2014
DOI: 10.1182/blood.v124.21.5775.5775
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A Phase II Trial of Chloroquine in Combination with Bortezomib and Cyclophosphamide in Patients with Relapsed and Refractory Multiple Myeloma

Abstract: Background: preclinical data suggest that autophagy can serve as an adaptive mechanism facilitating tumor cell survival and resistance to therapy-induced apoptosis. Subsequently, inhibitors of autophagy are thought to enhance the efficacy of therapeutic strategies designed to induce tumor cell apoptosis. Based upon our preclinical results, we hypothesized that the addition of chloroquine, an autophagy inhibitor, to the combination of a proteasome inhibitor, and cyclophosphamide might result in a synergistic ef… Show more

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Cited by 25 publications
(26 citation statements)
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“…Moreover, chloroquine has also been found to cause cancer vessel normalization 70 , which could potentially account for some of the improvement in intratumoral liposome accumulation observed in this study. It is worth emphasizing that regimens consisting of high doses of chloroquine in combination with chemotherapy for extended periods of time have demonstrated acceptable toxicity profiles in cancer patients 71 . Therefore, the combination of chloroquine with cancer nanotherapeutics is likely to be tolerable and have other advantages in addition to improving nanoparticle biodistribution.…”
Section: Discussionmentioning
confidence: 99%
“…Moreover, chloroquine has also been found to cause cancer vessel normalization 70 , which could potentially account for some of the improvement in intratumoral liposome accumulation observed in this study. It is worth emphasizing that regimens consisting of high doses of chloroquine in combination with chemotherapy for extended periods of time have demonstrated acceptable toxicity profiles in cancer patients 71 . Therefore, the combination of chloroquine with cancer nanotherapeutics is likely to be tolerable and have other advantages in addition to improving nanoparticle biodistribution.…”
Section: Discussionmentioning
confidence: 99%
“…Given the activity of carfilzomib in bortezomib‐resistant MM, early clinical studies are ongoing, examining the combination of panobinostat and carfilzomib in relapsed/refractory MM and are expected to yield favourable results (NCT01496118). On the other hand, a phase II trial evaluating the use of both bortezomib and the autophagy inhibitor chloroquine in patients with relapsed and/or refractory MM, supported by the finding of synergistic MM cell death in the pre‐clinical setting, showed a clinical benefit rate of 40%, further cementing the role of the aggresome‐autophagy pathway in proteasome inhibitor‐resistant MM (Montanari et al , ).…”
Section: Mechanisms Of Resistance To Proteasome Inhibitorsmentioning
confidence: 99%
“…Some approaches attempt to inhibit autophagy in order to induce apoptosis following drug treatment. In phase I and phase II clinical trials, the combination of autophagy inhibitors with bortezomib showed promising results for the treatment of relapsed or refractory patients [227,228]. In addition, the combination of carfilzomib with autophagy inhibitors potentiated apoptosis both in vitro and in vivo [229,230].…”
Section: Escape From Apoptosis Autophagy Activation and Dysregulatedmentioning
confidence: 99%