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?

项目摘要 在不同祖先的癌症患者中，其肿瘤的组成存在分子差异， 以及他们对治疗的反应这些分子差异远远超出了种系差异， 也包括体细胞和非突变的改变。与欧美患者相比，非洲- 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。 癌这种死亡率与不可避免的耐药性有关，通常来自骨转移。虽然访问- 对于参加研究的非裔美国人患者， 积极的监视计划。总的来说，有证据表明，分子差异丰富了不同的 祖先可以在改变肿瘤发生和对治疗的反应方面发挥作用。 在解决上述问题方面存在重大挑战。患者肿瘤的大型分子谱队列 在非欧洲裔美国人患者中代表性不足，并且只有有限的细胞系来源于 这样的病人。我们还需要有效的方法来在免疫活性的细胞中快速模拟体内肿瘤演变， 和对疾病敏感的方式，开发相应的治疗方法，是生物相关的。 为了应对这些重大挑战，我的中心愿景是在一个祖先群体中研究肿瘤的演变。 公正的方式。这将使我们能够识别目前在基因组中存在的强大的驱动分子改变。 由于现有非欧洲裔美国人患者队列的有限性， 有效治疗此类肿瘤。受我自己的一部分病人的启发， BRUTE（BaR编码的无监督肿瘤进化图）的发展， 类器官肿瘤移植系统在雄激素治疗中首次验证了BRUTE肿瘤的原理- 依赖性前列腺组织衍生系统强烈识别ERF和其他未被重视的致癌基因 在非裔美国人患者中，这种改变是独一无二的。 使用我们易于处理的BRUTE系统和正交方法，我们将在一个祖先无偏的 方式A）解剖学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）癌前体群体中未来耐药细胞的生物学，以及C）如何 针对非欧洲裔美国人患者中富集的分子改变。 这是第一个我们所知道的自发重演分子驱动的肿瘤进化系统 在代表性不足的患者队列中观察到的变化。因此，我们可以用它来问：为什么非裔美国人 前列腺癌患者比欧美患者更容易死于骨转移？我们能 在药物暴露前检测并消除代表性不足的患者肿瘤中未来的耐药细胞？ 我们能开发出靶向治疗来利用在非裔美国人中观察到的分子改变吗？ 前列腺癌患者？