AN INTEGRATED PLATFORM FOR NOVEL PERSONALIZED LIVER CANCER THERAPEUTICS

新型个性化肝癌治疗的综合平台

• 批准号: 10721585
• 负责人: Arvin Dar
• 金额: $ 25.35万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721585
• 关键词: Affect; Alcohols; Animal Model; Asian; Asian population; Authorization documentation; Biological Markers; Biology; Black Populations; Black, Indigenous, People of Color; Cancer Etiology; Characteristics; Chemicals; Chinese; Cirrhosis; Clinic; Clinical; Clinical Data; Clinical Management; Communication; Consent; Data; Development; Drug Screening; Drug toxicity; Drug usage; E-learning; Educational Intervention; Epigenetic Process; Equity; Ethnic Origin; Ethnic Population; Etiology; Evaluation; FDA approved; Feedback; Feeds; Focus Groups; Funding; Future; Genetic; Genomics; Goals; Grant; HBV HCC; Health; Hepatitis B Virus; Hepatitis C virus; Hispanic; Hispanic Populations; Intervention; Latinx; Lead; Link; Liver diseases; Malignant neoplasm of liver; Modeling; Organoids; Parents; Participant; Patient Education; Patients; Pre-Clinical Model; Precision therapeutics; Prevalence; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Race; Reporting; Research; Risk Factors; Testing; Therapeutic; Tissue Donations; Tissues; Toxic effect; Translations; Treatment Efficacy; chronic liver disease; clinical material; community based participatory research; digital intervention; drug discovery; drug efficacy; drug use screening; efficacy trial; ethnic disparity; ethnic diversity; feasibility trial; field study; improved; insight; kinase inhibitor; liver cancer model; mortality; multidisciplinary; nonalcoholic steatohepatitis; novel; patient stratification; patient subsets; patient-level barriers; personalized therapeutic; pre-clinical; pre-clinical research; preclinical study; preference; racial disparity; racial diversity; racial minority; racial population; response; satisfaction; screening; tumor; usability; willingness

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.

总结 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，HCC 死亡率受种族/族裔的影响很大，死亡率最高的是少数种族， 黑人，土著和有色人种（BIPOC）。这部分是由于（a）目前FDA批准的 （B）缺乏个性化（生物标志物引导的）治疗选择，这由于缺乏 来自不同种族背景的HCC临床前模型。 因此，迫切需要确定新的个性化治疗选择，这些选择在临床上得到验证。 临床前HCC模型，代表HCC患者中观察到的种族/民族多样性。 在这份补充我们母公司RO 1的提案中，我们扩大了原有团队，以整合新的专业知识 在公平研究，定性分析，通信研究，社区参与式研究， 实施，和组织研究（穆罕默德，Bickell），以现有的一个在临床管理 肝脏疾病（Villanueva）、化学生物学（Dar）、HCC动物模型（Lujambio）和患者来源的类器官 和2D线（Guccione）。 我们试图检验的主要假设是，BIPOC患者将报告组织的显著屏障 捐赠，并通过促进这种临床前模型（即PDO）的创建，从不同的病因和 广泛的民族/种族背景，我们将确定药物疗效和毒性的差异， 特定肿瘤遗传和表观遗传背景。 我们建议（a）阐明BIPOC HCC患者捐献组织的障碍和促进因素;（B）开发和 测试针对不同种族群体的文化定制教育干预，以鼓励组织捐赠 （c）建立更好的临床前模型（即患者衍生的类器官，PDO）， 考虑到病因学和种族-民族背景差异。后一种模型将输入到我们的原始模型中。 用于药物筛选的管道，旨在确定新的精确治疗线索。 拟议中的研究将增加我们对限制或实现组织捐赠的障碍的理解 从BIPOC HCC患者和定制的干预策略，以提高临床前模型的可用性， BIPOC患者，最终改善临床前研究并转化为临床。 主要交付成果包括新的临床前模型和来自经过充分验证的 化学起点和对HCC患者分层和治疗的机理见解。