Novel Therapeutic Approaches Targeting Tumor Suppressor Deficiencies in Advanced Prostate Cancer

项目摘要/摘要 虽然与十年前相比，晚期前列腺癌(PCA)有更多的治疗选择，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一种 生物标记物驱动的方法，对将从靶向治疗、免疫治疗或 联合疗法。应聘者的职业目标是利用癌症基因组学和生物学来识别 精准前列腺癌治疗的治疗靶点和更好的联合免疫疗法。最近的申请者 探索了一种新的概念性方法，称为“综合本质”，以促进本质的识别 肿瘤抑制基因缺失背景下的基因(赵等人，《自然》2017年)。此方法已启用 HER确定染色质重塑蛋白CHD1作为PTEN缺失的PCa的潜在治疗靶点，并 从机制上揭示CHd1转录激活致癌的NF-κB下游基因。整体而言 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 肿瘤抑制基因PTEN、TP53和RB1缺失的前列腺癌的免疫治疗 富于转移的。在这里，中心假设是CHD1的耗尽抑制了免疫抑制 PCa中的肿瘤微环境，从而抑制CHd1/NF-κB通路可以克服对PCa的耐药性 免疫疗法；以及“综合重要性”方法能够确定治疗靶点 高级PCA包含TP53和RB1更改。在强劲的初步数据的指导下，这些假设将 通过追求三个具体目标进行测试：(1)阐明CHD1背后的内在和外在机制 在体内对前列腺癌进展的贡献；(2)结合免疫评价CHd1/NF-κB抑制 检查点阻断；以及(3)识别含有TP53或RB1缺乏症的PCa的合成必需基因。这个 这一方案的创新之处来自于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，使用新的分子技术进行无偏分析 概况分析和免疫表型鉴定，以及下一代全基因组CRISPR筛查。建议数 这项研究意义重大，因为它有望为患有糖尿病的患者提供精确的医学方法 先进的PCA包含不同的癌症基因组学，并建立可操作的管道来探索靶向 广泛癌症类型的治疗学。它还将使申请者能够提交竞争性R01申请 在拟议奖项的第四个年头。此外，申请者还组建了一支出色的合作导师团队 由Ronald DePinho博士、James Allison博士和Christopher J.Logothetis博士组成，他们将在 PCA小鼠模型、癌症免疫学、免疫疗法和前列腺癌的翻译研究，并将 支持她向独立过渡。此外，优秀的智力环境，技术资源， MD安德森癌症中心的设施将使申请者能够实现她提出的项目目标，并 在获奖期间发展她的独立事业。

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.