A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients

Arnaout, Angel; Robertson, Susan J.; Pond, Gregory R.; Lee, Hoyun; Jeong, Ahwon; Ianni, Luisa; Kroeger, Lynne; Hilton, John; Coupland, Stuart G.; Gottlieb, Chloe; Hurley, Bernard; McCarthy, Anne Marie; Clemons, Mark

doi:10.1007/s10549-019-05381-y

Cited by 58 publications

(47 citation statements)

References 39 publications

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“…Else, the clinical usefulness of CQ may have been limited because high doses are required to compensate for its nonselective distribution in vivo, with high intersubject variability in the steady state blood concentrations of CQ and accumulation of its metabolites, desethylchloroquine, and bisdesethylchloroquine, responsible for related adverse effects [188,189]. [187]. # This study achieved a Response Rate of 30%.…”

Section: Clinical Trialsmentioning

confidence: 99%

“…Recently, Arnaout et al (NCT02333890) published the results from a randomized, double-blind clinical trial evaluating the effects of treatment with single-agent CQ 500 mg daily for 2-to 6-weeks prior to breast surgery. Results showed that in the preoperative setting, the treatment was not associated with significant effects on breast cancer cell proliferation, while it was associated with toxicity that may affect its broader use in oncology [187]. The disappointing results achieved in clinical trials could be in part ascribed to the choose of the wrong target.…”

Section: Clinical Trialsmentioning

confidence: 99%

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Targeting Autophagy in Breast Cancer

Cocco

Leone

Piezzo

et al. 2020

IJMS

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Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment.

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Section: Clinical Trialsmentioning

confidence: 99%

Section: Clinical Trialsmentioning

confidence: 99%

Targeting Autophagy in Breast Cancer

Cocco

Leone

Piezzo

et al. 2020

IJMS

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“…CQ and HCQ are mostly included in treatment regimens to increase the sensitivity of chemotherapeutics. CQ treatment at a relatively high daily dose of 500 mg resulted in no significant difference in the classic cellular proliferation marker, Ki67 index, in newly diagnosed breast cancer patients in a Phase II, doubleblind, randomized trial (Arnaout et al, 2019). CQ at a daily dose of 150 mg was able to reduce the proliferating cell nuclear antigen (PCNA) index in breast ductal carcinoma (Espina et al, 2017).…”

Section: Cancermentioning

confidence: 99%

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

2020

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Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells. Based on the nature of these materials, their size and degradation rate, four types of autophagy have been described, i.e. chaperone mediated autophagy, microautophagy, macroautophagy, and selective autophagy. One of the major regulators of this process is mTOR, which inhibits the downstream pathway of autophagy following the activation of its complex 1 (mTORC1). Alkylphosphocholine (APC) derivatives represent a novel class of antineoplastic agents that inhibit the serine-threonine kinase Akt (i.e. protein kinase B), which mediates cell survival and cause cell cycle arrest. They induce autophagy through inhibition of the Akt/mTOR cascade. They interfere with phospholipid turnover and thus modify signaling chains, which start from the cell membrane and modulate PI3K/Akt/ mTOR, Ras-Raf-MAPK/ERK and SAPK/JNK pathways. APCs include miltefosine, perifosine, and erufosine, which represent the first-, second-and third generation of this class, respectively. In a high fraction of human cancers, constitutively active oncoprotein Akt1 suppresses autophagy in vitro and in vivo. mTOR is a downstream target for Akt, the activation of which suppresses autophagy. However, treatment with APC derivatives will lead to dephosphorylation (hence deactivation) of mTOR and thus induces autophagy. Autophagy is a double-edged sword and may result in chemotherapeutic resistance as well as cancer cell death when apoptotic pathways are inactive. APCs display differential autophagy induction capabilities in different cancer cell types. Therefore, autophagy-dependent cellular responses need to be well understood in order to improve the chemotherapeutic outcome.

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“…Out of 92 studies included, eight were on COVID-19 [21][22][23][24][25][26][27][28], 13 studies were on malaria [29][30][31][32][33][34][35][36][37][38][39][40][41], 11 on other infectious conditions [42][43][44][45][46][47][48][49][50][51][52][53], 31 were on rheumatology , four on dermatologic diseases [85][86][87][88], eight on cancer [89][90][91][92][93][94][95][96], ve were on metabolic disease [97][98][99][100][101],...…”

Section: Study Characteristicsmentioning

confidence: 99%

Systematic Review and Meta-analysis of the Safety of Chloroquine and Hydroxychloroquine From Randomized Controlled Trials on Malarial and Non-malarial Conditions

Botelho

Bolfi

Leite

et al. 2020

Preprint

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Background: Despite the expectations regarding the effectiveness of chloroquine (CQ) and hydroxychloroquine (HCQ) for coronavirus disease (COVID-19) management, concerns about their adverse events have remained. Objectives: The objective of this systematic review was to evaluate the safety of CQ and HCQ from malarial and non-malarial randomized clinical trials (RCTs). Methods: The primary outcomes were the frequencies of serious adverse events (SAEs), retinopathy, and cardiac complications. Search strategies were applied to MEDLINE, EMBASE, LILACS, CENTRAL, Scopus, and Trip databases. We used random-effects model to pool results across studies and Peto one-step odds ratio (OR) for event rates below 1 %. Both-armed zero-event studies were excluded from the meta-analyses. We used the Grading of Recommendations Assessment, Development, and Evaluation system to evaluate the certainty of evidence.Results: Ninety-two RCTs were included. We found no significant difference between CQ/HCQ and control (placebo or non-CQ/HCQ) in the frequency of SAEs (OR: 0.98, 95 % confidence interval [CI]: 0.71–1.36, 25 trials, 11,605 participants, moderate certainty of evidence). No clear relationship was observed between CQ/HCQ and retinopathy (OR: 1,63, 95 % CI: -0.4–6.57, 5 trials, 344 participants, very low certainty of evidence). There was a low certainty of evidence of the effect of CQ/HCQ versus control on cardiac complications (Relative risk: 1.48, 95 % CI: 1.1–1.98, 8 trials, 5,970 participants).Conclusions: CQ and HCQ might be safe, with low frequency of SAEs on malarial and non-malarial conditions. No clear effect of their use on the incidence of retinopathy and cardiac complications was observed.The protocol for this systematic review was registered with PROSPERO (registration number: CRD42020177818)

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A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients

Cited by 58 publications

References 39 publications

Targeting Autophagy in Breast Cancer

Targeting Autophagy in Breast Cancer

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

Systematic Review and Meta-analysis of the Safety of Chloroquine and Hydroxychloroquine From Randomized Controlled Trials on Malarial and Non-malarial Conditions

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