Abstract 2802: Development of a surrogate tissue pharmacodynamic (PD) assay for clinical use with FX-909, a novel inhibitor of the urothelial luminal lineage transcription factor peroxisome proliferator-activated receptor gamma (PPARG) (2023)

Abstract Targeting lineage-defined transcription factors with small molecules is a proven and effective therapeutic strategy, as demonstrated by estrogen and androgen receptor therapies for breast and prostate cancers. Expression of the transcription factor PPARG is associated with the luminal lineage subtype, which accounts for two-thirds of all advanced urothelial cancer (UC) patients. Taking into consideration the difficulty in obtaining sequential tumor biopsies in late-stage cancer patients, the feasibility of an accessible, less invasive surrogate tissue to evaluate PD biomarkers that support proof of mechanism of drug action, clinical proof of concept and ultimately the selection of optimal dosing, was evaluated. FX-909, a covalent PPARG inverse agonist is projected to initiate Phase 1 clinical studies in 2023 aimed at serving patients with advanced UC. In vivo UMUC9 UC xenograft model efficacy studies were performed in NGC mice treated with FX-909 at 0.03 mg/kg to 1 mg/kg BID for 21 days. Preclinical pharmacology studies were performed in Sprague Dawley male rats treated with FX-909 at 3, 10 and 30 mg/kg BID for 28 days to investigate potential biomarkers associated with on-target effects of FX-909. Ex vivo cultured human skin explant models derived from donors undergoing abdominoplasty procedures were utilized to bridge the interspecies translational gap to test the effect of FX-909 on human tissue. Tumor tissue from mouse xenografts, as well as inguinal white adipose tissue (iWAT) and skin tissue were collected. Changes in known PPARG target gene expression were measured by qPCR and transcriptomic differences by RNA-Seq. A subset of genes exhibited similar dose dependent trends in rat skin and adipose tissues, including known PPARG targets such as, Rbp4, Cidea and Ivd, fitting the expected decreasing exponential curve. Overall, 30% of all genes that responded to FX-909 treatment in skin displayed a similar dose-dependent response profile in iWAT with median Pearson correlations ranging from r=0.33-0.92, exemplified by the Ivd correlation, r=0.91 [p-value&amp;lt;0.0002], where approximately 50% gene suppression was observed at the lowest dose level. Importantly in UMUC9 models, dose-dependent suppression of FABP4/Fabp4 target gene showed strong correlation [r=0.98, p-value=0.003] between tumor and skin tissues. Based on these preclinical data and confirmatory experiments in the ex vivo setting, a novel FX-909 signature is under development to predict target modulation in the tumor. The consistent correlation of PPARG target gene suppression in tumor and normal tissues across species provide a strong rationale for a surrogate biospecimen collection, such as a skin punch biopsy, to establish the PK/PD relationship between the dose and response to FX-909 in the clinic. Citation Format: Jennifer A. Mertz, Stefan A. Kirov, Kaylyn E. Williamson, Marton Munz, Robert J. Sims, Michaela Bowden. Development of a surrogate tissue pharmacodynamic (PD) assay for clinical use with FX-909, a novel inhibitor of the urothelial luminal lineage transcription factor peroxisome proliferator-activated receptor gamma (PPARG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2802.