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Preclinical analyses of advanced prostate cancer in genetically-engineered mice

基因工程小鼠晚期前列腺癌的临床前分析

基本信息

批准号：
10587422
负责人：
Cory Abate-Shen
金额：
$ 57.58万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-06 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587422
关键词：
Acceleration Allografting Androgens Antiandrogen Therapy BRCA1 gene BRCA2 gene Biochemical Biological Biological Assay Biological Process Cancer Etiology Castration Cells Cessation of life Clinical Trials Complement DNA Damage DNA Repair DNA Repair Gene DNA analysis Development Disease Disease Progression Double Strand Break Repair Drug Combinations Drug Targeting Foundations Funding Future Generations Genes Genetically Engineered Mouse Human Individual Malignant neoplasm of prostate Metastatic Prostate Cancer Modeling Molecular Mus Neoplasm Metastasis Organoids Patients Pharmaceutical Preparations Phenotype Play Primary Neoplasm Prostate Prostatic Neoplasms Resistance Resources Role Series Treatment Failure Tumor Suppressor Genes Variant advanced prostate cancer bone cancer therapy candidate identification chemotherapy clinical investigation clinical practice clinically relevant computerized tools deprivation disorder risk gene function genome integrity genome-wide individual patient innovation insight loss of function men new therapeutic target pre-clinical precision oncology prostate cancer progression prostate carcinogenesis repair function response single nucleus RNA-sequencing targeted agent treatment response tumor

项目摘要

Project Summary/Abstract Advanced prostate cancer represents a major cause of cancer death in men, usually as a consequence of treatment failure, which gives rise to aggressive disease variants that are highly metastatic. Among the major biological processes that are causally dysregulated in advanced prostate cancer are those related to DNA repair. Notably, BRCA1 and BRCA2, are among the most frequently altered DNA repair genes in advanced prostate cancer, and are also key targets for its treatment. To study their functions in prostate cancer, we have generated genetically-engineered mouse models (GEMMs) based on inducible loss-of-function of Brca1 and Brca2 in the prostate. In preliminary studies, we have found that loss-of-function of Brca2 results in aggressive prostate tumors with highly penetrant metastases, including to bone, that are coincident with increased DNA damage and accelerated by androgen deprivation. In parallel, we have developed computational tools to elucidate the molecular determinants of Brca1 and Brca2 functions in prostate cancer. We have also developed a new precision oncology platform called OncoLoop, to computationally match individual patients to individual GEMMs, and to predict and validate drugs that target specific patient-GEMM pairs. Leveraging these models and resources, we will systematically investigate the functions of BRCA1 and BRCA2 in prostate cancer, guided by the hypothesis that defective DNA repair plays an important role in prostate cancer progression and treatment, particularly in the context of androgen deprivation. In Aim 1, we will investigate the consequences of loss-of-function of Brca1 and Brca2 in GEMMs, GEMM-derived organoid models, and patient-derived human organoid models for prostate tumorigenesis, metastasis, and DNA damage response. These studies will provide fundamental insights into the functions of BRCA1 and BRCA2 in prostate cancer and elucidate the relationship of DNA repair mechanisms for disease progression. In Aim 2, we will investigate molecular determinants of DNA repair functions in prostate cancer by identifying and functionally characterizing master regulators (MRs) that represent mechanistic determinants of Brca1 and Brca2 loss-of- function in prostate tumors and metastases. MRs will be prioritized based on conservation with human prostate cancer, and functionally validated in mouse and human organoids. We will complement these studies by analyses of tumors and metastases using single-nuclei RNA-sequencing (snRNA-seq) to identify MR signatures associated with specific cell states. In Aim 3, we will leverage our GEMMs, GEMM-derived organoids and allografts, and patient-derived organotypic models to pursue co-clinical investigations of DNA repair function in prostate cancer. In Aim 3A, we will systematically evaluate drugs/drug combinations currently in or advancing to clinical practice. In Aim 3B, we will use the OncoLoop platform to predict new drugs that target DNA repair in prostate-specific contexts. Overall, these studies will provide biological and molecular insights to inform on current trials and to support the development of future ones.

项目总结/文摘