different sensitivities to Folfirinox, suggesting that less fibrosis could enhance response to chemotherapy. ROCK2 is a major driver of cancer fibrosis, which we could target using the novel, FDA-approved anti-fibrotic ROCK2 inhibitor, KD025 (Kadmon, USA). In patient derived models of pancreatic cancer, we demonstrate that priming with KD025 disrupts the extracellular matrix whilst also reducing overall metastatic spreading and burden in this disease. Parallel anchorage independent growth, fluid flow–induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how ROCK2 inhibition can reduce PC spread.