Autophagy Inhibition in Pancreatic Adenocarcinoma

Boone, Brian A.; Zeh, Herbert J.; Bahary, Nathan

doi:10.1016/j.clcc.2017.10.013

Cited by 34 publications

(31 citation statements)

References 79 publications

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“…Furthermore, consistent HCQ plasma concentrations were not achieved within our trial population and large interpatient variability in HCQ levels has been demonstrated in a recent clinical trial, in combination with everolimus, in renal cell cancer [38]. Together, this perhaps explains the lack of correlation with in vitro assessment; an issue that has been previously demonstrated within solid tumours [46][47][48]. A major drawback to HCQ dose optimisation and ultimate achievement of autophagy inhibition is the risk of adverse effects when using higher doses for longer durations, particularly retinopathy [39,49].…”

Section: Discussionmentioning

confidence: 54%

A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease

et al. 2020

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In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment 'successes' was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment 'successes', molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in 'success' rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the 'success' rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.

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Section: Discussionmentioning

confidence: 54%

A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease

et al. 2020

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“…It has been reported that autophagy is related to various malignant tumors. For example, the decline in autophagy activity is associated with the occurrence and development of pancreatic cancer, breast cancer, cervical squamous cell carcinoma, colon cancer and ovarian cancer, demonstrating that abnormal expression of autophagy-related genes have a close correlation with the occurrence of tumor (20–24). At present, there are few reports on the correlation of occurrence of EM with LC3 and Beclin1.…”

Section: Discussionmentioning

confidence: 99%

Expression and significance of autophagy genes LC3, Beclin1 and MMP-2 in endometriosis

Sui

Sun

et al. 2018

Exp Ther Med

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Expression of autophagy-related proteins, microtubule-associated protein light chain 3 (LC3) and Beclin1, and matrix metalloproteinase-2 (MMP-2) was investigated in serum and peritoneal fluid of patients with endometriosis (EM). The messenger ribonucleic acid (mRNA) expression levels of MMP-2, LC3 and Beclin1 in endometrial tissues of EM patients and correlation of these genes with EM and their significance were evaluated. The serum, peritoneal fluid and endometrial tissues of 84 patients treated in The First Affiliated Hospital of Qiqihar Medical University (Qiqihar, China) from March 2016 to March 2017 were collected. The serum, peritoneal fluid and endometrial tissues of 42 EM patients were used as the experimental group, while those of 42 non-EM patients were used as the control group. The levels of LC3, Beclin1 and MMP-2 in serum and peritoneal fluid of EM patients and non-EM patients were quantitatively detected via enzyme-linked immunosorbent assay (ELISA), followed by comparative analysis based on data in both groups. In addition, mRNA expression of LC3, Beclin1 and MMP-2 in the endometrium in both groups were detected via reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and differences in expression of these genes between the groups were analyzed and evaluated. Correlation of LC3, Beclin1 and MMP-2 with EM was explored. Results of ELISA showed that levels of LC3 and Beclin1 in the EM group were significantly lower than those in the control group, while levels of MMP-2 in serum and peritoneal fluid of the EM group were significantly higher than those in the control group (P<0.05). Results of RT-qPCR revealed that mRNA expression of LC3 and Beclin1 in the endometrium of patients in the EM group were obviously decreased compared with those in the control group, while the expression of MMP-2 was high, and differences in expression were statistically significant (P<0.05). The expression of MMP-2 is high, and expression of LC3 and Beclin1 is low in serum, peritoneal fluid and endometrium of EM patients, and investigating the expression of MMP-2, LC3 and Beclin1 in EM is helpful to further clarify the pathogenesis of EM, and guide the clinical diagnosis and treatment.

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“…Autophagy is elevated in pancreatic ductal adenocarcinomas (PDAs) and pancreatic tumors, with higher levels of autophagic flux associated with worse overall survival (OS). [2][3][4][5] Preclinical and early clinical studies support the notion that targeting autophagy may be a useful strategy in treating PDA. 2,6-8 9,10 There is emerging evidence that autophagy inhibition can also enhance antitumor immunity, but to date, no clinical data support an associated increase in inflammatory cells within the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients

Zeh

Bahary

Boone

et al. 2020

Clinical Cancer Research

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Purpose: We hypothesized that autophagy inhibition would increase response to chemotherapy in the preoperative setting for patients with pancreatic adenocarcinoma. We performed a randomized controlled trial to assess the autophagy inhibitor hydroxychloroquine in combination with gemcitabine and nab-paclitaxel. Experimental Design: Participants with potentially resectable tumors were randomized to two cycles of nab-paclitaxel and gemcitabine (PG) alone or with hydroxychloroquine (PGH), followed by resection. The primary endpoint was histopathologic response in the resected specimen. Secondary clinical endpoints included CA 19-9 serum biomarker response and margin negative R0 resection. Exploratory endpoints included markers of autophagy, immune infiltrate, and serum cytokines. Results: Thirty-four patients in the PGH arm and 30 in the PG arm were evaluable for the primary endpoint. The PGH arm demonstrated statistically improved Evans grade histopathologic responses (P = 0.00016), compared to control. In patients with elevated CA 19-9, a return to normal was associated with improved overall and recurrence-free survival (P < 0.0001). There were no differences in serious adverse events between arms and chemotherapy dose number was equivalent. The PGH arm had greater evidence of autophagy inhibition in their resected specimens (increased SQSTM1, P = 0.027, as well as increased immune cell tumor infiltration, P = 0.033). OS (P = 0.59) and RFS (P = 0.55) did not differ between the two arms. Conclusions: The addition of hydroxychloroquine to preoperative gemcitabine and nabpaclitaxel chemotherapy in patients with resectable pancreatic adenocarcinoma resulted in greater pathological tumor response, improved serum biomarker response, and evidence of autophagy inhibition and immune activity. Research.

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Autophagy Inhibition in Pancreatic Adenocarcinoma

Cited by 34 publications

References 79 publications

A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease

A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease

Expression and significance of autophagy genes LC3, Beclin1 and MMP-2 in endometriosis

A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients

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