5 results on '"Craig Kanugh"'
Search Results
2. Supplementary Figures from Identification of Selective Lead Compounds for Treatment of High-Ploidy Breast Cancer
- Author
-
Mark E. Burkard, Beth A. Weaver, Sandeep Saha, Kari B. Wisinski, Josephine M. Harter, Jennifer J. Laffin, Craig Kanugh, Hyunjung Kim, Ryan A. Denu, Amber Lasek, Lauren M. Zasadil, Robert F. Lera, Brittany Zachek, and Alka Choudhary
- Abstract
This file contains supplementary figures S1-S4. These illustrate correlation of ploidy from chromosome 17 FSIH versus 6-chromosome FISH, chromosome spreads of cell lines, additional dose-response curves, and data demonstrating DPBQ does not operate by binding DNA or by inhibiting topoisomerase II.
- Published
- 2023
3. Identification of Selective Lead Compounds for Treatment of High-Ploidy Breast Cancer
- Author
-
Hyun-Jung Kim, Lauren M. Zasadil, Beth A. Weaver, Ryan A. Denu, Robert F. Lera, Brittany Zachek, Jennifer Laffin, Josephine Harter, Kari B. Wisinski, Amber Lasek, Mark E. Burkard, Craig Kanugh, Sandeep Saha, and Alka Choudhary
- Subjects
0301 basic medicine ,Cancer Research ,Cell type ,Proline ,medicine.drug_class ,Karyotype ,Antineoplastic Agents ,Apoptosis ,Breast Neoplasms ,Kaplan-Meier Estimate ,Biology ,Antimetabolite ,Article ,Polyploidy ,03 medical and health sciences ,Breast cancer ,Cell Line, Tumor ,Drug Discovery ,medicine ,Benzoquinones ,Biomarkers, Tumor ,Humans ,In Situ Hybridization, Fluorescence ,Cell Proliferation ,Cell growth ,Topoisomerase ,Cancer ,Gene signature ,medicine.disease ,Prognosis ,Molecular biology ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Cancer research ,biology.protein ,Female ,Ploidy ,Tumor Suppressor Protein p53 ,Signal Transduction - 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-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.
- Published
- 2015
4. Immunohistochemical evaluation of MYC expression in mantle cell lymphoma
- Author
-
Craig Kanugh, Kreg M. Grindle, David T. Yang, KyungMann Kim, Gene R Shaw, Jennifer Laffin, Matthew J. Oberley, Chong Zhang, Brad S. Kahl, and Saurabh Rajguru
- Subjects
Adult ,Male ,Disease free survival ,Histology ,Kaplan-Meier Estimate ,Lymphoma, Mantle-Cell ,Biology ,Article ,Disease-Free Survival ,Protein expression ,Pathology and Forensic Medicine ,Proto-Oncogene Proteins c-myc ,immune system diseases ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Humans ,RNA, Messenger ,In Situ Hybridization, Fluorescence ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Tissue microarray ,General Medicine ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Tissue Array Analysis ,Cancer research ,Female ,Mantle cell lymphoma - Abstract
To assess the validity and potential clinical utility of evaluating MYC expression by immunohistochemistry (IHC) in mantle cell lymphoma (MCL).MYC IHC was scored on a tissue microarray containing 62 MCLs and 29 controls by two pathologists. Inter-observer correlation was high (intra-class correlation of 0.98). MYC IHC scores correlated with MYC expression (Spearman's rank correlation 0.69, P0.0001) and weakly with Ki67 proliferation index (Spearman's rank correlation 0.30, P = 0.03). Six blastic MCLs did not have higher mean MYC IHC scores or MYC mRNA expression than non-blastic MCLs. None of 57 cases assessed, including all of the blastic cases, showed MYC rearrangement by fluorescence in-situ hybridization. Multivariate analysis with backward selection from potential predictors including age, lactate dehydrogenase, leukocyte count, MIPI score, ECOG performance status, blastic morphology and Ki67 index showed that MYC IHC score is an independent predictor of progression-free survival (hazard ratio 2.34, 95% CI 1.42-3.88, P = 0.0009) and overall survival (hazard ratio 1.90, 95% CI 1.05-3.43, P = 0.034).We show that a new monoclonal anti-MYC antibody can enable accurate and reproducible visual assessment of MYC expression that is independently predictive of clinical outcomes in MCL.
- Published
- 2013
5. Centrosome amplification induces high grade features and is prognostic of worse outcomes in breast cancer
- Author
-
Lauren M. Zasadil, Mark E. Burkard, Beth A. Weaver, Jennifer Laffin, Ryan A. Denu, and Craig Kanugh
- Subjects
Adult ,Dedifferentiated ,0301 basic medicine ,PLK4 ,China ,Cancer Research ,Centriole ,Mitosis ,Breast Neoplasms ,Protein Serine-Threonine Kinases ,Biology ,Polyploidy ,03 medical and health sciences ,Breast cancer ,Tubulin ,Cell Line, Tumor ,Chromosome instability ,medicine ,Genetics ,Humans ,Pericentrin ,Antigens ,In Situ Hybridization ,Aged ,Neoplasm Staging ,Pericentriolar material ,Aged, 80 and over ,Centrosome ,Ploidies ,Gene Amplification ,Cancer ,Cell Dedifferentiation ,Middle Aged ,Prognosis ,medicine.disease ,Polyglutamylated tubulin ,Chromosomal instability ,3. Good health ,030104 developmental biology ,Oncology ,Cancer research ,Female ,Research Article - Abstract
Background Centrosome amplification (CA) has been reported in nearly all types of human cancer and is associated with deleterious clinical factors such as higher grade and stage. However, previous reports have not shown how CA affects cellular differentiation and clinical outcomes in breast cancer. Methods We analyzed centrosomes by immunofluorescence and compared to ploidy and chromosomal instability (CIN) as assessed by 6-chromosome FISH in a cohort of 362 breast cancers with median clinical follow-up of 8.4 years. Centrosomes were recognized by immunofluorescence using antibodies for pericentriolar material (PCM; pericentrin) and centrioles (polyglutamylated tubulin). CA was experimentally induced in cell culture by overexpression of polo-like kinase 4 (PLK4). Results CA is associated with reduced all-cause and breast cancer-specific overall survival and recurrence-free survival. CA correlates strongly with high-risk subtypes (e.g. triple negative) and higher stage and grade, and the prognostic nature of CA can be explained largely by these factors. A strong correlation between CA and high tumor ploidy demonstrates that chromosome and centrosome doubling often occur in concert. CA is proposed to be a method of inducing CIN via aberrant mitotic cell divisions; consonant with this, we observed a strong correlation between CA and CIN in breast cancers. However, some CA tumors had low levels of CIN, indicating that protective mechanisms are at play, such as centrosome clustering during mitosis. Intriguingly, some high-risk tumors have more acentriolar centrosomes, suggesting PCM fragmentation as another mechanism of CA. In vitro induction of CA in two non-transformed human cell lines (MCF10A and RPE) demonstrated that CA induces a de-differentiated cellular state and features of high-grade malignancy, supporting the idea that CA intrinsically causes high-grade tumors. Conclusions CA is associated with deleterious clinical factors and outcomes in breast cancer. Cell doubling events are the most prevalent causes of CA in cancer, although PCM fragmentation may be a secondary cause. CA promotes high-risk breast cancer in part by inducing high-grade features. These findings highlight the importance of centrosome aberrations in the biology of human breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2083-x) contains supplementary material, which is available to authorized users.
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.