Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine
Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G). PH potentiates the effects of G in in vitro, orthotopic mouse models, and a patient-derived xenograft model of PDAC. Proteomic and single-cell RNA sequencing (RNA-seq) analyses reveal that GPH treatment upregulates autophagy and endoplasmic reticulum (ER) stress-related transcripts. GPH treatment decreases the number of Ki67, fibroblast-associated protein (FAP), and alpha-smooth muscle actin (SMA)-expressing fibroblasts with a decrease in autophagy-related transcripts. The GPH treatment increases M1 polarization and CD4<sup>+</sup> and CD8<sup>+</sup> T cells and reduces CD4<sup>+</sup> and CD8<sup>+</sup> regulatory T cells (Tregs). These effects of GPH were confirmed in paired biopsies obtained from patients treated in a clinical trial (NCT04524702).
Authors
- Sanjay S. Reddy (ORCID: https://orcid.org/0000-0001-9306-2574)
- Ashiq Masood (ORCID: https://orcid.org/0000-0002-1848-1178)
- Jeremy B. Foote (ORCID: https://orcid.org/0000-0002-6621-6096)
- Madhu Sudhana Saddala (ORCID: https://orcid.org/0000-0002-6373-7080)
- Cameron J. Herting (ORCID: https://orcid.org/0000-0002-4937-8392)
- Vikas P. Sukhatme
- Manoj Bhasin (ORCID: https://orcid.org/0000-0001-5172-420X)
- Ateeq Khaliq (ORCID: https://orcid.org/0000-0001-5200-081X)
- Gregory B. Lesinski (ORCID: https://orcid.org/0000-0002-8787-7678)
- Yuvasri Golivi
- Jeffrey M. Switchenko (ORCID: https://orcid.org/0000-0002-5563-9325)
- Olatunji B. Alese (ORCID: https://orcid.org/0000-0001-8079-4725)
- Bassel F. El‐Rayes (ORCID: https://orcid.org/0000-0002-2661-5746)
- Julienne L. Carstens (ORCID: https://orcid.org/0000-0001-9914-0430)
- Upender Manne
- Sujith Sarvesh (ORCID: https://orcid.org/0000-0002-2689-6568)
- Dhana Sekhar Reddy Bandi (ORCID: https://orcid.org/0000-0003-0405-5503)
- Karina J. Yoon (ORCID: https://orcid.org/0000-0002-0830-571X)
- Mehmet Akce (ORCID: https://orcid.org/0000-0003-4747-7722)
- Ganji Purnachandra Nagaraju
Institutions
- University of Alabama at Birmingham Hospital (US)
- Emory University (US)
- University of California, Irvine (US)
- University of Alabama at Birmingham (US)
- Bristol-Myers Squibb (United States) (US)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-12-26
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101881
- Citations
- 10
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 2.83
Funders
- Emory University
- University of Alabama at Birmingham
- University of Alabama
- Morningside Foundation
- Comprehensive Cancer Center, University of Chicago Medical Center