CHD1 and TAK1 Synthetic Lethality in Prostate Cancer

CHD1 和 TAK1 在前列腺癌中的综合致死率

• 批准号: 8873686
• 负责人: Scott D Cramer
• 金额: $ 16.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-06 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8873686
• 关键词: Affect; Androgen Antagonists; Antineoplastic Agents; Apoptosis; Bar Codes; Biological Models; Bladder; Breast; Cell Cycle Progression; Cell model; Cells; Chromosomal Rearrangement; Collaborations; Colon Lymphoma; Complex; Control Groups; DNA Sequence Alteration; DNA Sequence Rearrangement; DNA-Binding Proteins; DU145; Data; Dependence; Disease; Epigenetic Process; Exploratory/Developmental Grant; Funding Mechanisms; Future; Gene Amplification; Gene Deletion; Genes; Genetic; Genome; Genomic DNA; Goals; Growth; Harvest; Health; Histones; Human; Human Genetics; In Vitro; Infection; LNCaP; Lead; Lesion; Libraries; Link; MAP Kinase Kinase Kinase; MAP3K7 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mutate; Mutation; PARP inhibition; PC3 cell line; PI3K/AKT; PTEN gene; Pathway interactions; Phosphotransferases; Poly(ADP-ribose) Polymerases; Primary Neoplasm; Prostate; Prostatic Neoplasms; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Reading; Recurrence; Regimen; Research; Resistance; Role; Signal Pathway; Testing; The Cancer Genome Atlas; Therapeutic; Transforming Growth Factor beta; Tumor Suppressor Proteins; Variant; Work; Xenograft procedure; base; biological adaptation to stress; cancer genomics; cell motility; clinically relevant; cytokine; deep sequencing; genome-wide; helicase; high risk; in vivo; in vivo Model; inhibitor/antagonist; killings; men; novel; personalized medicine; phase II trial; prostate cancer cell; public health relevance; repaired; small hairpin RNA; targeted sequencing; therapeutic target; translational approach; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Prostate cancer is a complex disease characterized by recurrent gene deletions and amplifications. Human genetic data demonstrate correlation between dual loss of CHD1 and MAP3K7 with lethal prostate cancer. We recently showed in both published and unpublished data that MAP3K7 and CHD1 loss leads to aggressive castrate-resistant prostate cancer. We did this with two independent model systems providing strong support for the overall conclusions of the studies that provide a functional link between these two novel tumor suppressors and prostate cancer aggressiveness. Because MAP3K7 and CHD1 are both tumor suppressors, and by definition lost or inactivated in prostate cancer, neither are directly targetable with therapeutic strategies. We hypothesize that cells with loss of MAP3K7 and CHD1 have dependence on novel survival pathways and we propose to exploit these pathways to kill tumors that have lost MAP3K7 and/or CHD1. We will use two complementary approaches to identify therapeutic vulnerabilities. In Aim 1 we will screen human prostate cells with knockdown of CHD1 and/or MAP3K7 for the ability of common prostate cancer drugs to inhibit growth and tumorigenesis in vitro and in vivo. In aim 2 we will use a genome-wide shRNA screen to identify synthetic lethal targets in cells with loss of MAP3K7 and/or CHD1. This is a high-risk, high-gain project appropriate for an R21 type funding mechanism. Each aim is independent and each needs to be done. Together the two aims will define potential therapeutic approaches to an extremely aggressive variant of prostate cancer.