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Addressing biological and therapeutic gaps in rare neuroendocrine cancer with a novel organoid-based model

利用新型类器官模型解决罕见神经内分泌癌的生物学和治疗差距

基本信息

批准号：
10693929
负责人：
PATRICIA Leal DAHIA
金额：
$ 48.35万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2021-09-08 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693929
关键词：
Address Adrenal Glands Aggressive course Area Behavior Biological Biological Models Biology CDK4 gene Catecholamines Cells Clinical Clinical Management Clinical Trials Data Detection Development Diagnosis Disease Drug Screening Early Diagnosis Epithelium Experimental Designs Experimental Models Future Genetic Human Individual Investigation Knowledge Low Prevalence Malignant - descriptor Malignant Neoplasms Malignant Paraganglionic Neoplasm Malignant Pheochromocytoma Metastatic Pheochromocytoma Methods Modeling Molecular Morphologic artifacts Neoplasm Metastasis Nervous System Neural Crest Neuroendocrine Tumors Organoids Outcome Paraganglia structure Paraganglioma Patient-Focused Outcomes Patients Pharmaceutical Preparations Pheochromocytoma Population Primary Neoplasm Property Recurrence Research Resources Survival Rate Testing Therapeutic Tumor Biology Tumor Markers anticancer research chemotherapy clinical application clinical heterogeneity clinical predictors design drug candidate drug sensitivity effective therapy high-throughput drug screening improved insight molecular marker neuroendocrine cancer novel novel therapeutics pluripotency predict clinical outcome predictive marker targeted agent therapeutic evaluation therapeutic target transcriptome tumor tumor behavior tumor initiation tumor progression whole genome

项目摘要

This proposal responds to the provocative question PQ9: What methods can be developed to effectively study small or rare populations relevant to cancer research? We will address this question by generating organoid models of pheochromocytomas and paragangliomas (PPGL) to fill gaps in the mechanisms underlying tumor behavior and in therapeutic opportunities. PPGLs are rare catecholamine-secreting, neural crest-derived tumors originating from adrenal or extra adrenal paraganglia, respectively. Malignant PPGLs can only be recognized after detection of metastases, implying a late diagnosis. Approximately 30-40% of paragangliomas, and 10-15% of pheochromocytomas can develop metastases. In addition, PPGLs are clinically heterogeneous, can be recurrent and invasive, even without metastasis, but predictors of clinical behavior are lacking. Treatment options are currently limited, with modest effects on survival, and advances in this area are dampened by a scarcity of research models. Therefore, there is a critical need for developing models to uncover biological mechanisms that facilitate clinical outcome prediction and reveal molecular vulnerabilities which can be explored for therapeutic purposes. Our preliminary data indicate that we can successfully generate PPGL organoids that are amenable for drug screen. Our aims are: 1) to determine if PPGL organoids recapitulate features of the parental tumor; 2) to leverage PPGL organoids to investigate outstanding biological questions, including the existence of cell subtypes that may be related to tumor outcome, and 3) to utilize PPGL organoids for high- throughput drug screening that uncover vulnerabilities for future therapeutic testing, including novel leads suggested in our preliminary data. The proposed project will serve as a useful resource for designing future studies to decode the cellular and molecular mechanisms underlying PPGL development and clinical heterogeneity. Results from these studies may provide the groundwork for future testing of candidate drugs that might have immediate clinical application.

这一建议回应了PQ9的挑衅性问题：什么方法可以有效地发展