Targeting convergent oncogenic signaling during AR inhibition to overcome metastasis and immune evasion in prostate cancer

AR抑制过程中靶向汇聚致癌信号以克服前列腺癌的转移和免疫逃避

• 批准号: 10665659
• 负责人: Andrew J Armstrong
• 金额: $ 44.29万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665659
• 关键词: Acetates; Androgen Receptor; Biological Markers; Biopsy; Cancer Biology; Castrate sensitive prostate cancer; Castration; Cause of Death; Cell Survival; Cells; Cessation of life; Circulation; Clinical; Clinical Trials; Correlative Study; Cultured Tumor Cells; Data; Disease Resistance; Drug resistance; Genetic Engineering; Goals; Hormonal; Hormones; Human; Immune; Immune Evasion; Immune system; Immunocompetent; Immunocompromised Host; Immunotherapy; Innovative Therapy; MAP Kinase Gene; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Modeling; Neoplasm Circulating Cells; Neoplasm Metastasis; Oncogenic; Outcome; PD-1 blockade; PDL1 pathway; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Pre-Clinical Model; RNA analysis; Receptor Inhibition; Receptor Signaling; Reporting; Resistance; Signal Transduction; Snails; Stress; T cell response; Testing; Therapeutic; Tissues; Transgenic Mice; Translational Research; Translations; Up-Regulation; Xenograft Model; Xenograft procedure; abiraterone; biological adaptation to stress; castration resistant prostate cancer; clinical translation; enzalutamide; experimental study; gene regulatory network; hormone resistance; hormone therapy; immune checkpoint; improved; in vivo; inhibitor; men; novel; novel therapeutics; overexpression; p38 Mitogen Activated Protein Kinase; patient derived xenograft model; pharmacologic; phosphoproteomics; pre-clinical; preclinical study; predictive marker; prevent; programmed cell death ligand 1; prostate cancer cell line; prostate cancer metastasis; prostate cancer model; reconstitution; resistance mechanism; small molecule; standard of care; therapeutic target; therapy resistant; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor-immune system interactions

ABSTRACT The major cause of death for nearly all men with prostate cancer is metastasis of therapy-resistant disease. Current standard-of-care therapies to treat metastatic castration-resistant prostate cancer (mCRPC) include novel hormonal agents that inhibit the androgen receptor (AR), including abiraterone acetate and enzalutamide. These hormonal therapies have significantly prolonged survival of men with mCRPC; however, acquired resistance to these drugs is inevitable within 1-2 years. Therefore, there is a major unmet clinical need to identify mechanisms of resistance and innovative therapies to treat hormone therapy-resistant disease. In our preliminary studies, we have determined that enzalutamide promotes evolutionary selection for cells with a pro-survival, immuno-evasive, and metastatic phenotype mediated by a p38α/Snail/PD-L1 gene regulatory network. Our central hypothesis is that the p38α/Snail/PD-L1 axis promotes both cell-intrinsic hormone therapy resistance and cell-extrinsic immune evasion. The main objective of this R01 proposal is to interrogate the importance of p38α and cellular plasticity signaling with hormone resistance and immune evasion in preclinical studies and in patients with metastatic prostate cancer. In aim 1, we will test the potential of p38α as a cell intrinsic mechanism of AR therapy resistance and metastasis, and overcome this induced resistance with small molecule p38α inhibition in the mCRPC setting. To accomplish this goal, we will conduct both preclinical mechanistic studies in vivo and clinical correlative analyses in circulating tumor cells and metastatic biopsies from men with mCRPC. In aim 2, we will test the hypothesis that the p38α/Snail/PD-L1 axis mediates cell extrinsic immune evasion in AR therapy resistant tumors. Using immunocompetent transgenic mouse models and patient-derived xenografts with humanized immune systems, we will mechanistically assess the relationship between p38α and PD-L1 upregulation, dissect the downstream effects of p38α activation, and explore the therapeutic benefit of targeting the p38α/PD-L1 axis in AR therapy resistant mCRPC. We will couple these experiments to clinical correlative analysis using banked circulating tumor cells and metastatic tissues previously collected from men with mCRPC before and after progression on abiraterone acetate or enzalutamide. Our data provide strong evidence that AR therapy resistance converges on a p38α/Snail/PD-L1 stress- plasticity axis that can be therapeutically targeted to improve clinical outcomes in prostate cancer. The overall goal of this proposal is to provide the preclinical and clinical correlative studies to justify clinical trials to provide near-term benefit for men with metastatic, hormone therapy-resistant prostate cancer.

