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.

项目概要/摘要尽管与十年前相比，晚期前列腺癌 (PCa) 的治疗选择更多，但这些治疗仅限于一小部分患者，因此，确定新的治疗靶点并开发新的治疗靶点至关重要。生物标志物驱动的方法对最能从靶向治疗、免疫治疗或申请人的职业目标是利用癌症基因组学和生物学来识别。申请人最近发现了用于精准治疗 PCa 的治疗靶点和更好的组合免疫疗法。探索了一种称为“综合本质”的新颖概念方法，以促进识别本质肿瘤抑制基因缺陷的背景下的基因（Zhao et al., Nature 2017）。她确定染色质重塑蛋白 CHD1 作为 PTEN 缺失 PCa 的潜在治疗靶点，并揭示了 CHD1 转录激活致癌 NF-κB 下游基因的机制。此应用程序的目标是搜索特定于上下文的治疗靶点以及组合针对具有肿瘤抑制因子 PTEN、TP53 和 RB1 缺陷的 PCa 进行免疫治疗，这些基因是此处，中心假设是 CHD1 缺失会抑制免疫抑制。 PCa中的肿瘤微环境，从而抑制CHD1/NF-κB通路可以克服耐药性免疫疗法；并且“综合本质”方法能够识别治疗靶点在强有力的初步数据的指导下，这些假设将包含 TP53 和 RB1 改变的高级 PCa。通过追求三个具体目标进行测试：(1) 阐明 CHD1 的内在和外在机制 (2) 结合免疫评估CHD1/NF-κB抑制作用检查点封锁；以及 (3) 鉴定具有 TP53 或 RB1 缺陷的 PCa 的合成必需基因。该提案的创新源于新颖的基于计算的合成必需基因识别方法和新建立的 PCa 小鼠模型，使用分子新技术进行公正的分析分析和免疫表型分析，以及下一代全基因组 CRISPR 筛选。研究意义重大，因为它有望为患有以下疾病的患者阐明精准医疗方法包含多种癌症基因组学的先进PCa，并建立可操作的管道来探索靶向它还将使申请人能够提交具有竞争力的 R01 申请。此外，申请人还组建了一支出色的联合导师团队。由 Ronald DePinho、James Allison 和 Christopher J. Logothetis 博士组成，他们将扩大她的培训范围 PCa小鼠模型、癌症免疫学、免疫治疗和前列腺癌转化研究，并将支持她向独立过渡的还有优秀的智力环境、技术资源、 MD 安德森癌症中心的设施和设施将使申请人能够实现其提出的项目目标，并且在获奖期间发展她的独立事业。