Targeting of the Hedgehog/GLI and mTOR pathways in advanced pancreatic cancer, a phase 1 trial of Vismodegib and Sirolimus combination

Ryan M. Carr, Narjust Duma, Angela L. McCleary-Wheeler, Luciana L. Almada, David L. Marks, Rondell P. Graham, Thomas C. Smyrk, Val Lowe, Mitesh J. Borad, George Kim, Geoffrey B. Johnson, Jacob B. Allred, Jun Yin, Vun Sin Lim, Tanios Bekaii-Saab, Wen We Ma, Charles Erlichman, Alex A. Adjei, Martin E. Fernandez-Zapico

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background/Objectives: Preclinical data indicated a functional and molecular interaction between Hedgehog (HH)/GLI and PI3K-AKT-mTOR pathways promoting pancreatic ductal adenocarcinoma (PDAC). A phase I study was conducted of Vismodegib and Sirolimus combination to evaluate maximum tolerated dose (MTD) and preliminary anti-tumor efficacy. Methods: Cohort I included advanced solid tumors patients following a traditional 3 + 3 design. Vismodegib was orally administered at 150 mg daily with Sirolimus starting at 3 mg daily, increasing to 6 mg daily at dose level 2. Cohort II included only metastatic PDAC patients. Anti-tumor efficacy was evaluated every two cycles and target assessment at pre-treatment and after a single cycle. Results: Nine patient were enrolled in cohort I and 22 patients in cohort II. Twenty-eight patients were evaluated for dose-limiting toxicities (DLTs). One DLT was observed in each cohort, consisting of grade 2 mucositis and grade 3 thrombocytopenia. The MTD for Vismodegib and Sirolimus were 150 mg daily and 6 mg daily, respectively. The most common grade 3–4 toxicities were fatigue, thrombocytopenia, dehydration, and infections. A total of 6 patients had stable disease. No partial or complete responses were observed. Paired biopsy analysis before and after the first cycle in cohort II consistently demonstrated reduced GLI1 expression. Conversely, GLI and mTOR downstream targets were not significantly affected. Conclusions: The combination of Vismodegib and Sirolimus was well tolerated. Clinical benefit was limited to stable disease in a subgroup of patients. Targeting efficacy demonstrated consistent partial decreases in HH/GLI signaling with limited impact on mTOR signaling. These findings conflict with pre-clinical models and warrant further investigations.

Original languageEnglish (US)
Pages (from-to)1115-1122
Number of pages8
JournalPancreatology
Volume20
Issue number6
DOIs
StatePublished - Sep 2020

Keywords

  • Hedgehog
  • Pancreatic cancer
  • Sirolimus
  • Vismodegib
  • mTOR

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Gastroenterology

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