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

• 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
• 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

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PQ 9这一具有挑衅性的问题：可以制定哪些方法来有效地 研究与癌症研究相关的小规模或罕见人群？我们将通过生成 嗜铬细胞瘤和副神经节瘤（PPGL）的类器官模型，以填补潜在机制的空白 肿瘤行为和治疗机会。PPGL是一种罕见的分泌儿茶酚胺的神经嵴源性 分别来自肾上腺或肾上腺外副神经节的肿瘤。恶性PPGL只能是 在检测到转移后识别，意味着晚期诊断。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在临床上是异质性的， 可能是复发性和侵袭性的，甚至没有转移，但缺乏临床行为的预测因素。治疗 目前的选择有限，对生存的影响不大，这一领域的进展受到了 缺乏研究模式。因此，迫切需要开发模型来揭示生物学特性， 促进临床结果预测并揭示可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，我们可以成功地产生PPGL类器官， 可以进行药物筛查我们的目标是：1）确定PPGL类器官是否概括了 亲代肿瘤; 2）利用PPGL类器官来研究悬而未决的生物学问题，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- 通过药物筛选，发现未来治疗测试的漏洞，包括新的线索 我们的初步数据显示。拟议的项目将作为一个有用的资源，设计未来的 研究，以解码PPGL发展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， 可能会立即应用于临床。