Doxorubicin is one of the most effective and widely used chemotherapy agents for breast cancer. However, resistance to this anthracycline agent is common, leading to treatment failure and poor prognosis. Triple negative breast cancer (TNBC), a clinical subtype type seen disproportionately in African American and Latina women (1, 2), is characterized by higher recurrence and lower overall survival following anthracycline treatment (1, 3). Developing targeted therapies for TNBC, especially those that do not respond to doxorubicin, is the most urgent priority for the clinical treatment of this aggressive disease (4). Several mechanisms have been implicated in doxorubicin resistance, including an increase in drug efflux pathways (5), epidermal growth factor receptor signaling (6), and mutations in the tumor suppressors ATM or p53 (7-9), but these findings have not been widely translated for clinical benefit. Recent studies from whole genome sequencing of over 1,000 breast cancers reveal that the tumor suppressor p53 is mutated in 43-62% (10, 11), making it one the most commonly mutated genes in this cancer type. p53 is required for DNA damage induced apoptosis, so therapies designed to increase the sensitivity of p53 mutant breast cancer cells to genotoxic therapy would be immensely beneficial. We recently reported that the DNA repair protein DNAPK regulates p53 independent apoptosis (12), pointing to a novel pathway to sensitize p53 mutant tumors. To identity additional genes that regulate p53 independent cell death, we performed a kinome wide siRNA doxorubicin sensitizer screen with p53 mutant cancer cells. The doxorubicin survival genes identified function in G2/M cell cycle regulation, DNA repair, and apoptosis. Based on these findings, we hypothesize that targeting these doxorubicin survival genes will lead to p53 independent apoptotic or mitotic cell death and will sensitize breast tumors to doxorubicin. Our partnership combines expertise in DNA repair, cancer biology, and functional genetics together with the outstanding research environments of the FHCRC and NMSU. Our objectives in this pilot proposal are: 1. Identify mechanisms leading to p53 independent cell death. We will determine if depletion of doxorubicin survival genes exacerbates DNA damage and increases apoptosis in doxorubicintreated p53 deficient triple negative breast cancer cells. We will determine if silencing doxorubicin survival genes affects cell cycle progression and DNA replication, and assess the mechanism of progression into mitotic cell death. 2. Validate candidate therapeutic targets in preclinical models of breast cancer. In parallel with Aim 1, we will determine if knockdown of doxorubicin survival genes in breast cancer xenografts improves response to doxorubicin. The outcome will be mechanistically and preclinically validated targets for doxorubicin resistant TNBC. Knowledge ofthe pathways that control sensitivity to doxorubicin will identity new candidate drug targets for breast cancer therapy, and will point to new biomarkers to stratify patients and inform clinical care. Because doxorubicin resistance leads to treatment failure and subsequent mortality, these findings will elucidate new strategies to treat these unresponsive aggressive tumors.
| Grandori, Carla; Kemp, Christopher J (2018) Personalized Cancer Models for Target Discovery and Precision Medicine. Trends Cancer 4:634-642 |
| Ortega, Sigolène; McAlvain, Megan Stamey; Briant, Katherine J et al. (2018) Perspectives of Community Advisory Board Members in a Community-Academic Partnership. J Health Care Poor Underserved 29:1529-1543 |
| Sanchez, N S; Quinn, K E; Ashley, A K et al. (2018) In the ovine pituitary, CXCR4 is localized in gonadotropes and somatotropes and increases with elevated serum progesterone. Domest Anim Endocrinol 62:88-97 |
| Molina, Yamile; Briant, Katherine J; Sanchez, Janeth I et al. (2018) Knowledge and social engagement change in intention to be screened for colorectal cancer. Ethn Health 23:461-479 |
| Lui, Goldie Y L; Grandori, Carla; Kemp, Christopher J (2018) CDK12: an emerging therapeutic target for cancer. J Clin Pathol 71:957-962 |
| Gurley, Kay E; Ashley, Amanda K; Moser, Russell D et al. (2017) Synergy between Prkdc and Trp53 regulates stem cell proliferation and GI-ARS after irradiation. Cell Death Differ 24:1853-1860 |
| Tham, Heidi M; Hohl, Sarah; Copeland, Wade et al. (2017) Enhancing Biospecimen Knowledge Among Health Care Providers and Representatives From Community Organizations. Health Promot Pract 18:715-725 |
| Pauli, Chantal; Hopkins, Benjamin D; Prandi, Davide et al. (2017) Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine. Cancer Discov 7:462-477 |
| Ornelas, India J; Deschenie, Desiree; Jim, Jesse et al. (2017) Yéego Gardening! A Community Garden Intervention to Promote Health on the Navajo Nation. Prog Community Health Partnersh 11:417-425 |
| Sands, Bryan; Brent, Roger (2016) Overview of post Cohen-Boyer methods for single segment cloning and for multisegment DNA assembly. Curr Protoc Mol Biol 113:3.26.1-3.26.20 |
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