Simulating Ancestrally Unbiased Tumor Evolution To Interrogate Drug Resistance

模拟祖先无偏见的肿瘤进化来询问耐药性

• 批准号: 10687776
• 负责人: Rohit Bose
• 金额: $ 145.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687776
• 关键词: Address; Affect; African American; American; Anatomy; Awareness; Bar Codes; Biological Response Modifier Therapy; Biology; Cancer Patient; Cell Line; Cells; Development; Drug Exposure; Drug resistance; European; Evolution; Future; Health Services Accessibility; High-Risk Cancer; Hormones; Immune system; Immunocompetent; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Modeling; Molecular; Molecular Profiling; Molecular Target; Nature; Oncogenic; Organoids; Patients; Population; Prostate; Surveillance Program; System; Therapeutic; Tissues; Vision; androgen sensitive; cohort; effective therapy; high risk; in vivo; in vivo Model; mortality; participant enrollment; premalignant; targeted treatment; treatment response; tumor; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY Among cancer patients of distinct ancestries, there are molecular differences in the composition of their tumors, and their responses to therapies. These molecular distinctions extend well beyond germline differences, and encompass somatic and non-mutational alterations as well. Compared to European-American patients, African- American prostate cancer patients ’have a markedly higher risk of both developing and dying from prostate cancer. This mortality is related to inevitable drug resistance, and often from bone metastases. Although access- to-care contributes, there is also a higher risk of cancer progression for African-American patients enrolled in active surveillance programs. Collectively, there is evidence that molecular distinctions enriched among different ancestries can play a role in altering tumorigenesis and response to therapies. There are significant challenges in addressing the above. Large molecular profiling cohorts of patient tumors are underrepresented for non-European American patients, and there are only limited cell-lines derived from such patients. We also need effective ways to rapidly model tumor evolution in vivo in an immunocompetent and hormone-sensitive manner, to develop corresponding therapies that are biologically relevant. To address these significant challenges, my central vision is to interrogate tumor evolution in an ancestrally unbiased manner. This would enable us to identify powerful driver molecular alterations that are currently underappreciated due to the limited nature of existing non-European American patient cohorts, and also develop effective therapies against such tumors. Inspired by a subset of my own patients, the centerpiece of this proposal is the development of BRUTE (BaRcoded Unsupervised Tumor Evolution FIGURE), an immunocompetent organoid-based tumor graft system. The first proof-of-principle iteration of BRUTE tumors in an androgen- dependent prostate-tissue derived system strongly identified ERF and other underappreciated oncogenic alterations enriched uniquely among African-American patients. Using our tractable BRUTE system and orthologous approaches, we will investigate in an ancestrally unbiased manner A) how the anatomic niche and immune system alter the selection of tumorigenic and drug-resistant cells, B) the biology of the future drug-resistant cells among the precancerous bulk population, and C) how to target the molecular alterations that are enriched among non-European American patients. This is the first tumor evolution system of which we are aware that spontaneously recapitulates molecular driver alterations observed in underrepresented patient cohorts. Thus, we can use it to ask: why are African-American prostate cancer patients more likely to die of bone metastases than European-American patients? Can we detect and eliminate the future drug resistant cells in underrepresented patients’ tumors prior to drug exposure? And can we develop targeted therapies to exploit the molecular alterations observed in African-American prostate cancer patients?

项目概要 在不同血统的癌症患者中，其肿瘤的组成存在分子差异， 以及它们对治疗的反应。这些分子差异远远超出了种系差异，并且 与欧洲裔美国患者相比，非洲裔患者也包括体细胞和非突变改变。 美国前列腺癌​​患者患前列腺癌和死于前列腺癌的风险明显更高 这种死亡率与不可避免的耐药性有关，并且通常来自骨转移。 护理贡献，入组的非洲裔美国患者癌症进展的风险也更高 总体而言，有证据表明不同类型之间的分子差异有所增加。 祖先可以在改变肿瘤发生和对治疗的反应中发挥作用。 解决上述问题存在重大挑战。 非欧美患者的代表性不足，并且源自的细胞系有限 我们还需要有效的方法来在免疫功能正常的体内快速模拟肿瘤的进化。 和激素敏感的方式，开发相应的生物学相关的疗法。 为了应对这些重大挑战，我的中心愿景是探究肿瘤在祖先的进化过程中的进化。 这将使我们能够识别当前强大的驱动分子改变。 由于现有的非欧美患者群体的有限性，该疾病未被充分认识，并且还发展 针对此类肿瘤的有效疗法受到我自己的一部分患者的启发，这是该提案的核心。 是 BRUTE（条形码无监督肿瘤进化图）的开发，这是一种具有免疫活性的 基于类器官的肿瘤移植系统。 BRUTE 肿瘤在雄激素中的首次原理验证迭代。 依赖性前列腺组织衍生系统强烈识别 ERF 和其他未被充分认识的致癌因素 这种变化在非裔美国患者中尤为丰富。 使用我们易于处理的 BRUTE 系统和直系同源方法，我们将以祖先公正的方式进行调查 A) 解剖生态位和免疫系统如何改变致瘤性和耐药性的选择 细胞，B) 癌前群体中未来耐药细胞的生物学，以及 C) 如何 针对非欧裔美国患者中丰富的分子改变。 这是我们所知的第一个自发重现分子驱动因素的肿瘤进化系统 因此，我们可以用它来问：为什么是非裔美国人。 前列腺癌患者比欧美患者更容易死于骨转移？ 在药物暴露之前检测并消除代表性不足的患者肿瘤中未来的耐药细胞？ 我们能否开发靶向疗法来利用在非裔美国人中观察到的分子改变 前列腺癌患者？