P2, N=20, Recruiting, Melanoma Institute Australia | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2025 --> Jun 2026

P2, N=660, Active, not recruiting, St. Jude Children's Research Hospital | Trial completion date: Jan 2028 --> Oct 2031 | Trial primary completion date: Nov 2025 --> Oct 2028

Taken together, these findings establish a mechanistic foundation for a proposed therapeutic optimization strategy: Reducing vismodegib dosing while leveraging its inhibition-driven elevation of simvastatin systemic/tissue exposure, thereby mitigating dose-limiting skeletal toxicity while maintaining anti-tumor efficacy. This mechanism-based strategy provides a clinically actionable framework for pediatric medulloblastoma with urgent unmet therapeutic needs.

Rarely, this condition is related to a suppressor of fused gene mutation, which occurs downstream from Smoothened, and is unresponsive to Smoothened inhibitors including vismodegib and sonidegib. Genetic testing was negative for patched 1 and patched 2 mutations but positive for a heterozygous suppressor of fused mutation. Patients with basal cell nevus syndrome should be treated with surgical excision, counseled on sun protection, screened and monitored for complications, and treated with vismodegib (if associated with patched 1 mutation) or itraconazole (if associated with suppressor of fused mutation).

P2, N=20, Terminated, European Organisation for Research and Treatment of Cancer - EORTC | Trial completion date: Dec 2025 --> Sep 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Jun 2025; Poor accrual

Solasodine inhibited the proliferation of AGS and MKN74 gastric cancer cells and regulated cell cycle (Cyclin D1 and p27) and apoptosis (Bax and Bcl-2) markers in a dose-dependent manner, consistent with the Gli1/2 inhibitor Gant61 but not the Smo inhibitor vismodegib...Moreover, solasodine inhibited Gli1 rather than Smo expression in Hh signaling overexpressed Ptch (-/-) MEF cells. Our findings demonstrate that solasodine inhibits gastric cancer proliferation by targeting Hh/Gli1 signaling, underscoring its potential as a potent agent for prevention and/or inhibition of gastric cancer.

Inhibition of SMO through genetic knockdown or with a potent, selective SMO inhibitor, Glasdegib, reduces the survival of cells from nonresponder patients. Notably, SMO inhibition also sensitizes TKI-nonresponder stem/progenitor cells to Bostutinib, a second-generation TKI, both in vitro and in a patient-derived xenotransplantation (PDX) model. These findings present a promising therapeutic target and a model for curative combination therapies in stem-cell-driven cancers.

Vismodegib was well tolerated with mainly grade 1-2 toxicities, but it did not meet the primary end point. Select patients with specific SMO and PTCH1 alterations had notable responses, warranting further comprehensive molecular analyses to elucidate resistance mechanisms.

Accordingly, we evaluated the sensitivity of the organoids to the Sonic Hedgehog inhibitor vismodegib and Yes-associated protein 1 inhibitor verteporfin, both of which demonstrated potent in vitro antitumor activity in organoid cultures. This model offers a valuable preclinical platform for investigating the molecular pathology of this rare malignancy and accelerating the development of targeted therapies.

P2, N=82, Recruiting, University Hospital, Lille | Not yet recruiting --> Recruiting | Trial completion date: Jul 2028 --> Jun 2029 | Trial primary completion date: Jul 2028 --> Jun 2029

Cell cycle-related proteins in NSCLC cells were decreased by veratramine treatment. Veratramine suppresses lung cancer cell growth by inhibiting the Hh signaling pathway, suggesting its potential applicability in the treatment of NSCLC.

Screening of SAG1.3 derivatives identified compound 11 that competed with BODIPY-cyclopamine binding at different FZDs and inhibited WNT-induced FZD dynamics and β-catenin signaling in HEK293 cells. Furthermore, compound 11 blocked WNT-3A-induced Lgr5 gene expression in human primary hepatocyte spheroids and reduced the viability of RNF43-mutated but not RNF43-wildtype pancreatic cancer cells. Based on our data, we suggest that compound 11 acts on FZDs to limit WNT- and WNT-surrogate-induced receptor dynamics providing a valid proof-of-concept for targeting FZDs with small molecule compounds.