The clinical value of using chloroquine or hydroxychloroquine as autophagy inhibitors in the treatment of cancers: A systematic review and meta-analysis.
ABSTRACT: BACKGROUND:Autophagy is a mechanism which relies on lysosomes for clearance and recycling of abnormal proteins or organelles. Many studies have demonstrated that the deregulation of autophagy is associated with the development of various diseases including cancer. The use of autophagy inhibitors is an emerging trend in cancer treatment. However, the value of autophagy inhibitors remains under debate. Thus, a meta-analysis was performed, aiming to evaluate the clinical value of autophagy-inhibitor-based therapy. METHODS:We searched for clinical studies that evaluated autophagy-inhibitor-based therapy in cancer. We extracted data from these studies to evaluate the relative risk (RR) of overall response rate (ORR), 6-month progression-free survival (PFS) rate, and 1-year overall survival (OS) rate. RESULTS:Seven clinical trials were identified (n?=?293). Treatments included 2 combinations of hydroxychloroquine and gemcitabine, 1 combination of hydroxychloroquine and doxorubicin, 1 combination of chloroquine and radiation, 2 combinations of chloroquine, temozolomide, and radiation, and 1 hydroxychloroquine monotherapy. Autophagy-inhibitor-based therapy showed higher ORR (RR: 1.33, 95% confidence interval [CI]: 0.95-1.86, P?=?.009), PFS (RR: 1.72, 95% CI: 1.05-2.82, P?=?.000), OS (RR: 1.39, 95% CI: 1.11-1.75, P?=?.000) values than the therapy without inhibiting autophagy. CONCLUSION:This meta-analysis showed that autophagy-inhibitor-based therapy has better treatment response compared to chemotherapy or radiation therapy without inhibiting autophagy, which may provide a new strategy for the treatment of cancers.
Project description:BACKGROUND:Immune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors. METHODS:We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity. RESULTS:Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P?<?.001), OS (HR, 0.68; 95% CI 0.53-0.87; P?=?.002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P?<?.001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P?<?.001); types of checkpoint inhibitor for ORR (P?<?.001); histology (P?=?.025), age (P?=?.038), gender (P?<?.001), and types of checkpoint inhibitor (P?<?.001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P?=?.007), AEs leading to treatment discontinuation (RR, 1.29; P?=?.022), serious AEs (RR 1.70; P?=?.006), immune mediated AEs of any grade (RR, 2.37; P?<?.001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P?<?.001). CONCLUSIONS:PD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.
Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network. Overall design: RNA-seq of high and low progression free survival patients
Project description:BACKGROUND:Combination therapy based on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is an emerging trend in cancer treatment, but the clinical value of EGFR-TKIs combination therapy remains controversial. Thus, we conducted a comprehensive analysis of randomized controlled trials (RCTs) comparing EGFR-TKIs combination therapies with monotherapies, aiming to evaluate the safety and efficacy of EGFR-TKIs based combination therapy and to find a more beneficial combination strategy. METHODS:We searched for clinical studies that evaluated EGFR-TKIs combination therapy in cancer. We extracted data from these studies to evaluate the relative risk (RR) of overall response rate (ORR) and grade 3/4 treatment-related adverse events (AEs), the hazard ratios (HRs) of overall survival (OS), and progression-free survival (PFS). RESULTS:Fourteen RCTs were identified (n = 3774). Treatments included combinations of EGFR-TKIs and chemotherapy, combinations of EGFR-TKIs and radiotherapy, and combinations of EGFR-TKIs and bevacizumab. EGFR-TKIs combination therapies showed higher ORR [RR: 1.62; 95% confidence interval (95% CI):1.16-2.26; P = .005], PFS (HR: 0.76; 95% CI: 0.64-0.89; P = .001), and OS (HR: 0.88; 95% CI: 0.79-0.97; P = .013) values than monotherapies. However, higher grade 3/4 treatment-related AEs (RR: 1.79; 95% CI: 1.02-3.15; P = .000) were observed in combination therapy than in monotherapy. CONCLUSION:Our pooled analysis and subgroup analysis results showed that the addition of chemotherapy to EGFR-TKIs better benefits PFS and safety. Adding bevacizumab was associated with better ORR and OS. The efficacy and safety of a bevacizumab-EGFR-TKIs-chemotherapy combination should be investigated further.
