Targeting of the Hedgehog/GLI and mTOR pathways in advanced pancreatic cancer, a phase 1 trial of Vismodegib and Sirolimus combination.
Adult
Aged
Anilides
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Biopsy
Carcinoma, Pancreatic Ductal
/ drug therapy
Drug Therapy, Combination
Female
Hedgehog Proteins
/ antagonists & inhibitors
Humans
Immunosuppressive Agents
/ adverse effects
Male
Maximum Tolerated Dose
Middle Aged
Negative Results
Neoplasm Metastasis
Pancreatic Neoplasms
/ drug therapy
Pyridines
/ administration & dosage
RNA, Neoplasm
/ chemistry
Signal Transduction
/ drug effects
Sirolimus
/ adverse effects
TOR Serine-Threonine Kinases
/ drug effects
Treatment Outcome
Hedgehog
Pancreatic cancer
Sirolimus
Vismodegib
mTOR
Journal
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
ISSN: 1424-3911
Titre abrégé: Pancreatology
Pays: Switzerland
ID NLM: 100966936
Informations de publication
Date de publication:
Sep 2020
Sep 2020
Historique:
received:
17
04
2020
revised:
19
06
2020
accepted:
20
06
2020
pubmed:
12
8
2020
medline:
27
8
2021
entrez:
12
8
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND/OBJECTIVES
OBJECTIVE
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
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
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
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.
Identifiants
pubmed: 32778368
pii: S1424-3903(20)30213-1
doi: 10.1016/j.pan.2020.06.015
pii:
doi:
Substances chimiques
Anilides
0
Hedgehog Proteins
0
HhAntag691
0
Immunosuppressive Agents
0
Pyridines
0
RNA, Neoplasm
0
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Sirolimus
W36ZG6FT64
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1115-1122Informations de copyright
Copyright © 2020. Published by Elsevier B.V.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declared no conflicts with this submission.