Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine

Ganji Purnachandra Nagaraju; Madhu Sudhana Saddala; Jeremy B Foote; Ateeq M Khaliq; Ashiq Masood; Yuvasri Golivi; Dhana Sekhar Reddy Bandi; Sujith Sarvesh; Sudhir Putty Reddy; Jeffrey Switchenko; Julienne L Carstens; Mehmet Akce; Cameron Herting; Olatunji B Alese; Karina J Yoon; Upender Manne; Manoj K Bhasin; Gregory B Lesinski; Vikas P Sukhatme; Bassel F El-Rayes

doi:10.1016/j.xcrm.2024.101881

Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine

Cell Rep Med. 2024 Dec 17:101881. doi: 10.1016/j.xcrm.2024.101881. Online ahead of print.

Authors

Ganji Purnachandra Nagaraju¹, Madhu Sudhana Saddala², Jeremy B Foote³, Ateeq M Khaliq⁴, Ashiq Masood⁴, Yuvasri Golivi¹, Dhana Sekhar Reddy Bandi¹, Sujith Sarvesh¹, Sudhir Putty Reddy⁵, Jeffrey Switchenko⁶, Julienne L Carstens¹, Mehmet Akce¹, Cameron Herting⁷, Olatunji B Alese⁷, Karina J Yoon⁸, Upender Manne⁹, Manoj K Bhasin¹⁰, Gregory B Lesinski⁷, Vikas P Sukhatme¹¹, Bassel F El-Rayes¹²

Affiliations

¹ Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
² Bioinformatics, Genomics and Proteomics, University of California, Irvine, Irvine, CA 92697, USA.
³ Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
⁴ Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁵ Department of Protein Sciences & Mass Spectrometry, Translational Medicine, Bristol Myers Squibb, Princeton, NJ 08543, USA.
⁶ Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁷ Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
⁸ Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
⁹ Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
¹⁰ Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
¹¹ Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Department of Medicine, Emory University, Atlanta, GA 30322, USA.
¹² Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA. Electronic address: belrayes@uabmc.edu.

PMID: 39730001
DOI: 10.1016/j.xcrm.2024.101881

Abstract

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⁺ and CD8⁺ T cells and reduces CD4⁺ and CD8⁺ regulatory T cells (Tregs). These effects of GPH were confirmed in paired biopsies obtained from patients treated in a clinical trial (NCT04524702).

Keywords: autophagy; cancer associated fibroblasts; chemotherapy; hydroxychloroquine; immune cells; pancreatic ductal adenocarcinoma; paricalcitol; proteomics; single-cell RNA-seq analyses; vitamin D receptor.

Associated data

ClinicalTrials.gov/NCT04524702