权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Comprehensive genomic profiling of aggressive hormone sensitive prostate cancer

侵袭性激素敏感前列腺癌的全面基因组分析

基本信息

批准号：
9886101
负责人：
CHRISTOPHER J SWEENEY
金额：
$ 61.62万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9886101
关键词：
Ablation Address Aftercare American College of Radiology Imaging Network Androgens BRCA2 gene Biochemical Biological Biological Markers Cessation of life Characteristics Clinical Clinical Data Clinical Trials Companions DNA DNA Repair DNA Sequence Alteration Data Development Disease Disease Resistance Drug Evaluation Early identification Eastern Cooperative Oncology Group Enrollment Expression Profiling Gene Expression Gene Expression Profiling Gene Mutation Genes Genetic Transcription Genome Genomics Hormones Lead Literature Localized Disease Malignant neoplasm of prostate Medical Research Metastatic Prostate Cancer Metastatic to Modeling Mutation Naturopathic Doctor Outcome PTEN gene Pathway interactions Patient Selection Patient-Focused Outcomes Patients Prognostic Marker Prostate Publishing RB1 gene RNA Randomized Controlled Trials Recurrence Relapse Resistance Sampling Screening Result Source Systemic Therapy TP53 gene Time Tissues Training Tumor Suppressor Genes Widespread Disease Work Zoledronic Acid abiraterone androgen deprivation therapy base biomarker validation cancer survival castration resistant prostate cancer chemotherapy docetaxel drug efficacy efficacy trial exome exome sequencing gene repair genomic profiles hormone therapy improved insight loss of function men outcome forecast phase III trial pre-clinical predictive marker predictive modeling prevent prognostic prognostic of survival prospective response side effect tumor

项目摘要

Despite a high rate of screening resulting in early identification of most of the 174,650 new cases of prostate cancer in the USA, there are still about 31,620 deaths for metastatic and treatment resistant disease. To enable gene profiling of the samples to identify prognostic and predictive biomarkers we have collected tumor samples from 988 unique patients enrolled on two completed phase 3 trials:  E3805 CHAARTED: ChemoHormonal Therapy versus Androgen Ablation Trial for Extensive Disease in Prostate cancer. Sweeney et al, N Eng J Med 2015, 373(8):737-46.  MRC PR08 STAMPEDE: Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial, James, N. D., et al Lancet 2016, 387(10024):1163-1177. This offers a very unique opportunity to study gene profiles and identify biomarkers associated with a good versus poor response to hormonal therapy for metastatic hormone sensitive prostate cancer (mHSPC). This 5- year R01 application focuses on assessing genomic profiles related to alterations of tumor suppressor genes leading to loss of function of p53, PTEN and RB1. Preclinical and clinical data supports the hypothesis that the presence of mutations in these tumor suppressors genes are associated with a poor response to ADT. The samples from the two trials provide the opportunity for the first time to prospectively assess whether one or more of these mutations can identify patients prior to starting treatment who are destined to have a poor response to ADT. In turn, the presence of one or more of these mutations may identify patients who benefit from adding in docetaxel early. This may allow accurate patient selection and spare patients who did not benefit from early docetaxel the side effects of this chemotherapeutic. We will first perform whole exome sequencing of the tumor and germline DNA and comprehensive RNA profile using the Affymetrix platform from the CHAARTED trial to efficiently and comprehensively interrogate the genome. We will then develop clinicogenomic models to determine whether more accurate prognostication and prediction of benefit from early docetaxel can be achieved with a combination of variables from the exome mutation and/or gene expression profiles (GEP) and/or clinical factors. Having locked down models, we will then attempt to validate the prognostic and predictive models in the STAMPEDE samples. It is also worth highlighting, this broad approach with whole exome sequencing and GEP will also allow us to interrogate and other explore other hypotheses based on emerging preclinical and clinical data such as those pertaining to DNA Damage Repair genes (e.g. BRCA2). This work may also lead to identification of pathways to target to prevent emergence of resistance to ADT and improve the survival of men with mHSPC.

尽管筛查率很高，导致174,650例新病例中的大多数被早期发现