PTHrP-associated gene programs in cancer cachexia and hypercalcemia and therapeutic targeting with anti-PTHrP antibody.

e16413 Background: Parathyroid hormone-related protein (PTHrP), a ligand of parathyroid hormone receptor-1 (PTH1R) encoded by PTHLH , is abundantly secreted by diverse cancers and mediates tumor progression and malignancy-associated hypercalcemia, making it an attractive therapeutic target. In pancreatic cancer (PC), PTHLH is frequently co-amplified with KRAS and promotes disease progression and cachexia through disruption of adipose de novo lipogenesis. However, PTHrP-associated gene programs relevant to cancer cachexia and hypercalcemia remain poorly defined. This study investigated PTHrP-associated genes and evaluated the effects of the PTHrP-targeting antibody BGM-2121 on tumor growth, cachexia, and hypercalcemia. Methods: The prognostic impact of PTHLH expression across cancer types was assessed using the Kaplan–Meier Plotter database. Correlations between PTHLH and selected gene expression profiles in pancreatic cancer were analyzed across two independent cohorts (n = 177 and 96) from cBioPortal. The antitumor efficacy of BGM-2121 was evaluated in PC cell line–derived xenograft (CDX) models and patient-derived xenograft (PDX) models. The effects of BGM-2121 on cancer-associated cachexia and hypercalcemia were assessed in relevant animal models. Results: High PTHLH mRNA expression was significantly associated with poor overall survival in over 350 patients with lung, liver, gastric, or colorectal cancers (p < 0.002) and with inferior overall and disease-free survival in pancreatic cancer (p < 0.0001). Co-expression analyses from two independent cohorts identified significant positive correlations between PTHLH and cachexia- or hypercalcemia-associated genes, including ACKR3/CXCR7 , ANGPTL2 , IL11 , TGFB1 , MMP2 , and MMP14 . Several of these genes have been reported as downstream targets of PTHrP signaling, supporting a functional role of PTHrP in cancer-associated cachexia and hypercalcemia. BGM-2121 treatment demonstrated significant antitumor activity in two CDX models (CFPAC-1 and BxPC3) and two PDX models of PC. In 786-O xenografts, BGM-2121 significantly suppressed cachexia and normalized serum calcium levels. Conclusions: These findings define PTHrP-associated gene programs linked to cancer cachexia and hypercalcemia and demonstrate the therapeutic potential of PTHrP blockade. The PTHrP-targeting antibody BGM-2121 suppresses tumor growth and alleviates systemic complications in preclinical models, supporting PTHrP as a promising target for cancers with aggressive progression and metabolic dysregulation.