Microfluidic isolation and molecular analysis of circulating tumor cells for the study of neuroendocrine transdifferentiation in prostate cancer

循环肿瘤细胞的微流体分离和分子分析用于前列腺癌神经内分泌转分化的研究

• 批准号: 10597026
• 负责人: Ravi Amrit Madan
• 金额: $ 59.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597026
• 关键词: Androgen Receptor; Biopsy; Biopsy Specimen; Blood; Cancer Patient; Castrate sensitive prostate cancer; Cell Separation; Cells; Clinical; Clinical Trials; Collaborations; Collection; DNA Sequence Alteration; DNA analysis; Development; Disease; EZH2 gene; Evaluation; Evolution; Exposure to; Extramural Activities; Frequencies; Future; General Hospitals; Genetic Transcription; Genomics; Goals; Immune; Immune response; Immuno-Chemotherapy; Immunotherapy; Incidence; Leukapheresis; Malignant Neoplasms; Malignant neoplasm of prostate; Massachusetts; Metastatic Prostate Cancer; Methods; Microfluidic Microchips; Microfluidics; Molecular; Molecular Analysis; Molecular Profiling; Monitor; Neoplasm Circulating Cells; Neoplasm Metastasis; Neuroendocrine Prostate Cancer; Neurosecretory Systems; Outcome; Patients; Pattern; Phenotype; Process; Prostate Cancer therapy; Public Health; RB1 gene; Research; Research Project Grants; Resources; Systemic Therapy; TP53 gene; Technology; Therapeutic; Time; Tissues; Translational Research; United States National Institutes of Health; cancer cell; castration resistant prostate cancer; clinical biomarkers; clinical center; clinical development; design; docetaxel; immunotherapy trials; improved; innovation; insight; liquid biopsy; multidisciplinary; neuroendocrine phenotype; next generation; novel; novel strategies; participant enrollment; precision oncology; prevent; prostate biopsy; prostate cancer progression; protein biomarkers; rare cancer; refractory cancer; standard of care; targeted treatment; tool; transdifferentiation; treatment response; tumor; tumor DNA

PROJECT SUMMARY / ABSTRACT Although next-generation androgen receptor (AR)-targeted therapies have increased survival in prostate cancer patients, recent studies reveal that exposure to these therapies result in transdifferentiation to an aggressive neuroendocrine (NE) phenotype in nearly one fifth of cases. The molecular determinants of lineage plasticity in prostate cancer are poorly understood, and there is an unmet need for non-invasive methods to study the emergence of treatment-induced lineage plasticity over time. Our team at the Massachusetts General Hospital (MGH) recently developed a novel microfluidic chip, the LPCTC-iChip, for the high-throughput isolation of circulating tumor cells (CTCs) from an entire leukapheresis product, thus providing a non-invasive alternative to serial tumor biopsies for real-time molecular profiling. In this extramural-intramural collaborative patient-centric translational research project, we propose to incorporate the LPCTC-iChip into an NCI intramural clinical trials to investigate NE transdifferentiation in prostate cancer. The overall objective of this application is to gain insight into the temporal development, molecular determinants, and clinical impact of NE transdifferentiation by analyzing CTCs in comparison to matched tumor biopsies from prostate cancer patients in a chemoimmunotherapy trial at the NIH Clinical Center. Our central hypothesis is that CTC analyses can capture the dynamic lineage state of prostate cancers during and after therapy, and that immune responses can delay the clinical impact of the NE phenotype. To attain the overall objective, the following three specific aims will be pursued: 1) Evaluate matched CTCs and metastatic biopsies from patients with heavily pre-treated metastatic castration- resistant prostate cancer for hallmarks of NE phenotype; 2) Evaluate serial CTCs in patients with metastatic castration-sensitive prostate cancer for NE transdifferentiation during therapy; and 3) Determine the association between immune responses, NE phenotype, and clinical outcomes. The LPCTC-iChip will be physically placed at the NIH Clinical Center, and serial CTCs and matched biopsies from mCRPC and mCSPC patients enrolled in the chemoimmunotherapy study of M7824+M9241+docetaxel (NCT04633252) will be analyzed for genomic, transcriptional, and protein markers of the NE phenotype. The proposed research is innovative because it utilizes a novel microfluidic device, the LPCTC-iChip, for the isolation of CTCs to interrogate a highly relevant problem in prostate cancer. The research is significant because it is expected to provide a non-invasive alternative to tissue biopsy for monitoring treatment- induced lineage plasticity, as well as provide a strong scientific framework for the design of future clinical trials to prevent and treat lethal NE phenotype prostate cancers. This intramural-extramural collaboration leverages unique resources from MGH and NCI to understand an important disease process, NE transdifferentiation, with implications for prostate cancer treatment monitoring and therapy.

项目概要/摘要 尽管下一代雄激素受体（AR）靶向疗法已提高了患者的生存率 前列腺癌患者，最近的研究表明，接触这些疗法会导致转分化 近五分之一的病例出现侵袭性神经内分泌（NE）表型。分子决定因素 对前列腺癌谱系可塑性的了解知之甚少，并且对非侵入性治疗的需求尚未得到满足 研究治疗引起的谱系可塑性随时间的出现的方法。我们的团队在 麻省总医院 (MGH) 最近开发了一种新型微流控芯片 LPCTC-iChip，用于 从整个白细胞去除术产品中高通量分离循环肿瘤细胞 (CTC)，从而 为实时分子分析提供连续肿瘤活检的非侵入性替代方案。在这个 校外-校内协作以患者为中心的转化研究项目，我们建议 将 LPCTC-iChip 纳入 NCI 壁内临床试验，以研究 NE 转分化 前列腺癌。该应用程序的总体目标是深入了解时间发展， 通过与 CTC 进行比较来分析 NE 转分化的分子决定因素和临床影响 NIH 临床化学免疫治疗试验中来自前列腺癌患者的匹配肿瘤活检 中心。我们的中心假设是 CTC 分析可以捕获前列腺的动态谱系状态 治疗期间和治疗后的癌症，免疫反应可以延迟 NE 的临床影响 表型。为实现总体目标，将追求以下三个具体目标： 1）评估 来自经过大量预处理的转移性去势患者的匹配 CTC 和转移性活检 具有 NE 表型特征的耐药性前列腺癌； 2) 评估患者的连续 CTC 治疗期间用于 NE 转分化的转移性去势敏感型前列腺癌； 3) 确定 免疫反应、NE 表型和临床结果之间的关联。 LPCTC-iChip 将 实际放置在 NIH 临床中心，以及来自 mCRPC 和的连续 CTC 和匹配活检 mCSPC患者参加M7824+M9241+多西他赛化疗免疫治疗研究 (NCT04633252) 将分析 NE 表型的基因组、转录和蛋白质标记。 所提出的研究具有创新性，因为它利用了一种新型微流体装置 LPCTC-iChip， 分离 CTC 来研究前列腺癌中一个高度相关的问题。研究意义重大 因为它有望为监测治疗提供组织活检的非侵入性替代方案 - 诱导谱系可塑性，并为未来临床设计提供强有力的科学框架 预防和治疗致命性 NE 表型前列腺癌的试验。此次校内校外合作 利用 MGH 和 NCI 的独特资源来了解重要的疾病过程 NE 转分化，对前列腺癌治疗监测和治疗具有影响。