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.

项目摘要/摘要 前列腺癌致死性主要是由于转移，这在骨骼中最常发生，是 与高发病率有关。尽管最近取得了进展，但目前的治疗方法尚未治愈，因此很新 迫切需要治疗策略。鉴于转移性进展和治疗性抗性 发生在整个生物体的背景下，受肿瘤微环境的影响，一个重要 挑战我们当前对转移性进展的理解是研究模型的匮乏 在其生理环境中的转移，尤其是概括了人类骨骼的模型 前列腺癌。 该提案的总体目标是了解致命中的分子改变 前列腺癌为疾病结果做出了贡献，以及如何利用这种知识来发展更有效 疗法。特别是，我的初步数据强烈建议MYC是骨转移进展的驱动力。 鉴于MYC传统上很难以治疗为目标，因此该建议将利用独特的鼠标 骨转移模型以解决针对MYC信号依赖性的特定治疗漏洞 在前列腺癌中。具体而言，在AIM 1中，我将研究对ATAD2-溴构域的小分子抑制作用 抑制转移和耐药性的策略。在AIM 2中，我将使用CRISPR屏幕来识别合成 MYC激活高的前列腺肿瘤的致命脆弱性。在AIM 3中，我将利用CRISPR技术 从体面编辑小鼠前列腺的基因组，以简化表型的研究 前列腺癌进展的遗传改变的后果。 该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和 创新研究计划中的杰出咨询委员会将我的职业转向特定的精度 药物治疗前列腺癌骨转移的方法。该建议将提供 概念基础工作，初步数据和竞争性R01提交的实验工具，因此 启动我的独立职业。 如果成功，该奖项将为新的有针对性代理商提供原则证明，并发现 在体内发生的转移性前列腺癌中的新治疗脆弱性。该建议将推进 通过潜在导致可指导临床试验的新型临床检验假设的领域。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 癌症。