Targeting of the Hedgehog/GLI and mTOR pathways in advanced pancreatic cancer,a phase 1 trial of Vismodegib and Sirolimus combination |
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| Affiliation: | 1. Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA;2. Department of Medical Oncology, Department of Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55902, USA;3. Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin, Madison, WI, USA;4. Department of Laboratory Medicine Pathology, Mayo Clinic, Rochester, MN, USA;5. Department of Radiology, Mayo Clinic, Rochester, MN, USA;6. Division of Hematology-Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA;7. Division of Hematology-Oncology, The George Washington University, Washington, DC, USA;8. Division of Nuclear Medicine, Mayo Clinic, Rochester, MN, USA;9. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA;1. Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan;2. Department of Surgery, Sendai City Medical Center, Sendai, Japan;3. Department of Pathology, Sendai City Medical Center, Sendai, Japan;4. Natori-Chuo-Clinic, Natori, Japan;1. Department of Pathology, Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital, CSIC, University of Sevilla, Seville 41013, Spain;2. Department of Pathology, La Merced Hospital, AGS Osuna, Osuna, Spain;1. Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, California;2. NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg;3. Department of Radiation Oncology, Centre François Baclesse, Esch-sur-Alzette, Luxembourg;2. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;3. Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas;4. Département de Pathologie et de Biopathologie, Centre Jean Perrin, Clermont-Ferrand, France; and EA 4766, ERTICa, Université d’Auvergne, Clermont-Ferrand, France;6. Inserm Unit 1030, DHU TORINO, Gustave Roussy and University Paris Sud, France;1. Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China;2. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China |
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| Abstract: | Background/ObjectivesPreclinical 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.MethodsCohort 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.ResultsNine 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.ConclusionsThe 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. |
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| Keywords: | Pancreatic cancer Hedgehog mTOR Sirolimus Vismodegib |
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