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：
10522915
负责人：
Leah Marie Cook
金额：
$ 35.11万
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/10522915
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 Metastatic to Modeling Molecular Mus Neoplasm Metastasis Nonmetastatic Outcome Pain Patient-Focused Outcomes Patients Phenotype Pilot Projects Prostate Protein-Serine-Threonine Kinases Receptor Signaling Receptors, Adrenergic, beta-1 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 base bone cancer recurrence 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

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cast割的前列腺癌（MCRPC）是致命的，目前是无法治愈的。约90％ CRPC患者对第二行雄激素剥夺疗法具有抗性（ADT；哪个主要目标雄激素受体（AR）信号传导，并伴有骨转移性疾病。虽然ADT仍然是有益的 MCRPC患者的治疗，MCRPC癌症抗性机制，特别是在骨骼中环境是CRPC转移最常见的部位，对环境知之甚少。理解贡献需要进一步发展有效疗法的PCA疾病进展因素。 ADT是先前证明对多形核白细胞/中性粒细胞的分化和功能至关重要（PMN）是占骨髓腔的40-50％的“第一响应者”先天免疫细胞。我们最近显示，PMN受到保护免受骨转移性前列腺癌（BM-PCA）的保护，但是PMN 随着肿瘤的进展，抗肿瘤免疫反应会减少。检查PMN表型变化通过患者的PCA进展，我的组在功能和分子上表征外周血来自不同阶段的PCA患者的PMN：1）局部PCA，2）骨转移性骑马敏感（MCSPC）， 3）MCRPC患者。我们发现，通过增加，第二行ADT高度抑制了PMN功能受体1转化生长因子β（TGFβ）的表达，一种抗炎细胞因子对促进BM-PCA和癌症引起的骨病。使用临床前骨转移小鼠模型，我们能够使用第二线ADT与任一双极结合使用第二行ADT显着抑制MCRPC的生长雄激素疗法（BAT；外源睾丸激素）以增强PMN抗肿瘤反应或PMN特异性通用 TβR1的缺失。根据我们的初步发现，我们假设：抗肿瘤PMN被抑制/ 通过TβR1信号调节雄激素调节“关闭”，可以利用这以改善MCRPC 结果。这将在以下目的中进行测试：目标1。定义雄激素调节对PMN的影响抗肿瘤免疫响应。 AIM 2。确定TβR1介导的PMN免疫反应的机理 BM-PCA。 AIM 3。描述双重TβR1/AR调控以改善MCRPC的治疗潜力治疗结果。主要目标：制定一种治疗BM-PCA的新型免疫治疗策略通过增强PMN抗肿瘤反应并克服对ADT的PCA耐药性。研究设计：对于目标1，我们将确定雄激素信号传导对PMN极化离体的影响（使用患者衍生的PMN和小鼠骨髓PMN）和体内使用正常的PCA，非转移性和骨转移性PCA细胞）和体内（使用小鼠内部骨转移模型）。对于AIM 2，我们将描述TβR1在PMN中的作用使用TβR1基因敲除模型对MCRPC的响应。对于AIM 3，我们将定义使用的治疗潜力蝙蝠与新型的骨靶向TβR1抑制剂的组合。