Molecular origins and evolution to treatment resistance in genitourinary cancers

泌尿生殖系统癌症治疗耐药性的分子起源和进化

• 批准号: 10515410
• 负责人: Jihye Park
• 金额: $ 33.04万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515410
• 关键词: Androgen Antagonists; Automobile Driving; Biological; Biology; Bladder; Cells; Cellular Structures; Chromatin; Clinical; Collaborations; Communities; Computing Methodologies; Data; Development; Disease; Disease Resistance; Epigenetic Process; Evolution; Face; Funding; Genetic Transcription; Immune; Immune system; Immunotherapy; Intrinsic factor; Investigation; Kidney; Laboratories; Leadership; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of testis; Malignant neoplasm of urinary bladder; Methods; Modality; Molecular; Molecular Profiling; Multiomic Data; Patients; Process; Prostate; Research; Resistance; Role; Scientist; Solid Neoplasm; Specialist; System; Testis; Therapeutic; Training; Translations; Urogenital Cancer; analytical tool; cancer genomics; cancer immunotherapy; cancer risk; cloud based; drug development; drug discovery; experience; multidisciplinary; novel; novel therapeutics; patient oriented; patient stratification; programs; response; therapeutically effective; therapy resistant; translational impact; treatment stratification; tumor; whole genome

PROJECT SUMMARY Under Unit Director Dr. Eliezer Van Allen's leadership, the Van Allen laboratory's NCI funded research programs study genitourinary (GU) cancers (prostate, bladder, kidney, testes), with a focus on understanding treatment resistance in these diseases through integrative computational and molecular approaches grounded in the patient experience. With her multidisciplinary training and collaborative leadership, Research Specialist Dr. Jihye Park has been an integral part of these research programs contributing to various discovery and novel computational methods. Our research programs led to the discovery of the molecular basis of selective chemosensitivity in bladder and testes cancers, and biological understanding of androgen inhibitor resistance in prostate cancer, creating new drug discovery paradigms and means of patient stratification. We also developed integrative computational and experimental approaches to discover the interaction relevant to treatment resistance across the tumor, germline, and immune axes with our patient-centered paradigm in GU cancers. Furthermore, we discovered tumor-intrinsic factors determining cancer immunotherapy in solid tumors, directly invoking chromatin dysregulation as a cause of selective immunotherapy response and forming the basis for new files of drug development and therapeutic combinations. Despite these advances, the majority of patients with advanced GU cancers still experience resistance to therapies and the biological relevance and interplay of specific germline, somatic, or immune systems in these cancers are still largely unknown. Furthermore, we face computational challenges to handle vast amounts of new types of data to analyze efficiently. Dr. Park is now leading the effort to utilize integrated patient-centered approaches, specifically longitudinal single cell transcriptional and whole genome and epigenetic characterization of tumors, to understand the biological basis of molecular sensitization with tumor evolution perspectives and determine the paradigms that drive lethal immunotherapy resistant disease in GU cancers. Dr. Park will also contribute to the development of comprehensive and scalable analytic tools that can integrate multi-omics data and study systems level interactions between germline, somatic, and immune systems. These methods will be implemented within an open cloud-based platform (Terra) and amplify collaborations within the cancer community. Overall, Dr. Park's recent and ongoing contributions aim to reveal the integrated molecular factors that drive lethal disease in GU cancers and elucidate the biology of these processes, toward translation of effective therapeutic and patient stratification modalities, and broader accessibility of comprehensive computational methods utilizing cutting edge molecular profiling approaches. With Unit Director Dr. Eliezer Van Allen, Dr. Park's leadership and scientific and computational efforts will continue to establish an interdisciplinary and highly collaborative group with scientists from diverse scientific domains driving these comprehensive clinical computational research programs. 1

项目摘要 在单位主任埃利泽博士货车艾伦的领导下，货车艾伦实验室的国家癌症研究所资助的研究项目 研究泌尿生殖系统（GU）癌症（前列腺，膀胱，肾脏，睾丸），重点是了解治疗 这些疾病的耐药性，通过综合计算和分子方法， 患者体验凭借她的多学科培训和协作领导能力，研究专家Jihye博士 公园一直是这些研究计划的一个组成部分，有助于各种发现和小说 计算方法我们的研究项目导致了选择性的分子基础的发现， 膀胱癌和睾丸癌的化疗敏感性，以及对雄激素抑制剂耐药性的生物学理解， 前列腺癌，创造新的药物发现范例和患者分层的方法。我们还开发 综合计算和实验方法，以发现与治疗相关的相互作用 我们以患者为中心的范式在GU癌症中的肿瘤，生殖系和免疫轴上的耐药性。 此外，我们发现了决定实体瘤中癌症免疫治疗的肿瘤内在因素， 调用染色质失调作为选择性免疫治疗反应的原因，并形成基础 药物开发和治疗组合的新文件。尽管有这些进步，但大多数患者 晚期GU癌症仍然经历对治疗的抗性以及生物学相关性和相互作用， 在这些癌症中特定的生殖系、体细胞或免疫系统仍然是未知的。此外，我们面临 处理大量新型数据以进行有效分析的计算挑战。朴医生现在 领导努力利用以患者为中心的综合方法，特别是纵向单细胞 肿瘤的转录和全基因组和表观遗传学表征，以了解生物学基础 分子敏化与肿瘤演变的观点，并确定驱动致命的范例， GU癌症中的免疫疗法抗性疾病。朴博士还将为发展 全面和可扩展的分析工具，可以集成多组学数据和研究系统级别 生殖系、体细胞和免疫系统之间的相互作用。这些方法将在 开放基于云的平台（Terra），并扩大癌症社区内的合作。总的来说，朴医生 最近和正在进行的贡献旨在揭示驱动GU致死性疾病的整合分子因子 癌症和阐明这些过程的生物学，朝着翻译的有效治疗和患者 分层模式，以及利用尖端技术的综合计算方法的更广泛的可及性 分子谱分析方法。与单位主任埃利泽博士货车艾伦，博士公园的领导和科学， 计算工作将继续建立一个跨学科的和高度合作的小组与科学家 从不同的科学领域推动这些全面的临床计算研究计划。 1