Novel Therapeutic Approaches Targeting Tumor Suppressor Deficiencies in Advanced Prostate Cancer

针对晚期前列腺癌肿瘤抑制因子缺陷的新治疗方法

基本信息

批准号：
10020761
负责人：
Di Zhao
金额：
$ 24.79万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10020761
关键词：
Award Bioinformatics CHD1 gene CRISPR screen Cancer Biology Cancer Center Cancer Etiology Cancer Relapse Caring Cell Line Cell Proliferation Cessation of life Clinical Combination immunotherapy Combined Modality Therapy Data Development Environment Essential Genes Genes Genetic Transcription Genetically Engineered Mouse Genomics Goals Hand IL6 gene Immunophenotyping Immunotherapy Infiltration Loss of Heterozygosity Malignant Neoplasms Malignant neoplasm of prostate Medical Mentors Molecular Profiling Morbidity - disease rate Mus Mutation Nature Neoplasm Metastasis Oncogenes Oncogenic Outcome PTEN gene Pathway interactions Patient Selection Patients Phenotype Positioning Attribute Prostate Cancer therapy Prostatic Neoplasms Proteins RB1 gene Refractory Research Research Personnel Resistance Resources TP53 gene Testing Therapeutic Uses Training Training Programs Treatment Efficacy Tumor Suppressor Genes Tumor Suppressor Proteins United States advanced prostate cancer androgen deprivation therapy antitumor effect base biomarker-driven cancer cell cancer genomics cancer type career castration resistant prostate cancer chromatin remodeling druggable target immune checkpoint blockade in vivo inhibitor/antagonist innovation insight loss of function men mortality mouse model multidisciplinary new technology new therapeutic target next generation novel novel therapeutic intervention patient stratification patient subsets personalized immunotherapy precision medicine prostate cancer progression recruit stem success targeted treatment therapeutic target therapy development transcriptomics translational cancer research treatment response tumor tumor immunology tumor microenvironment tumor-immune system interactions whole genome

项目摘要

Project Summary/Abstract Although more treatment options for advanced prostate cancer (PCa) compared to a decade ago, these therapies are limited to a subset of patients. Thus, it is critical to identify novel therapeutic targets and develop a biomarker-driven approach to stratify patients who will most benefit from targeted therapy, immunotherapy or combination therapy. The career goal of applicant is to leverage cancer genomics and biology to identify therapeutic targets and better combinatory immunotherapies for precision PCa treatment. Applicant recently explored a novel conceptual approach called “Synthetic Essentiality” to facilitate the identification of essential genes in the context of tumor suppressor gene deficiencies (Zhao et al., Nature 2017). This approach enabled her to identify chromatin-remodeling protein CHD1 as a potential therapeutic target in PTEN-loss PCa, and to uncover mechanistically that CHD1 transcriptionally activates oncogenic NF-κB downstream genes. The overall objective in this application is to search context-specific therapeutic targets as well as combinatorial immunotherapy for PCa harboring deficiencies of the tumor suppressors PTEN, TP53, and RB1, which are enriched in metastasis. Here, the central hypotheses are that CHD1 depletion inhibits the immunosuppressive tumor microenvironment in PCa, and thus inhibiting the CHD1/NF-κB pathway can overcome resistance to immunotherapy; and that the “Synthetic Essentiality” approach enables identification of therapeutic targets for advanced PCa containing TP53 and RB1 alterations. Guided by strong preliminary data, these hypotheses will be tested by pursuing three Specific Aims: (1) Illuminate the intrinsic and extrinsic mechanisms underlying CHD1 contribution to PCa progression in vivo; (2) Evaluate CHD1/NF-κB inhibition in combination with immune checkpoint blockade; and (3) Identify synthetic essential genes for PCa harboring TP53 or RB1 deficiency. The innovation of this proposal stems from the novel computation-based synthetic essential gene identification approach and newly established PCa mouse models, unbiased analyses using novel technologies of molecular profiling and immunophenotyping, and next-generation whole genome CRISPR screening. The proposed research is significant because it is expected to illuminate precision medicine approaches for patients with advanced PCa containing diverse cancer genomics, and establish an operable pipeline to explore targeted therapeutics for broad cancer types. It will also position the applicant to submit a competitive R01 application during the 4th year of the proposed Award. In addition, applicant has assembled an extraordinary co-mentor team consisting of Drs. Ronald DePinho, James Allison and Christopher J. Logothetis, who will expand her training in PCa mouse modeling, cancer immunology, immunotherapy and prostate cancer translational research, and will support her transition to independence. In addition, the outstanding intellectual environment, technical resources, and facilities at MD Anderson Cancer Center will enable the applicant to achieve her proposed project goals and develop her independent career in the award period.

项目摘要/摘要尽管与十年前相比，晚期前列腺癌（PCA）的治疗选择更多疗法仅限于一部分患者。这是至关重要的生物标志物驱动的方法来分层将受益于靶向疗法，免疫疗法或联合疗法。申请人的职业目标是利用癌症基因组学和生物学来识别用于精确PCA治疗的治疗靶标和更好的组合免疫疗法。申请人最近探索了一种称为“合成本质性”的新型概念方法，以促进确定必需品基因在肿瘤抑制基因缺陷的背景下（Zhao等，自然，2017年）。启用了此方法她将染色质复制蛋白CHD1识别为PTEN-LOSS PCA的潜在治疗靶标，并从机械上发现CHD1转录会激活下游基因的致癌NF-κB。总体本应用程序中的目的是搜索特定上下文的治疗目标和组合 PCA的免疫疗法具有肿瘤补充剂PTEN，TP53和RB1的缺陷，富含转移。在这里，中心假设是CHD1抑郁抑制免疫抑制作用 PCA中的肿瘤微环境，因此抑制CHD1/NF-κB途径可以克服对免疫疗法；并且“综合本质”方法可以识别治疗靶标的含有TP53和RB1改变的高级PCA。在强大的初步数据的指导下，这些假设将通过追求三个特定目标来测试：（1）阐明CHD1的内在和外在机制体内PCA进展的贡献；（2）评估CHD1/NF-κB抑制与免疫结合检查点封锁；（3）确定具有TP53或RB1缺乏的PCA的合成基因。这该提案的创新源于新型基于计算的合成基本基因鉴定方法和新建立的PCA小鼠模型，使用分子的新技术进行公正的分析分析和免疫定型，以及下一代全基因组CRISPR筛查。提议研究很重要，因为预计它将针对患者阐明精度医学方法含有潜水癌基因组学的高级PCA，并建立可操作的管道来探索目标广泛癌症类型的治疗。它还将定位提交竞争性R01申请的申请在拟议奖的第四年。此外，适用的人组装了一个非凡的联合委员会团队由Drs组成。罗纳德·迪帕尼奥（Ronald Depinho），詹姆斯·艾莉森（James Allison）和克里斯托弗·J·洛格蒂蒂斯（Christopher J. PCA小鼠建模，癌症免疫学，免疫疗法和前列腺癌转化研究，并将支持她向独立过渡。此外，杰出的知识环境，技术资源， MD Anderson癌症中心的设施将使申请人能够实现其拟议的项目目标和在颁奖时期发展她的独立职业。