抽象的 几乎所有前列腺癌男性死亡的主要原因是耐药性疾病的转移。 目前治疗转移性去势抵抗性前列腺癌 (mCRPC) 的标准护理疗法包括 抑制雄激素受体（AR）的新型激素药物，包括醋酸阿比特龙和 然而，这些激素疗法显着延长了 mCRPC 男性的生存期。 对这些药物的获得性耐药在1-2年内是不可避免的，因此，临床上存在重大未满足的问题。 需要确定耐药机制和创新疗法来治疗激素治疗耐药 在我们的初步研究中，我们已经确定恩杂鲁胺促进疾病的进化选择。 由 p38α/Snail/PD-L1 基因介导的具有促生存、免疫逃避和转移表型的细胞 我们的中心假设是 p38α/Snail/PD-L1 轴促进细胞内在的调节网络。 激素治疗耐药性和细胞外源性免疫逃避 该 R01 提案的主要目标是 探讨 p38α 和细胞可塑性信号传导与激素抵抗和免疫的重要性 临床前研究和转移性前列腺癌患者的逃避。 在目标 1 中，我们将测试 p38α 作为 AR 治疗耐药的细胞内在机制的潜力，以及 转移，并在 mCRPC 环境中通过小分子 p38α 抑制克服这种诱导的耐药性。 为了实现这一目标，我们将进行临床前体内力学研究和临床相关研究 对患有 mCRPC 的男性循环肿瘤细胞和转移性活检进行分析。 在目标 2 中，我们将检验 p38α/Snail/PD-L1 轴介导细胞外源性免疫逃避的假设。 使用免疫活性转基因小鼠模型和患者来源的 AR 治疗耐药肿瘤。 具有人源化免疫系统的异种移植物，我们将机械地评估 p38α 之间的关系 和 PD-L1 上调，剖析 p38α 激活的下游效应，并探索治疗益处 我们将这些实验与临床结合起来。 使用储存的循环肿瘤细胞和先前从男性收集的转移组织进行相关分析 接受醋酸阿比特龙或恩杂鲁胺治疗前和进展后的 mCRPC。 我们的数据提供了强有力的证据，表明 AR 治疗耐药性集中于 p38α/Snail/PD-L1 应激 - 可塑性轴可以作为治疗目标来改善前列腺癌的临床结果。 该提案的目标是提供临床前和临床相关研究，以证明临床试验的合理性，以提供 对于患有转移性、激素治疗耐药的前列腺癌的男性来说，近期受益。

项目成果

Clinical trials for metastatic castrate-resistant prostate cancer-who is looking after the control patients? Questions for the future.

• DOI: 10.1016/j.annonc.2022.03.272
• 发表时间: 2022-06
• 期刊: Annals of oncology : official journal of the European Society for Medical Oncology

KLF4 Induces Mesenchymal-Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors.

• DOI: 10.3390/cancers13205135
• 发表时间: 2021-10-13
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Subbalakshmi AR;Sahoo S;McMullen I;Saxena AN;Venugopal SK;Somarelli JA;Jolly MK
• 通讯作者: Jolly MK

Expression of immune checkpoints on circulating tumor cells in men with metastatic prostate cancer.

• DOI: 10.1186/s40364-021-00267-y
• 发表时间: 2021-02-18
• 期刊: Biomarker research
• 影响因子: 11.1
• 作者: Zhang T;Agarwal A;Almquist RG;Runyambo D;Park S;Bronson E;Boominathan R;Rao C;Anand M;Oyekunle T;Healy P;McNamara MA;Ware K;Somarelli JA;George DJ;Armstrong AJ
• 通讯作者: Armstrong AJ

Second generation anti-androgens and androgen deprivation therapy with radiation therapy in the definitive management of high-risk prostate cancer.

• DOI: 10.1038/s41391-022-00598-3
• 发表时间: 2023-03
• 期刊: PROSTATE CANCER AND PROSTATIC DISEASES
• 影响因子: 4.8
• 作者: Wang, Edina C.;Lee, W. Robert;Armstrong, Andrew J.
• 通讯作者: Armstrong, Andrew J.

Dynamical modeling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity.

• DOI: 10.1136/jitc-2023-006766
• 发表时间: 2023-09
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9