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Safety and Biologic Response of Pre-operative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma
Open accessAbstract
Purpose Autophagy is a cell survival mechanism that plays a critical role in pancreatic carcinogenesis. Murine studies have previously demonstrated that treatment with the late-autophagy inhibitor chloroquine in combination with chemotherapy limited tumor growth.Methods In this phase 1/2 trial, we examined treatment with hydroxychloroquine (HCQ) and gemcitabine for patients with pancreatic adenocarcinoma. The primary endpoints were safety and tolerability, evaluated by Storer's dose escalation design. Secondary endpoints were CA 19-9 biomarker response, R0 resection rates, survival, and correlative studies of autophagy.Results Thirty-five patients were enrolled. There were no dose-limiting toxicities and no grade 4/5 events related to treatment. Nineteen patients (61 %) had a decrease in CA 19-9 after treatment. Twenty-nine patients (94 %) underwent surgical resection as scheduled, with a 77 % R0 resection rate. Median overall survival was 34.8 months (95 % confidence interval, 11.57 to not reached). Patients who had more than a 51 % increase in the autophagy marker LC3-II in circulating peripheral blood mononuclear cells had improvement in disease-free survival (15.03 vs. 6.9 months, p < 0.05) and overall survival (34.83 vs. 10.83 months, p < 0.05). No outcome differences were demonstrated in the 81 % of patients with abnormal p53 expression assessed by immunohistochemistry in the resected specimens.Conclusions Preoperative autophagy inhibition with HCQ plus gemcitabine is safe and well tolerated. Surrogate biomarker responses (CA 19-9) and surgical oncologic outcomes were encouraging. p53 status was not associated with adverse outcomes.
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“Mitophagy, the selective engulfment and degradation of mitochondria through autophagy, has also been shown to be important in PDAC tumorigenesis in mice and organoid models211”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [211]
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Metadata
- Authors
- Boone, B. A., Bahary, N., Zureikat, A. H., Moser, A. J., Normolle, D. P., Wu, W.-C., Singhi, A. D., Bao, P., Bartlett, D. L., Liotta, L. A., Espina, V., Loughran, P., Lotze, M. T., & Zeh, H. J.
- Affiliations
- University of Pittsburgh (US)
- Beth Israel Deaconess Medical Center (US)
- George Mason University (US)
- Corresponding author
- Lotze, Michael T.
- Zeh, Herbert J.
- ORCID
- Venue
- Annals of Surgical Oncology
- Published
- 2015-04-24
- Volume
- 22
- Issue
- 13
- Pages
- 4402-4410
- ISSN
- 1068-9265 (ISSN-L)
- 1534-4681
- PMC
- PMC4663459
- OpenAlex
- W2018872699
- Cited by
- 234
- References
- 52
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 24 · 2023: 21 · 2022: 23 · 2021: 37 · 2020: 32 · 2019: 20 · 2018: 27 · 2017: 18 · 2016: 8 · 2015: 2
- FWCI
- 8.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Annals of Surgical Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (L30 CA170992, R01CA181450, P30CA047904, T32CA113263)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- pancreatic ductal adenocarcinoma, autophagy inhibition, hydroxychloroquine, gemcitabine, neoadjuvant therapy, CA19-9, LC3-II, p53, R0 resection, overall survival, safety and tolerability, biomarker response
- MeSH terms
- Gemcitabine, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic, Autophagy, Deoxycytidine, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Hydroxychloroquine, Immunoenzyme Techniques, Male, Middle Aged, Neoplasm Staging, Pancreatic Neoplasms, Prognosis, Prospective Studies, Safety, Biomarkers, Survival Rate, CA-19-9 Antigen, Antirheumatic Agents
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