Project description:<h4>Background</h4>Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in these patients.<h4>Methods</h4>Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). Demographic data, treatment regimens, objective response rate (ORR), median progression-free survival (PFS), median overall survival (OS), 6-months PFS rate, 1-year OS and grade 3/4 toxicities were extracted. We also compared the main outcomes of interest between bevacizumab and other angiogenesis inhibitors. All analyses were performed using Comprehensive Meta Analysis software (Version 2.0).<h4>Results</h4>A total of 842 patients were included for analysis: 343 patients were treated with bevacizumab, 386 with other angiogenesis inhibitors and 81 with thalidomide. The pooled ORR, 6-months PFS, and 1-year OS for recurrent GBM patients receiving angiogenesis inhibitors was 20.1%, 19.5% and 29.3%, respectively. The use of single agent bevacizumab in recurrent GBM significantly improved ORR and 6-months PFS when compared to other angiogenesis inhibitors [relative risk (RR) 2.93, 95% CI 1.38-6.21; p = 0.025; and RR 2.36 95% CI 1.46-3.82; p<0.001, respectively], while no significant difference in 1-year OS was found between the two groups (p = 0.07). when compared to thalidomide, bevacizumab treatment in recurrent GBM significantly improved ORR (RR 6.8, 95%CI: 2.64-17.6, p<0.001), but not for 6-months PFS (p = 0.07) and 1-year OS (p = 0.31). As for grade 3/4 toxicities, the common toxicity was hypertension with pooled incidence of 12.1%, while high-grade thromboembolic events (2.2%), hemorrhage (5.1%) and GI perforation (2.8%) associated with angiogenesis inhibitors were relatively low.<h4>Conclusions</h4>In comparison with other angiogenesis inhibitors and thalidomide, the use of single agent bevacizumab as salvage treatment for recurrent GBM patients improve ORR and 6-months PFS, but not for 1-year OS.
Project description:Macroautophagy can promote cellular survival or death depending on the cellular context and its extent. We hypothesized that autophagy induction would synergize with a therapeutic agent targeting the autophagic cargo. To test this hypothesis, we treated breast cancer MDA-MB-231 cells with tamoxifen (TMX), which induces autophagy through an estrogen receptor-independent pathway. Induction of autophagy reduced cellular levels of RRM2, a subunit of ribonucleotide reductase (RR), the rate limiting enzyme in the production of deoxyribonucleotide triphosphates (dNTPs). This autophagy inducer was combined with COH29, an inhibitor developed in our laboratory that targets RR through a novel mechanism. The combination therapy showed synergistic effects on cytotoxicity in vitro and in an in vivo xenograft model. This cytotoxicity was blocked by knockdown of the autophagy protein ATG5 or addition of chloroquine, an autophagy inhibitor. The combined therapy also induced dNTP depletion and massive genomic instability, leading us to hypothesize that combining autophagy induction with RR inhibition can lead to mitotic catastrophe in rapidly dividing cells. We propose that this TMX + COH29 combined therapy may have clinical benefit. Furthermore, autophagy induction may be a general mechanism for augmenting the effects of chemotherapeutic agents.
Project description:Background: Controversy exists regarding whether EGFR-targeted therapy combined with GEMOX (gemcitabine and oxaliplatin) provides additional benefits over GEMOX alone for biliary tract cancer patients. Therefore, this meta-analysis of randomized controlled trials (RCTs) was performed to assess the efficacy and safety of the GEMOX + EGFR-targeted regimen, and subgroup analysis was conducted to identify groups that might benefit from targeted therapy. Methods: The PubMed, Cochrane Library, and ClinicalTrials.gov registries were searched for published studies. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were pooled using a fix-effect model. Risk-ratios (RRs) were used to analyse the objective response rate (ORR) and adverse events. Results: Four RCTs were assessed. GEMOX + EGFR-targeted therapy significantly improved PFS (HR = 0.80, 95% CI 0.66-0.94, P = 0.03) and was associated with a better ORR (RR = 1.52, 95% CI 1.13-2.04, P = <0.01), whereas the TKI group achieved a better ORR in subgroup analysis. Patients with cholangiocarcinoma responded well to the GEMOX + EGFR-targeted regimen, leading to a better ORR (RR = 1.78, 95% CI 1.21-2.61, P = <0.01). Unfortunately, PFS benefits were not translated into OS benefits (HR = 0.92, 95% CI 0.75-1.08, P = 0.39). Conclusion: GEMOX + EGFR-targeted therapy is a considerable and tolerable treatment option for patients with advanced BTCs, improving both PFS and ORR but not prolonging patient survival. Patients with cholangiocarcinoma would benefit the most from EGFR-targeted therapy.
