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.

摘要

项目成果

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

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.

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

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

An autologous humanized patient-derived xenograft (PDX) model for evaluation of nivolumab immunotherapy in renal cell cancer: a case report.

• DOI: 10.21037/sci-2022-029
• 发表时间: 2022
• 期刊: Stem cell investigation