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Leveraging PMN immune response to overcome ADT resistance in bone metastatic prostate cancer

利用 PMN 免疫反应克服骨转移性前列腺癌的 ADT 耐药性

基本信息

批准号：
10684116
负责人：
Grinu Mathew
金额：
$ 34.41万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684116
关键词：
Aftercare Androgen Receptor Androgen Therapy Androgens Anti-Inflammatory Agents Antitumor Response Biological Assay Bone Diseases Bone Marrow Bone neoplasms Cancer Patient Cells ChIP-seq Clinical Trials Co-Immunoprecipitations Development Diagnosis Disease Disease Progression Dose Enterobacteria phage P1 Cre recombinase Environment Gene Expression Generations Genetic Gonadotropin Hormone Releasing Hormone Growth Hormones Immune Immune Evasion Immune response Immunotherapeutic agent Immunotherapy In Vitro Knock-out Knockout Mice Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Molecular Mus Neoplasm Metastasis Nonmetastatic Outcome Pain Patient-Focused Outcomes Patients Pilot Projects Prostate Protein-Serine-Threonine Kinases Receptor Signaling Receptors, Adrenergic, beta-1 Recurrent Malignant Neoplasm Regulation Research Research Design Resistance Role Signal Transduction Site Stanolone Testing Testosterone Therapeutic Transforming Growth Factor beta Transforming Growth Factor beta Receptors androgen deprivation therapy antagonist anti-tumor immune response bone cancer recurrence carcinogenesis castration resistant prostate cancer clinical translation conditional knockout cytokine cytotoxic diagnostic tool efficacious treatment enzalutamide first responder fracture risk functional group high risk improved in vivo inhibitor knock-down mouse model neutrophil new therapeutic target novel peripheral blood pre-clinical prevent prostate cancer metastasis prostate cancer progression receptor response standard of care targeted treatment therapy outcome transcriptome transcriptome sequencing treatment group tumor tumor growth tumor immunology tumor progression

项目摘要

Metastatic castration-resistant prostate cancer (mCRPC) is deadly and currently incurable. Approximately 90% of patients CRPC become resistant to 2nd line androgen deprivation therapy (ADT; which primarily target androgen receptor (AR) signaling and present with bone metastatic disease. Although ADT remains a beneficial therapy for mCRPC patients, mechanisms of cancer resistance in mCRPC and specifically, in the bone environment, the most frequent site of CRPC metastasis, is poorly understood. Understanding contributing factors to PCa disease progression is needed for further development of efficacious therapies. ADT was previously shown to be critical for differentiation and function of polymorphonuclear leukocytes/neutrophils (PMNs) which are “first responder” innate immune cells that comprise ~40-50% of the bone marrow cavity. We recently showed that PMNs are protective against bone metastatic prostate cancer (BM-PCa) however, the PMN anti-tumoral immune response diminishes as the tumor progresses. To examine PMN phenotypical changes throughout PCa progression in patients, my group functionally and molecularly characterized peripheral blood PMNs from PCa patients at different stages: 1) Localized PCa, 2) bone metastatic hormone-sensitive (mCSPC), and 3) mCRPC patient. We found that PMN function was highly suppressed by 2nd line ADT through increased receptor 1 expression of transforming growth factor beta (TGFβ), an anti-inflammatory cytokine important for promoting BM-PCa and cancer-induced bone disease. Using preclinical bone metastasis mouse models, we were able to significantly suppress mCRPC growth in bone using 2nd line ADT in combination with either bipolar androgen therapy (BAT; exogenous testosterone) to boost PMN anti-tumor response OR PMN-specific genetic deletion of TβR1. Based on our preliminary findings, we hypothesize that: anti-tumor PMNs are suppressed/ “switched off” by androgen regulation via TβR1 signaling and this can be leveraged to improve mCRPC outcomes. This will be tested in the following aims: Aim 1. Define the impact of androgen regulation on PMN anti-tumor immune response. Aim 2. Determine the mechanism of TβR1-mediated PMN immune response in BM-PCa. Aim 3. Delineate the therapeutic potential of dual TβR1/AR regulation for improving mCRPC therapeutic outcomes. Primary Objective: To develop a novel immunotherapeutic strategy for treating BM-PCa by enhancing PMN anti-tumor response and overcoming PCa resistance to ADT. Study Design: For Aim 1, we will identify the impact of androgen signaling on PMN polarization ex vivo (using patient-derived PMNs and mouse bone marrow PMNs) and in vivo using normal PCa, non-metastatic and bone metastatic PCa cells) and in vivo (using mouse intratibial bone metastasis models). For Aim 2, we will delineate the role of TβR1 in PMN response to mCRPC using TβR1 knockout models. For Aim 3, we will define the therapeutic potential for using combination BAT with a novel bone-targeted TβR1 inhibitor.

