AN INTEGRATED PLATFORM FOR NOVEL PERSONALIZED LIVER CANCER THERAPEUTICS

摘要 肝细胞癌(HCC)是一个主要的健康问题，死亡率不断上升。在美国，肝细胞癌 死亡率受种族/族裔的影响很大，少数族裔的死亡率最高，例如 黑人、土著和有色人种(BIPOC)。这部分是由于(A)目前FDA批准的疗效有限 治疗和(B)缺乏个性化(生物标记物引导的)治疗选择，这一点因缺乏而更加严重 来自不同种族背景的肝细胞癌临床前模型。 因此，迫切需要确定新的个性化治疗选项，这些选项在 代表在肝癌患者中观察到的种族/民族多样性的临床前肝癌模型。 在这份补充我们母公司RO1的提案中，我们扩展了原有团队，以整合新的专业知识 在股权研究、定性分析、传播研究、基于社区的参与性研究、 实施和组织研究(Mohamed，Bickell)，以现有的临床管理为基础 肝病(Villanueva)、化学生物学(DAR)、肝细胞癌动物模型(Lujbio)和患者衍生的有机化合物 和二维线(Guccione)。 我们试图检验的主要假设是，BIPOC患者将报告对组织的显著屏障 以及通过促进从不同的病因学和 广泛的民族/种族背景，我们将确定药物疗效和毒性的差异与 与特定的肿瘤遗传和表观遗传背景有关。 我们建议(A)阐明BIPOC肝细胞癌患者捐献组织的障碍和促进者；(B)开发和 测试针对不同种族-民族群体的文化定制教育干预措施，以鼓励组织捐赠 以及(C)建立更好的临床前模型(即患者衍生的有机物，PDO)，以采取 考虑到病因和种族-民族背景的差异。后一种型号将添加到我们的原始版本中 药物筛选流水线，目的是确定新的精确治疗线索。 这项拟议的研究将增加我们对限制或允许组织捐赠的障碍的了解 从BIPOC肝癌患者到量身定制的干预策略，以提高临床前模型的可用性 BIPOC患者，最终改善了临床前研究并转化为临床。 关键交付成果包括新的临床前模型和源自经过充分验证的药物发现的线索 对肝细胞癌患者分层和治疗的化学起点和机械洞察力。

SUMMARY Hepatocellular carcinoma (HCC) is a major health problem, with increasing mortality rates. In the US, HCC mortality is strongly affected by race/ethnicity and the highest mortality is found among racial minorities such as Black, Indigenous and People of Color (BIPOC). This is partly due to (a) limited efficacy of current FDA-approved therapies and (b) a lack of personalized (biomarker-guided) therapeutic options, which is compounded by a lack of HCC preclinical models from diverse race-ethnic backgrounds. Thus, there is an urgent need to identify novel personalized therapeutic options that are validated in preclinical HCC models that represent the racial/ethnic diversity observed in HCC patients. In this proposal for a supplement to our parental RO1, we expand our original team to integrate new expertise in equity research, qualitative analytics, communications research community-based participatory research, implementation, and organizational research (Mohamed, Bickell), to the existing one in clinical management of liver disease (Villanueva), chemical biology (Dar), HCC animal models (Lujambio) and patient derived-organoids and 2D lines (Guccione). The major hypothesis that we seek to test is that BIPOC patients will report significant barriers to tissue donation and that by facilitating the creation of such preclinical models (i.e. PDO) from diverse etiology and a broad spectrum of ethnic/racial backgrounds, we will identify differences in drug efficacy and toxicity in relation to specific tumor genetic and epigenetic backgrounds. We propose to (a) Elucidate BIPOC HCC patients’ barriers and facilitators to donate tissue; (b) Develop and test a culturally tailored educational intervention for diverse racial-ethnic groups, to encourage tissue donation from HCC patients; and to (c) Establish better preclinical models (i.e. patient derived organoids, PDOs) that take into account differences in etiology and racial-ethnic background. The latter models will then feed into our original pipeline for drug screening, with the aim to identify new precision therapeutic leads. The proposed research will increase our understanding of the barriers that limit or enable tissue donation from BIPOC HCC patients and to tailored intervention strategies to improve availability of preclinical models from BIPOC patients, ultimately resulting in improved preclinical studies and translation into the clinics. Key deliverables include new preclinical models and leads for drug discovery derived from well-validated chemical starting points and mechanistic insights into patient stratification and therapeutics for HCC.