Project description:This meta-analysis was designed to compare the efficacy and safety of gemcitabine-based regimens for the treatment advanced breast cancer (ABC). Altogether 15 studies involving 8195 ABC patients were retrieved for analysis. Compared with non-gemcitabine-based chemotherapies, patients receiving gemcitabine-based therapy exhibited better overall survival (OS), progression free survival (PFS), and objective response rate (ORR) (HR = 1.12, 95% CI 1.05 to 1.19; HR = 1.16, 95% CI 1.03 to 1.30; HR = 1.14, 95% CI 1.04 to 1.24). Grade 3/4 hematologic toxicity was significantly high but manageable in gemcitabine-based groups. Subgroup analysis revealed that patients with first-line gemcitabine-based chemotherapy had better OS (HR = 1.19, 95% CI 1.07 to 1.32), PFS (HR = 1.17, 95% CI 1.08 to 1.27), and ORR (RR = 1.16, 95% CI 1.02 to 1.32). In addition, additional gemcitabine chemotherapy also showed better OS (HR = 1.17, 95% CI 1.06 to 1.30), PFS (HR = 1.20, 95% CI 1.11 to 1.30) and ORR (RR = 1.23, 95% CI 1.06 to 1.42) than gemcitabine replacement therapy. Furthermore, patients receiving gemcitabine-taxanes-based regimens had better OS (HR = 1.17, 95% CI 1.06 to 1.28), PFS (HR = 1.12, 95% CI 1.04 to 1.20) and ORR (RR = 1.17, 95% CI 1.01 to 1.35) than patients with non-gemcitabine-taxanes-based chemotherapy. These findings indicate that gemcitabine combination regimens could serve as a promising regimen for ABC patients, though increased hematologic toxicity should be considered with caution.
Project description:Chloroquine (CQ) is an antimalarial drug and late-stage inhibitor of autophagy currently FDA-approved for use in the treatment of rheumatoid arthritis and other autoimmune diseases. Based primarily on its ability to inhibit autophagy, CQ and its derivative, hydroxychloroquine, are currently being investigated as primary or adjuvant therapy in multiple clinical trials for cancer treatment. Oncogenic RAS has previously been shown to regulate autophagic flux, and cancers with high incidence of RAS mutations, such as pancreatic cancer, have been described in the literature as being particularly susceptible to CQ treatment, leading to the hypothesis that oncogenic RAS makes cancer cells dependent on autophagy. This autophagy "addiction" suggests that the mutation status of RAS in tumors could identify patients who would be more likely to benefit from CQ therapy. Here we show that RAS mutation status itself is unlikely to be beneficial in such a patient selection because oncogenic RAS does not always promote autophagy addiction. Moreover, oncogenic RAS can have opposite effects on both autophagic flux and CQ sensitivity in different cells. Finally, for any given cell type, the positive or negative effect of oncogenic RAS on autophagy does not necessarily predict whether RAS will promote or inhibit CQ-mediated toxicity. Thus, although our results confirm that different tumor cell lines display marked differences in how they respond to autophagy inhibition, these differences can occur irrespective of RAS mutation status and, in different contexts, can either promote or reduce chloroquine sensitivity of tumor cells.
Project description:BACKGROUND:Hydroxychloroquine or chloroquine with or without azithromycin have been widely promoted to treat coronavirus disease 2019 (COVID-19) following early in vitro antiviral effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). OBJECTIVE:The aim of this systematic review and meta-analysis was to assess whether chloroquine or hydroxychloroquine with or without azithromycin decreased COVID-19 mortality compared with the standard of care. DATA SOURCES:PubMed, Web of Science, Embase Cochrane Library, Google Scholar and MedRxiv were searched up to 25 July 2020. STUDY ELIGIBILITY CRITERIA:We included published and unpublished studies comparing the mortality rate between patients treated with chloroquine or hydroxychloroquine with or without azithromycin and patients managed with standard of care. PARTICIPANTS:Patients ?18 years old with confirmed COVID-19. INTERVENTIONS:Chloroquine or hydroxychloroquine with or without azithromycin. METHODS:Effect sizes were pooled using a random-effects model. Multiple subgroup analyses were conducted to assess drug safety. RESULTS:The initial search yielded 839 articles, of which 29 met our inclusion criteria. All studies except one were conducted on hospitalized patients and evaluated the effects of hydroxychloroquine with or without azithromycin. Among the 29 articles, three were randomized controlled trials, one was a non-randomized trial and 25 were observational studies, including 11 with a critical risk of bias and 14 with a serious or moderate risk of bias. After excluding studies with critical risk of bias, the meta-analysis included 11 932 participants for the hydroxychloroquine group, 8081 for the hydroxychloroquine with azithromycin group and 12 930 for the control group. Hydroxychloroquine was not significantly associated with mortality: pooled relative risk (RR) 0.83 (95% CI 0.65-1.06, n = 17 studies) for all studies and RR = 1.09 (95% CI 0.97-1.24, n = 3 studies) for randomized controlled trials. Hydroxychloroquine with azithromycin was associated with an increased mortality (RR = 1.27; 95% CI 1.04-1.54, n = 7 studies). We found similar results with a Bayesian meta-analysis. CONCLUSION:Hydroxychloroquine alone was not associated with reduced mortality in hospitalized COVID-19 patients but the combination of hydroxychloroquine and azithromycin significantly increased mortality.