转移性去势抵抗性前列腺癌（mCRPC）是致命的，目前无法治愈。约90% 的 CRPC 患者对二线雄激素剥夺疗法 (ADT；主要针对雄激素受体 (AR) 信号传导并伴有骨转移性疾病。尽管 ADT 仍然是有益的 mCRPC 患者的治疗、mCRPC 的抗癌机制，特别是骨骼的抗癌机制环境是 CRPC 转移最常见的部位，但人们对其知之甚少。了解贡献为了进一步开发有效的疗法，需要了解 PCa 疾病进展的因素。 ADT 为先前显示对多形核白细胞/中性粒细胞的分化和功能至关重要 (PMN) 是“第一反应者”先天免疫细胞，占骨髓腔的 40-50%。我们最近表明，PMN 对骨转移性前列腺癌 (BM-PCa) 具有保护作用，然而，PMN 随着肿瘤的进展，抗肿瘤免疫反应减弱。检查 PMN 表型变化在患者的整个 PCa 进展过程中，我的团队对外周血进行了功能和分子特征分析来自不同阶段PCa患者的PMN：1）局部PCa，2）骨转移激素敏感（mCSPC）， 3) mCRPC 患者。我们发现 PMN 功能被第二线 ADT 高度抑制，通过增加转化生长因子 β (TGFβ) 受体 1 的表达，TGFβ 是一种重要的抗炎细胞因子促进 BM-PCa 和癌症诱发的骨疾病。使用临床前骨转移小鼠模型，我们使用第二线 ADT 与双极治疗相结合，能够显着抑制骨中 mCRPC 的生长雄激素疗法（BAT；外源性睾酮）可增强中性粒细胞抗肿瘤反应或中性粒细胞特异性遗传 TβR1 缺失。根据我们的初步发现，我们假设：抗肿瘤 PMN 受到抑制/ 通过 TβR1 信号传导通过雄激素调节“关闭”，这可用于改善 mCRPC 结果。这将在以下目标中进行测试：目标 1. 定义雄激素调节对 PMN 的影响抗肿瘤免疫反应。目的 2. 确定 TβR1 介导的 PMN 免疫反应的机制骨髓-前列腺癌。目标 3. 描绘 TβR1/AR 双重调节改善 mCRPC 的治疗潜力治疗结果。主要目标：开发治疗 BM-PCa 的新型免疫治疗策略通过增强 PMN 抗肿瘤反应并克服 PCa 对 ADT 的抵抗。研究设计：对于目标 1，我们将确定雄激素信号传导对体外 PMN 极化的影响（使用患者来源的 PMN 和小鼠骨髓 PMN）和体内使用正常 PCa、非转移性和骨转移性 PCa 细胞）和体内（使用小鼠胫骨内骨转移模型）。对于目标 2，我们将描述 TβR1 在 PMN 中的作用使用 TβR1 敲除模型对 mCRPC 的反应。对于目标 3，我们将定义使用的治疗潜力 BAT 与新型骨靶向 TβR1 抑制剂的组合。