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  • 1
    Publication Date: 2018-06-02
    Description: Quinacrine (QNC), antiprotozoan drug commonly used against Malaria and Giardiasis , has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest antitumor effects of QNC through suppression of NF-B and activation of p53. This study demonstrates the anticancer effect of QNC via a novel pathway through the elimination of checkpoint kinase 1/2 (Chk1/2) under p53-inactivated conditions. Inhibition of p53 by PFT-α or siRNA promotes QNC-induced apoptosis in normal fibroblast and p53-intact cancer cells. Considering that Chk1/2 kinases exert an essential role in the control of cell cycle, inhibition of Chk1/2 by QNC may induce cell death via uncontrolled cell cycle progression. Indeed, QNC reduces Chk1/2 expression under p53-impaired cancer cells and induces cell death in the G 2 –M phase. QNC increases the binding between p-Chk1/2 and β-TrCP and promotes proteasome-dependent degradation. Moreover, QNC treatment displayed antitumor effects in a Villin-Cre;p53 +/LSL-R172H intestinal cancer mouse model system as well as HCT116 p53 –/– xenografts. Implications: QNC has been used for the past over 70 years without obvious side effects, as such it is a plausible drug candidate for relapsed cancers, small-cell lung cancer, breast cancer as well as various p53-inactivated human malignancies. Mol Cancer Res; 16(6); 935–46. ©2018 AACR .
    Print ISSN: 1541-7786
    Electronic ISSN: 1557-3125
    Topics: Medicine
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  • 2
    Publication Date: 2018-11-16
    Description: Purpose: IL15 induces the activation and proliferation of natural killer (NK) and memory CD8 + T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL15N72D:IL15RαSu/IgG1 Fc complex) over recombinant human IL15 (rhIL15) in animal models, we performed this first-in-human phase I trial of ALT-803 in patients with advanced solid tumors. Patients and Methods: Patients with incurable advanced melanoma, renal cell, non–small cell lung, and head and neck cancer were treated with ALT-803 0.3 to 6 μg/kg weekly intravenously or 6 to 20 μg/kg weekly subcutaneously for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, and lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity. Results: Twenty-four patients were enrolled; 11 received intravenous and 13 received subcutaneous ALT-803. Of these patients, nine had melanoma, six renal, three head and neck, and six lung cancer. Although total lymphocyte and CD8 + T-cell expansion were modest, NK cell numbers rose significantly. Neither anti–ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well tolerated, with adverse effects including fatigue and nausea most commonly with intravenous administration, whereas painful injection site wheal was reported most commonly with subcutaneous ALT-803. Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in patients with advanced cancer. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anticancer agents. Clin Cancer Res; 24(22); 5552–61. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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