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.

该建议对挑衅性问题PQ9做出了回应：可以开发哪些方法来有效地研究与癌症研究有关的小或稀有人群？我们将通过生成来解决这个问题嗜铬细胞瘤和paragangliomas（PPGL）的类器官模型，以填补基础机理的间隙肿瘤行为和治疗机会。 PPGL是罕见的儿茶酚胺分泌，神经rest衍生的肿瘤分别来自肾上腺或额外的肾上腺paraganglia。恶性PPGL只能是在检测转移酶后识别，这意味着诊断晚期。大约30-40％的Paragangliomas， 10-15％的嗜铬细胞瘤可以发展转移。此外，PPGL在临床上是异质的，即使没有转移，也可以复发和侵入性，但是缺乏临床行为的预测指标。治疗目前的期权受到限制，对生存产生适度的影响，并且该领域的进步受到了研究模型的稀缺性。因此，开发模型以发现生物学的迫切需要促进临床结果预测并揭示了可以探索的分子脆弱性的机制用于治疗目的。我们的初步数据表明，我们可以成功生成PPGL器官适合药物筛查。我们的目的是：1）确定PPGL器官是否概括了父母肿瘤； 2）利用PPGL器官来研究杰出的生物学问题，包括可能与肿瘤结局有关的细胞亚型的存在，以及3）利用PPGL器官进行高吞吐药物筛查发现未来治疗测试的脆弱性，包括新铅在我们的初步数据中提出了建议。拟议的项目将是设计未来的有用资源解码PPGL发育和临床基础的细胞和分子机制的研究异质性。这些研究的结果可能为未来测试候选药物的基础提供了基础可能会立即使用临床应用。