Overcoming Stromal Barriers to KRAS Inhibition in Pancreatic Cancer with VDR Agonist Therapy

Novel Therapeutics & Platforms

Ronald Evans, PhD (The Salk Institute)

Dannielle Engle, PhD (The Salk Institute)

Herve Tiriac, PhD (UC San Diego)

KRAS inhibitors (KRASis) are on track to be FDA approved for use in pancreatic ductal adenocarcinoma (PDA). However, not all patients will realize their full potential due to resistance mechanisms, including stromal activation of compensatory pathways. This proposal will test the hypothesis that VDR agonist can promote KRASi responses through inhibition of macrophage-mediated therapeutic resistance and immunosuppression. In Aim1, we will test the ability of VDR agonist to prevent and reverse KRASi resistance in human PDA organoid transplants and dissect the functional contribution of macrophage VDR activity. In Aim2, we will determine the potential for VDR agonist to promote KRASi synergy with immunotherapy and improve long-term survival in syngeneic orthotopic PDA transplants. As VDR agonists are FDA approved and recent clinical trials have shown they are safe for use in PDA patients, this work is poised to rapidly translate to the clinic and improve patient outcomes.