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

摘要 几乎所有前列腺癌患者的主要死亡原因是耐药疾病的转移。 目前治疗转移性去势抵抗性前列腺癌（mCRPC）的标准治疗包括 抑制雄激素受体（AR）的新型激素剂，包括醋酸阿比特龙和 恩杂鲁胺。这些激素疗法显著延长了mCRPC男性患者的生存期;然而， 对这些药物的获得性耐药性在1-2年内是不可避免的。因此，有一个重大的未满足的临床 需要确定耐药机制和创新疗法来治疗激素治疗耐药 疾病在我们的初步研究中，我们已经确定Enzalutamide促进了进化选择， 具有由p38α/Snail/PD-L1基因介导的促存活、免疫逃避和转移表型的细胞 监管网络。我们的中心假设是，p38α/Snail/PD-L1轴促进细胞内 激素治疗抗性和细胞-外源性免疫逃避。本R 01提案的主要目标是 探讨p38α和细胞可塑性信号在激素抵抗和免疫反应中的重要性 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治疗抗性的细胞内在机制的潜力， 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，我们将进行体内和临床相关的临床前机制研究， 来自mCRPC男性的循环肿瘤细胞和转移性活检的分析。 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， AR疗法抗性肿瘤。使用免疫活性转基因小鼠模型和患者来源的 我们将从机制上评估p38α与人源化免疫系统之间的关系， 和PD-L1上调，剖析p38α激活的下游效应，并探索治疗益处。 靶向p38α/PD-L1轴治疗AR治疗耐药mCRPC。我们将把这些实验与临床实验结合起来， 使用先前从男性收集的库存循环肿瘤细胞和转移组织的相关性分析 在醋酸阿比特龙或enzalutamide治疗进展之前和之后的mCRPC。 我们的数据提供了强有力的证据，表明AR治疗抗性集中在p38α/Snail/PD-L1应激上。 可塑性轴，可以治疗靶向改善前列腺癌的临床结果。整体 本提案的目的是提供临床前和临床相关研究，以证明临床试验的合理性， 对患有转移性、激素治疗抵抗性前列腺癌的男性的近期益处。

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.