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：
10304615
负责人：
PATRICIA Leal DAHIA
金额：
$ 52.54万
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/10304615
关键词：
Address Adrenal Glands Aggressive course Area Behavior Biological Biological Models Biological Response Modifier Therapy Biology CDK4 gene Catecholamines Cells Clinical Clinical Management Clinical Trials Data Detection Development Diagnosis Disease Drug Screening Early Diagnosis Epithelial Experimental Designs Experimental Models Future Genetic Human Individual Investigation Knowledge Low Prevalence Malignant - descriptor Malignant Neoplasms Malignant Paraganglionic Neoplasm Methods Modeling Molecular Morphologic artifacts Neoplasm Metastasis Nervous system structure Neural Crest Neuroendocrine Tumors Organoids Outcome Paraganglia structure Paraganglioma Patients Pharmaceutical Preparations Pheochromocytoma Population Primary Neoplasm Property Recurrence Research Resources Survival Rate Testing Therapeutic Tumor Biology Tumor Markers Tumor-Derived anticancer research base 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.

该提案回应了具有争议性的问题 PQ9：可以开发哪些方法来有效地研究与癌症研究相关的小规模或稀有人群？我们将通过生成来解决这个问题嗜铬细胞瘤和副神经节瘤（PPGL）的类器官模型填补了潜在机制的空白肿瘤行为和治疗机会。 PPGL 是一种罕见的儿茶酚胺分泌物，源自神经嵴肿瘤分别起源于肾上腺或肾上腺外副神经节。恶性 PPGL 只能是在检测到转移后才被识别，这意味着诊断较晚。大约 30-40% 的副神经节瘤， 10-15%的嗜铬细胞瘤可发生转移。此外，PPGL在临床上具有异质性，即使没有转移，也可能是复发性和侵袭性的，但缺乏临床行为的预测因素。治疗目前的选择有限，对生存影响不大，而且这一领域的进展受到了阻碍研究模型稀缺。因此，迫切需要开发模型来揭示生物学特征促进临床结果预测并揭示可探索的分子脆弱性的机制出于治疗目的。我们的初步数据表明我们可以成功生成 PPGL 类器官适合药物筛查。我们的目标是：1）确定 PPGL 类器官是否概括了亲本肿瘤； 2）利用PPGL类器官来研究突出的生物学问题，包括可能与肿瘤结果相关的细胞亚型的存在，以及 3) 利用 PPGL 类器官进行高高通量药物筛选，揭示未来治疗测试的漏洞，包括新的先导化合物我们的初步数据中建议。拟议的项目将作为设计未来的有用资源研究解码 PPGL 开发和临床的细胞和分子机制异质性。这些研究的结果可能为未来测试候选药物提供基础可能具有直接的临床应用。