HIF-2-Dependent Regulation of PTHrP and Paraneoplastic Hypercalcemia in Aggressive Clear-Cell Renal Cell Carcinoma

Authors

Arijit Mal
Bingqing Xie
Zane Gray
Charlotte Small
Susmita G Ramanand
Yunpeng Gao
Vanina Toffessi Tcheuyap
Sashi Debnath
Alana Christie
Jeffrey Miyata
Brooklyn Jackson
Hua Zhong
Boning Gao
Jay Lohrey
Naim M Maalouf
Sangeetha M Reddy
John D Minna
Ivan Pedrosa
Xiankai Sun
Ram S Mani
Payal Kapur
James Brugarolas

Language

English

Publication Date

12-2-2025

Journal

Cancer Discovery

DOI

10.1158/2159-8290.CD-25-0638

PMID

41065553

PMCID

PMC12642454

PubMedCentral® Posted Date

11-25-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a TG with paraneoplastic polycythemia). As in TGs, paraneoplastic HC in patients was associated with clear cell (cc)RCC (and sarcomatoid/rhabdoid differentiation) and was rapidly corrected by PT2977/belzutifan, which unlike bisphosphonates, downregulated PTHrP. Our data supports evaluating HIF-2 antagonists for ccRCC patients with paraneoplastic HC, which may serve as a predictive biomarker.

Keywords

Carcinoma, Renal Cell, Hypercalcemia, Parathyroid Hormone-Related Protein, Humans, Kidney Neoplasms, Basic Helix-Loop-Helix Proteins, Mice, Animals, Paraneoplastic Syndromes, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Male, Female, Endothelial PAS Domain-Containing Protein 1, kidney cancer, renal cancer, humoral hypercalcemia of malignancy (HHM), hypercalcemia of malignancy (HCM), cachexia, HIF, HIF2, EPAS1, zolendronate, RANKL, denosumab

Published Open-Access

yes

Recommended Citation

Mal, Arijit; Xie, Bingqing; Gray, Zane; et al., "HIF-2-Dependent Regulation of PTHrP and Paraneoplastic Hypercalcemia in Aggressive Clear-Cell Renal Cell Carcinoma" (2025). Faculty, Staff and Student Publications. 6402.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6402