AN INTEGRATED PLATFORM FOR NOVEL PERSONALIZED LIVER CANCER THERAPEUTICS

新型个性化肝癌治疗的综合平台

基本信息

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
项目类别：
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

项目摘要

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.

概括肝细胞癌 (HCC) 是一个主要的健康问题，在美国，HCC 的死亡率不断上升。死亡率很大程度上受种族/族裔影响，少数族裔死亡率最高，例如黑人、原住民和有色人种 (BIPOC) 这部分是由于 (a) 当前 FDA 批准的功效有限。疗法和（b）缺乏个性化（生物标志物引导）治疗选择，而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方案，并在这些方案中得到验证。代表 HCC 患者中观察到的种族/民族多样性的临床前 HCC 模型。在这个补充我们母公司 RO1 的提案中，我们扩大了原来的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），以现有的临床管理肝病 (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)。我们试图测试的主要假设是 BIPOC 患者会报告组织存在显着障碍捐赠，并通过促进根据不同病因学和研究方法创建此类临床前模型（即 PDO）广泛的种族/种族背景，我们将确定药物疗效和毒性的差异特定的肿瘤遗传和表观遗传背景。我们建议 (a) 阐明 BIPOC HCC 患者捐赠组织的障碍和促进因素；测试针对不同种族群体的文化定制教育干预措施，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背景的差异，后一个模型将被纳入我们最初的模型中。药物筛选管道，旨在确定新的精准治疗先导药物。拟议的研究将增加我们对限制或实现组织捐赠的障碍的理解来自 BIPOC HCC 患者的研究，以及量身定制的干预策略，以提高来自 BIPOC HCC 患者的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经过充分验证的药物发现线索 HCC 患者分层和治疗的化学起点和机制见解。