Abstract IA017: The role of vitamin D receptor agonists in the treatment of pancreatic adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is composed of multiple cell types and a dense extracellular matrix that may support cancer cell proliferation and impede chemotherapy delivery. Cancer-associated fibroblasts (CAF’s) in the tumor microenvironment secrete pro-inflammatory factors and components of the extracellular matrix. In PC laboratory models, engagement of the vitamin D receptor (VDR) by VDR agonists shifts CAFs toward a more quiescent phenotype with reduced tumor growth and improved chemotherapy penetration. In this talk, I will review our understanding of the role of the VDR in PDAC, including the proposed mechanisms of growth inhibition, transcriptional profile changes in VDR agonist-treated tumors, and the impact on the immune tumor environment in VDR agonist-treated tumors. I will present the preliminary results of the safety run-in of a two-stage randomized phase 2 study (NCT03520790) evaluating the clinical impact of paricalcitol, a synthetic VDR agonist, when given with standard systemic chemotherapy of gemcitabine and nab-paclitaxel in previously untreated patients with metastatic PDAC. In the run-in stage, 36 patients were randomized 1:1:1 to gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) given 3 weeks on and 1 week off in addition to: paricalcitol 75 mcg IV weekly, paricalcitol 16 mg oral daily, or placebo oral daily. Lastly, I will present the preliminary analysis of the pre-treatment and on-treatment (after 6-8 weeks of therapy) tissue biopsies taken from patients participating in this study, highlighting the results of whole transcriptome sequencing and multiplex spatial analyses used to characterize VDR signaling activity and the tumor microenvironment. Citation Format: Kimberly Perez. The role of vitamin D receptor agonists in the treatment of pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA017.