Identification of therapeutic vulnerabilities in prostate cancer bone metastasis

前列腺癌骨转移治疗脆弱性的鉴定

• 批准号: 10539239
• 负责人: Juan Martin Arriaga
• 金额: $ 19.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539239
• 关键词: Address; Advisory Committees; Award; Biological Models; Bromodomain; CRISPR screen; CRISPR/Cas technology; Cancer Etiology; Cessation of life; Clinical; Clinical Trials; Complement; Data; Dependence; Development; Development Plans; Disease; Disease Outcome; Disseminated Malignant Neoplasm; Electroporation; Epigenetic Process; Evaluation; Expenditure; Fracture; Genes; Genetically Engineered Mouse; Genomics; Goals; Histone Acetylation; Human; Indolent; Knock-out; Knowledge; Lead; Localized Disease; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Molecular; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Oncogenes; Pain; Patient Care; Patients; Penetrance; Pharmaceutical Preparations; Phenotype; Physiological; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Reader; Research; Resistance; Signal Transduction; Signaling Molecule; Site; Survival Rate; Techniques; Therapeutic; Training; Treatment Side Effects; Tropism; Universities; Whole Organism; androgen deprivation therapy; bone; career; career development; castration resistant prostate cancer; drug development; effective therapy; epigenomics; genome-wide; improved; in vivo; in vivo Model; inhibitor; innovation; interest; men; mortality; mouse genome; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; nuclease; overexpression; pre-clinical; precision medicine; preclinical study; prostate cancer metastasis; prostate cancer model; prostate cancer progression; small molecule; small molecule inhibitor; somatic cell gene editing; spinal cord compression; standard of care; targeted agent; targeted treatment; therapeutic development; therapy resistant; tool; transcription factor; treatment as usual; treatment response; treatment strategy; tumor; tumor microenvironment; tumor progression

Project Summary/Abstract Prostate cancer lethality is mainly due to metastasis, which occurs most frequently in bone and is associated with high morbidity. Despite recent progress, current treatments are not curative and therefore new therapeutic strategies are urgently needed. Given that both metastatic progression and therapeutic resistance occur in the context of a whole organism and are influenced by the tumor microenvironment, one significant challenge to our current understanding of metastatic progression is the paucity of models in which to study metastasis in its physiological context, and especially models that recapitulate the bone tropism of human prostate cancer. The overarching goal of this proposal is to understand how the molecular alterations present in lethal prostate cancers contribute to disease outcome and how to use this knowledge to develop more effective therapies. In particular, my preliminary data strongly suggests MYC as a driver of bone metastasis progression. Given that MYC has traditionally been hard to target therapeutically, this proposal will leverage unique mouse models of bone metastasis to address specific therapeutic vulnerabilities to target MYC signaling dependencies in prostate cancer. Specifically, in Aim 1 I will study small molecule inhibition of the ATAD2-bromodomain as a strategy to inhibit metastasis and therapy resistance. In Aim 2, I will use CRISPR screens to identify synthetic lethal vulnerabilities of prostate tumors with high MYC activation. In Aim 3, I will exploit CRISPR technology to somatically edit the genomes of mouse prostates in order to streamline the study of the phenotypic consequences of genetic alterations for prostate cancer progression. The career development plan outlined in this award leverages my training at Columbia University and an outstanding advisory committee into an innovative research plan to steer my career into specific precision medicine approaches for the treatment of prostate cancer bone metastasis. This proposal will provide the conceptual groundwork, preliminary data and experimental tools for a competitive R01 submission, thus launching my independent career. If successful, this award will provide proof-of-principle for a new class of targeted agents and uncover new therapeutic vulnerabilities in metastatic prostate cancer as occurs in vivo. This proposal will advance the field by potentially leading to novel clinically testable hypotheses that may guide clinical trials. Ultimately, these results will impact patient care by reducing the morbidity and mortality associated with metastatic prostate cancer.

项目总结/摘要 前列腺癌的致命性主要是由于转移，转移最常发生在骨中， 与高发病率有关。尽管最近取得了进展，但目前的治疗方法没有治愈性，因此是新的 迫切需要治疗策略。考虑到转移进展和治疗抵抗 发生在整个生物体的背景下，并受到肿瘤微环境的影响，一个重要的 我们目前对转移进展的理解所面临的挑战是缺乏研究模型 转移在其生理背景下，特别是概括人骨嗜性的模型， 前列腺癌 这项提案的首要目标是了解致命的分子改变是如何存在的。 前列腺癌有助于疾病的结果，以及如何利用这些知识来制定更有效的 治疗特别是，我的初步数据强烈表明MYC是骨转移进展的驱动因素。 鉴于MYC传统上难以治疗，该提案将利用独特的小鼠 骨转移模型，以解决针对MYC信号传导依赖性的特定治疗漏洞 在前列腺癌中。具体地，在目标1中，我将研究ATAD 2-溴结构域的小分子抑制作为ATAD 2-溴结构域的抑制剂。 抑制转移和治疗抗性的策略。在目标2中，我将使用CRISPR筛选来识别合成的 MYC高活化前列腺肿瘤的致命弱点。在目标3中，我将利用CRISPR技术 体细胞编辑小鼠前列腺的基因组，以简化表型 基因改变对前列腺癌进展的影响。 这个奖项中概述的职业发展计划利用了我在哥伦比亚大学的培训， 杰出的咨询委员会纳入一个创新的研究计划，以引导我的职业生涯到具体的精度 前列腺癌骨转移的治疗方法该提案将提供 竞争性R01提交的概念基础、初步数据和实验工具， 开始我的独立事业 如果成功，该奖项将为一类新的目标代理提供原理证明，并揭示 转移性前列腺癌的新的治疗弱点，如在体内发生的。这一建议将推动 通过潜在地导致可能指导临床试验的新的临床可检验的假设。最终，这些 结果将通过降低与转移性前列腺相关的发病率和死亡率来影响患者护理， 癌