Abstract A037: Inhibition of the HIF-2α-PTHrP axis ameliorates paraneoplastic hypercalcemia in clear cell renal cell carcinoma

Abstract Background In renal cell carcinoma (RCC) patients, hypercalcemia (HC) is an indicator of poor prognosis. HC is typically induced by parathyroid hormone–related protein (PTHrP). However, in HC, the upstream regulatory mechanisms driving PTHrP expression in RCC and role of hypoxia-inducible factor-2α (HIF-2α), a key oncogenic driver of clear cell RCC (ccRCC) is incompletely understood. So, we assessed its role in PTHLH (encoding PTHrP) regulation and assessed the therapeutic implications of HIF-2α inhibition. Methods Hypercalcemic patient-derived tumorgraft (TG) models of ccRCC were evaluated for serum calcium levels, circulating PTHrP, and chromatin accessibility using ATAC-seq. The effects of pharmacologic HIF-2α inhibition were tested in TGs using PT2399 and in patients using PT2977. Results In TG(HC), PTHLH locus remained uniquely accessible. While, PT2399 treatment diminished HIF-2 binding to the PTHLH promoter in turn reduced PTHLH expression (p<0.01), explaining selective PTHrP induction in a subset HIF-2–dependent tumors. In addition, HIF-2 inhibition led to rapid normalization of serum calcium levels (p<0.01) in majority of TG(HC) models, independent of changes in tumor burden. HC in RCC tumors is associated with clear-cell histology and sarcomatoid/rhabdoid differentiation (p<0.001). TG(HC) demonstrated increased sensitivity to HIF-2 inhibition (odds ratio = 3.03; 95% CI, 0.96–9.58). Consistent with preclinical findings, PT2977 treatment in patients resulted in effective correction of hypercalcemia and suppression of circulating PTHrP, in contrast to standard anti-resorptive therapies. Conclusions These findings establish HIF-2–dependent transcriptional control of PTHLH as a key mechanism underlying paraneoplastic hypercalcemia in ccRCC. Therapeutic inhibition of HIF-2 rapidly alleviates HC by suppressing PTHrP production, supporting a mechanism-driven treatment strategy. Further the study highlights HC/ PTHrP as a potential predictive biomarker of HIF-2 pathway dependence, forming the base for clinical evaluation. Citation Format: 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. Inhibition of the HIF-2α-PTHrP axis ameliorates paraneoplastic hypercalcemia in clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A037.