Introduction: Elevated Glioma-associated Oncogene Homolog-1 (Gli1) protein expression, a downstream target of the Hedgehog (Hh) pathway, has been shown to be an independent poor prognostic factor for high-grade serous ovarian cancer (HGSOC)1. Inhibition of Hh signaling in a Gli1-overexpressed HGSOC patient-derived xenograft (PDX) inhibited tumour growth, particularly in combination with chemotherapy2. However, early phase HGSOC clinical trials of vismodegib, a potent Hh inhibitor (SMO inhibitor), were disappointing, despite 13.5% of tumours having Hh-ligand overexpression3,4. We identified one of 15 HGSOC PDX screened, to have Indian Hh ligand-overexpression, as well as bi-allelic deletion of TSC1, which has been reported to derepress the mTOR pathway, driving non-cannonical Gli1 expression5,6. We explored the effect of vismodegib and the mTOR inhibitor, everolimus, in this HGSOC PDX model.
Method: A cell-line was generated from the well-characterised PDX (identity confirmed by PDX-specific p53 mutation). In vitro response to vismodegib was assessed. qRT-PCR was performed to establish Hh-ligand and Gli1 expression with and without vismodegib treatment. A PDX was generated from this cell-line and mice randomized to in vivo treatment with vismodegib alone, cisplatin alone, vismodegib in combination with cisplatin, everolimus alone, everolimus in combination with vismodegib, or vehicle.
Results: In vitro response of the Hh-high cell-line to vismodegib was noted (EC50 3.5µM). qRT-PCR analysis revealed down-regulation of Hh-ligand and Gli1 expression following in vitro vismodegib treatment. In vivo treatment with single agent vismodegib and everolimus however, did not result in in vivo efficacy and paradoxically, the addition of vismodegib abrogated most of the efficacy of cisplatin. Combination of vismodegib and everolimus caused short-lived in vivo response in 3 of 6 mice
Conclusion: Interactions resulting from in vivo Hh and mTOR pathway inhibition are being explored. These findings may provide important insights for improved design of Hh-pathway inhibitor clinical trials in solid tumours.