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• W4307910080 abstract "Background: Small molecule targeting of cell lineage-defining transcription factors is a demonstrated and effective therapeutic strategy in oncology, exemplified by estrogen receptor (ER) agents in luminal breast cancer. Two-thirds of advanced UC is classified as luminal and overexpression of PPARG is characteristic of this molecular subtype. Currently, there is a poor understanding of how recurrent missense mutations in PPARG and its obligate heterodimer retinoid X receptor alpha (RXRA) impact PPARG function; previous tool compounds designed to inhibit PPARG have minimal phenotypic activity in UC cell lines. Material and Methods: The PPARG inhibitor FTX-6746 was evaluated in UC cell lines including UMUC9 (PPARG amplification) and HT1197 (RXRA-S427F hotspot mutation), which activate PPARG by different genetic mechanisms. In vitro analyses included clonogenic growth assays and assessment of target gene modulation after treatment. in vivo studies were performed in NCG or Balb/C nude mice with oral administration of FTX-6746 at doses indicated below. Results: Our biochemical studies indicate that patient-derived missense mutations in PPARG and RXRA bias an active conformation of PPARG, mimicking an agonist-bound state. Addressing the limitations of previous tool compounds, we discovered novel inhibitors that drive a powerful repressive conformation of PPARG with high specificity (>100X selective over PPARA/ PPARD). This results in robust PPARG target gene silencing in cells (IC50 = 5 nM), and in vitro growth inhibition preferentially observed in cell lines with activated PPARG signaling. Tumor growth inhibition or regression was observed in two xenograft models of UC at well-tolerated oral doses with no tumor regrowth upon cessation of treatment. Treatment of UMUC9 xenograft tumors with 3, 10, 30 and 60 mg/kg twice daily of FTX-6746 resulted in up to 80% target gene suppression in tumor tissue at day 2 and up to >100% tumor growth inhibition at day 21. Similar efficacy was observed in HT1197 xenograft studies treated with 30 and 60 mg/kg twice daily of FTX-6746, with >45% target gene suppression at day 2 and 85–112% tumor growth inhibition at day 42.Tabled 1ModelDose (mg/kg)Schedule%Tumor Growth Inhibition%Target Gene Suppression (D2)UMUC93BID*205916UMUC910BID*2070NDUMUC930BID*208373UMUC930BID*2110580UMUC960BID*21108NDHT119730BID*428546HT119760BID*4211259 Open table in a new tab Conclusions: These collective results suggest that PPARG is a lineage-defining transcription factor in UC and small molecule PPARG inhibition will be an effective therapy for patients with advanced urothelial cancer harboring the luminal subtype. Conflict of interest: Ownership: All authors are shareholders in Flare Therapeutics." @default.
• W4307910080 created "2022-11-06" @default.
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• W4307910080 date "2022-10-01" @default.
• W4307910080 modified "2023-10-05" @default.
• W4307910080 title "Novel inhibitors of the luminal lineage transcription factor peroxisome proliferator-activated receptor gamma (PPARG) durably eradicate tumors in urothelial cancer (UC) animal models" @default.
• W4307910080 doi "https://doi.org/10.1016/s0959-8049(22)00889-9" @default.
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