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Project 2: Overcoming Microenvironment-Mediated Resistance to AR Pathway Inhibition in High-Risk Prostate Cancer

项目 2：克服微环境介导的高危前列腺癌 AR 通路抑制耐药性

基本信息

批准号：
10707969
负责人：
Brett Stewart Carver
金额：
$ 37.17万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-14 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707969
关键词：
Acetates Address Adjuvant Study Androgen Receptor Androgens Automobile Driving Basic Science Cells Clinical Clinical Sciences Clinical Trials Cytokine Receptors DNA Sequence Alteration Data Dependence Development Disease Disease Progression Doctor of Philosophy ERBB2 gene Epithelial Cells Generations Genes Genetically Engineered Mouse Goals Growth Factor Hormones Human Individual Ligands Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Mediator Metastatic Prostate Cancer Molecular Mus Neoadjuvant Therapy Neuregulin 1 Nonmetastatic PI3K/AKT PIK3CG gene PTEN gene Pathologic Pathway interactions Patients Phase Phase III Clinical Trials Play Population Population Dynamics Pre-Clinical Model Precision medicine trial Prevalence Prior Therapy Prostate Prostate Cancer therapy Prostatectomy Proto-Oncogene Proteins c-akt Radical Prostatectomy Receptor Inhibition Receptor Signaling Recurrence Reporting Resistance Role Science Shapes Signal Transduction Specimen Stromal Cells Technology Therapeutic Time Tissue-Specific Gene Expression Work abiraterone advanced prostate cancer androgen deprivation therapy antagonist cancer cell cancer initiation castration resistant prostate cancer cell growth clinical development cytokine disorder control early phase clinical trial enzalutamide high risk improved inhibitor men novel novel strategies phase III trial precision medicine preclinical trial primary endpoint prostate cancer cell prostate cancer model prostate cancer risk receptor response single cell sequencing single-cell RNA sequencing synergism targeted treatment therapeutic target tumor microenvironment

项目摘要

ABSTRACT/SUMMARY The majority of prostate cancers are dependent on androgen receptor (AR) signaling across clinical disease states. While initially approved for patients with metastatic castration-resistant prostate cancer, recent phase III trials have shown that second-generation AR pathway inhibitors (abiraterone acetate, enzalutamide, apalutamide, darolutamide) convey even greater benefit when used earlier in the disease course in patients with metastatic hormone-sensitive and non-metastatic castration-resistant prostate cancer. Indeed, this concept has also extended to the neoadjuvant treatment of patients with locally advanced high-grade primary prostate cancer. However, despite potent AR inhibition, complete pathologic response rates have remained low. Thus, there is a significant need to further define the mechanisms driving resistance to AR-targeted therapies in this unique context and develop therapeutic strategies that enhance response rates in patients with high-risk localized prostate cancer to shift the treatment paradigm from disease control to cure. Through single-cell RNA sequencing studies of human and mouse prostates, we recently discovered that neuregulin 1 (NRG1) is an AR-regulated gene in normal prostate stromal cells critical to sustaining survival of normal luminal epithelial cells. Parallel studies in prostate cancer preclinical models revealed that stromal- derived NRG1 in the prostate cancer microenvironment promotes cancer cell persistence following AR- targeted therapies. Secreted NRG1 promotes resistance through HER2/3-PI3K/AKT-mediated signaling in prostate cancer epithelial cells. We are now poised to define the NRG1 downstream signaling nodes driving cancer cell persistence to AR targeted therapies and optimize therapeutic strategies targeting the NRG1 axis in combination with AR inhibition. We will investigate the effects of targeting individual nodes of the NRG1- HER2/3-PI3K pathway to overcome resistance to AR-targeted therapies in preclinical trials using clinical-grade inhibitors of NRG1, HER2/3, PI3K, and AKT in combination with AR antagonists. Furthermore, in the proposed project we will take a comprehensive approach to defining the microenvironmental mechanisms contributing to prostate cancer cell persistence after AR-targeted therapy. Using single-cell sequencing technology, we will define the changes in prostate cancer microenvironmental cell populations following AR inhibition and evaluate differential gene expression within these cell populations to identify novel cytokine-receptor pairs contributing to cancer cell persistence in primary and metastatic prostate cancers. Finally, we will conduct a phase Ib/II neoadjuvant clinical trial of PI3K (copanlisib) and androgen-deprivation therapy prior to prostatectomy in patients harboring loss of PTEN, an established mediator of resistance to AR-targeted therapies. Our collective work will set the path for novel precision medicine–based neoadjuvant trials to improve the cure rates of men with high-risk localized prostate cancer.

摘要/总结大多数前列腺癌在临床疾病中依赖于雄激素受体（AR）信号传导。 states.虽然最初批准用于转移性去势抵抗性前列腺癌患者，但最近的III期试验表明第二代AR途径抑制剂（醋酸阿比特龙，恩杂鲁胺， apalutamide、darolutamide）在患者病程早期使用时获益更大患有转移性激素敏感性和非转移性去势抵抗性前列腺癌。这确这一概念还扩展到局部晚期高级别原发性肝癌患者的新辅助治疗。前列腺癌然而，尽管有有效的AR抑制，完全的病理反应率仍然存在，低因此，非常需要进一步定义驱动对AR靶向药物的抗性的机制。在这种独特的背景下治疗，并制定治疗策略，提高患者的反应率高危局限性前列腺癌的治疗模式从疾病控制转向治愈。通过对人类和小鼠前列腺的单细胞RNA测序研究，我们最近发现，神经调节蛋白1（NRG 1）是正常前列腺基质细胞中的AR调节基因，对维持前列腺增生症患者的存活至关重要。正常腔上皮细胞。在前列腺癌临床前模型中的平行研究显示，间质- 前列腺癌微环境中衍生的NRG 1促进AR后癌细胞的持续存在。靶向治疗。分泌的NRG 1通过HER 2/3-PI 3 K/AKT介导的信号传导促进耐药，前列腺癌上皮细胞我们现在准备定义NRG 1下游信令节点，驱动癌细胞对AR靶向治疗的持久性，并优化靶向NRG 1轴的治疗策略，与AR抑制的组合。我们将研究针对NRG 1的单个节点的影响， HER 2/3-PI 3 K通路在临床前试验中克服对AR靶向治疗的耐药性， NRG 1、HER 2/3、PI 3 K和AKT抑制剂与AR拮抗剂的组合。此外，在拟议的项目，我们将采取全面的方法来定义微环境机制，有助于 AR靶向治疗后的前列腺癌细胞持久性。利用单细胞测序技术，我们将定义AR抑制后前列腺癌微环境细胞群的变化，并评估这些细胞群中的差异基因表达，以鉴定新的精氨酸-受体对，与原发性和转移性前列腺癌中癌细胞的持续存在有关。最后，我们将进行Ib/II阶段前列腺切除术前PI 3 K（copanlisib）和雄激素剥夺治疗的新辅助临床试验携带PTEN缺失的患者，PTEN是对AR靶向疗法的抗性的既定介导物。我们的集体这项工作将为新的基于精确医学的新辅助治疗试验开辟道路，以提高男性的治愈率。患有高危局限性前列腺癌