Identification of Selective Lead Compounds for Treatment of High-Ploidy Breast Cancer

• Published in: Molecular cancer therapeutics Vol. 15; no. 1; pp. 48 - 59
• Main Authors: Choudhary, Alka, Zachek, Brittany, Lera, Robert F, Zasadil, Lauren M, Lasek, Amber, Denu, Ryan A, Kim, Hyunjung, Kanugh, Craig, Laffin, Jennifer J, Harter, Josephine M, Wisinski, Kari B, Saha, Sandeep, Weaver, Beth A, Burkard, Mark E
• Format: Journal Article
• Language: English
• Published: United States 01.01.2016
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Benzoquinones - chemistry; Benzoquinones - pharmacology; Biomarkers, Tumor; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Discovery; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Karyotype; Polyploidy; Prognosis; Proline - analogs & derivatives; Proline - chemistry; Proline - pharmacology; Signal Transduction - drug effects; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-15-0527

Increased ploidy is common in tumors but treatments for tumors with excess chromosome sets are not available. Here, we characterize high-ploidy breast cancers and identify potential anticancer compounds selective for the high-ploidy state. Among 354 human breast cancers, 10% have mean chromosome copy number exceeding 3, and this is most common in triple-negative and HER2-positive types. Women with high-ploidy breast cancers have higher risk of recurrence and death in two patient cohorts, demonstrating that it represents an important group for improved treatment. Because high-ploidy cancers are aneuploid, rather than triploid or tetraploid, we devised a two-step screen to identify selective compounds. The screen was designed to assure both external validity on diverse karyotypic backgrounds and specificity for high-ploidy cell types. This screen identified novel therapies specific to high-ploidy cells. First, we discovered 8-azaguanine, an antimetabolite that is activated by hypoxanthine phosphoribosyltransferase 1 (HPRT1), suggesting an elevated gene-dosage of HPRT1 in high-ploidy tumors can control sensitivity to this drug. Second, we discovered a novel compound, 2,3-diphenylbenzo[g]quinoxaline-5,10-dione (DPBQ). DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. Mechanistic analysis demonstrates that DPBQ elicits a hypoxia gene signature and its effect is replicated, in part, by enhancing oxidative stress. Structure-function analysis defines the core benzo[g]quinoxaline-5,10 dione as being necessary for the polyploid-specific effects of DPBQ. We conclude that polyploid breast cancers represent a high-risk subgroup and that DPBQ provides a functional core to develop polyploid-selective therapy. Mol Cancer Ther; 15(1); 48-59. ©2015 AACR.