| Reference | 1. Clin Cancer Res. 2017 Jun 1;23(11):2869-2879. doi: 10.1158/1078-0432.CCR-16-1742.
Epub 2016 Nov 23.
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Disruption of Autophagic Degradation with ROC-325 Antagonizes Renal Cell
Carcinoma Pathogenesis.
<br>
Carew JS(1)(2), Espitia CM(3), Zhao W(3), Han Y(2), Visconte V(2), Phillips J(2),
Nawrocki ST(4).
<br>
Author information: <br>
(1)Department of Medicine, Division of Translational and Regenerative Medicine,
University of Arizona Cancer Center, Tucson, Arizona. [email protected].
(2)Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
(3)Division of Hematology/Oncology, Cancer Therapy and Research Center at The
University of Texas Health Science Center at San Antonio, San Antonio, Texas.
(4)Department of Medicine, Division of Translational and Regenerative Medicine,
University of Arizona Cancer Center, Tucson, Arizona.
<br>
Purpose: Although autophagy plays important roles in malignant pathogenesis and
drug resistance, there are few clinical agents that disrupt this pathway, and the
potential therapeutic benefit of autophagy inhibition remains undetermined. We
used medicinal chemistry approaches to generate a series of novel agents that
inhibit autophagic degradation.Experimental Design: ROC-325 was selected as a
lead compound for further evaluation. Comprehensive in vitro and in vivo studies
were conducted to evaluate the selectivity, tolerability, and efficacy of ROC-325
in preclinical models of renal cell carcinoma (RCC) with HCQ serving as a
comparator. Markers of autophagy inhibition and cell death were evaluated in
tumor specimens.Results: ROC-325 exhibited superior in vitro anticancer effects
compared with the existing autophagy inhibitor hydroxychloroquine (HCQ) in 12
different cancer cell lines with diverse genetic backgrounds. Focused studies of
the mechanism of action and efficacy of ROC-325 in RCC cells showed that drug
treatment induced hallmark characteristics of autophagy inhibition, including
accumulation of autophagosomes with undegraded cargo, lysosomal deacidification,
p62 stabilization, and disruption of autophagic flux. Subsequent experiments
showed that ROC-325 antagonized RCC growth and survival in an ATG5/7-dependent
manner, induced apoptosis, and exhibited favorable selectivity. Oral
administration of ROC-325 to mice bearing 786-0 RCC xenografts was well
tolerated, was significantly more effective at inhibiting tumor progression than
HCQ, and inhibited autophagy in vivoConclusions: Our findings demonstrate that
ROC-325 has superior preclinical anticancer activity compared with HCQ and
support the clinical investigation of its safety and preliminary efficacy in
patients with RCC and other autophagy-dependent malignancies. Clin Cancer Res;
23(11); 2869-79. ©2016 AACR.
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2. Autophagy. 2017 Apr 3;13(4):765-766. doi: 10.1080/15548627.2017.1280222. Epub
2017 Jan 24.
<br>
Drain the lysosome: Development of the novel orally available autophagy inhibitor
ROC-325.
<br>
Carew JS(1), Nawrocki ST(1).
<br>
Author information: <br>
(1)a Department of Medicine , Division of Translational and Regenerative
Medicine, University of Arizona Cancer Center , Tucson , AZ , USA.
<br>
Although macroautophagy/autophagy is a key contributor to malignant pathogenesis
and therapeutic resistance, there are few FDA-approved agents that significantly
affect this pathway. We used medicinal chemistry strategies to develop ROC-325,
an orally available novel inhibitor of lysosomal-mediated autophagy. Detailed in
vitro and in vivo studies in preclinical models of renal cell carcinoma
demonstrated that ROC-325 triggered the hallmark features of lysosomal autophagy
inhibition, was very well tolerated, and exhibited significant superiority with
respect to autophagy inhibition and anticancer activity over hydroxychloroquine.
Our findings support the clinical investigation of the safety and preliminary
efficacy of ROC-325 in patients with autophagy-dependent malignancies and other
disorders where aberrant autophagy contributes to disease pathogenesis.<br>
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