Journal article
Identification of Selective Lead Compounds for Treatment of High-Ploidy Breast Cancer
Molecular cancer therapeutics, Vol.15(1), pp.48-59
01/01/2016
DOI: 10.1158/1535-7163.MCT-15-0527
PMCID: PMC4707107
PMID: 26586723
Abstract
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-specificmanner, 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. (C) 2015 AACR.
Details
- Title: Subtitle
- Identification of Selective Lead Compounds for Treatment of High-Ploidy Breast Cancer
- Creators
- Alka Choudhary - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USABrittany Zachek - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USARobert F. Lera - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USALauren M. Zasadil - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USAAmber Lasek - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USARyan A. Denu - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USAHyunjung Kim - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USACraig Kanugh - Univ Wisconsin, Wisconsin State Lab Hyg, Madison, WI 53706 USAJennifer J. Laffin - Univ Wisconsin, Wisconsin State Lab Hyg, Madison, WI 53706 USAJosephine M. Harter - Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol, Madison, WI USAKari B. Wisinski - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USASandeep Saha - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USABeth A. Weaver - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USAMark E. Burkard - Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.15(1), pp.48-59
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/1535-7163.MCT-15-0527
- PMID
- 26586723
- PMCID
- PMC4707107
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Number of pages
- 12
- Grant note
- UL1TR000427 / National Center for Advancing Translational Sciences; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) P30 CA014520 / Cancer Center Support IRG-58-011-48 / American Cancer Society Effcansah Mary Kay Foundation 2261 / Wisconsin Partnership New Investigator Program Award
- Language
- English
- Date published
- 01/01/2016
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984700655202771
Metrics
1 Record Views