SMAD4 loss is associated with response to neoadjuvant chemotherapy plus hydroxychloroquine in patients with pancreatic adenocarcinoma

Autor: Nathan Bahary, Naomi Fei, Rajesh Ramanathan, Melissa E. Hogg, Sijin Wen, Brian A. Boone, Herbert J. Zeh, Amer H. Zureikat, Aatur D. Singhi, Michael T. Lotze
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Oncology
Male
030213 general clinical medicine
medicine.medical_treatment
030226 pharmacology & pharmacy
law.invention
0302 clinical medicine
Randomized controlled trial
law
Antineoplastic Combined Chemotherapy Protocols
General Pharmacology
Toxicology and Pharmaceutics
Smad4 Protein
integumentary system
General Neuroscience
General Medicine
Articles
Middle Aged
Neoadjuvant Therapy
Exact test
Treatment Outcome
embryonic structures
Adenocarcinoma
Female
biological phenomena
cell phenomena
and immunity
Public aspects of medicine
RA1-1270
medicine.drug
Carcinoma
Pancreatic Ductal
Hydroxychloroquine
medicine.medical_specialty
animal structures
RM1-950
General Biochemistry
Genetics and Molecular Biology
Article
Disease-Free Survival
03 medical and health sciences
Pancreatectomy
Internal medicine
medicine
Autophagy
Humans
Pancreas
Aged
Retrospective Studies
Chemotherapy
business.industry
Research
medicine.disease
Gemcitabine
digestive system diseases
Clinical trial
Pancreatic Neoplasms
Tumor progression
Drug Resistance
Neoplasm
Therapeutics. Pharmacology
Neoplasm Recurrence
Local
business
Zdroj: Clinical and Translational Science, Vol 14, Iss 5, Pp 1822-1829 (2021)
Clinical and Translational Science
ISSN: 1752-8054
1752-8062
Popis: SMAD4, a tumor suppressor gene, is lost in up to 60%–90% of pancreatic adenocarcinomas (PDAs). Loss of SMAD4 allows tumor progression by upregulating autophagy, a cell survival mechanism that counteracts apoptosis and allows intracellular recycling of macromolecules. Hydroxychloroquine (HCQ) is an autophagy inhibitor. We studied whether HCQ treatment in SMAD4 deficient PDA may prevent therapeutic resistance induced by autophagy upregulation. We retrospectively analyzed the SMAD4 status of patients with PDA enrolled in two prospective clinical trials evaluating pre‐operative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ (NCT01128296). More recently, a randomized trial of gemcitabine/nab‐paclitaxel +/− HCQ evaluated Evans Grade histopathologic response (NCT01978184). The effect of SMAD4 loss on response to HCQ and chemotherapy was studied for association with clinical outcome. Fisher’s exact test and log‐rank test were used to assess response and survival. Fifty‐two patients receiving HCQ with neoadjuvant chemotherapy were studied. Twenty‐five patients had SMAD4 loss (48%). 76% of HCQ‐treated patients with SMAD4 loss obtained a histopathologic response greater than or equal to 2A, compared with only 37% with SMAD4 intact (p = 0.006). Although loss of SMAD4 has been associated with worse outcomes, in the current study, loss of SMAD4 was not associated with a detriment in median overall survival in HCQ‐treated patients (34.43 months in SMAD4 loss vs. 27.27 months in SMAD4 intact, p = 0.18). The addition of HCQ to neoadjuvant chemotherapy in patients with PDA may improve treatment response in those with SMAD4 loss. Further study of the relationship among SMAD4, autophagy, and treatment outcomes in PDA is warranted.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje