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因都是耐药疾病的转移。 目前治疗转移性去势耐受前列腺癌(MCRPC)的标准疗法包括 抑制雄激素受体(AR)的新型激素剂，包括醋酸阿比特龙和 苯扎鲁胺。这些激素疗法显著延长了患有mCRPC的男性的生存时间；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治疗激素治疗耐药的创新疗法 疾病。在我们的初步研究中，我们已经确定苯扎鲁胺促进了对 P38α/Snail/PD-L1基因介导的支持生存、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轴促进细胞内源性 激素治疗抵抗和细胞外源性免疫逃避。本R01提案的主要目标是 询问p38α和细胞可塑性信号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回避。 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。 转移，并在mCRPC环境中通过抑制小分子p38α来克服这种诱导的耐药性。 为了实现这一目标，我们将进行体内临床前机制研究和临床相关研究。 男性mCRPC患者循环肿瘤细胞和转移活检组织的分析。 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治疗耐药肿瘤。使用具有免疫功能的转基因小鼠模型和患者来源 移植的人源化免疫系统，我们将机械评估p38α之间的关系 和PD-L1上调，剖析p38α激活的下游效应，探讨其治疗效益 靶向p38α/PD-L1轴在AR耐药的mCRPC中的作用。我们将把这些实验与临床相结合 银行循环肿瘤细胞与男性转移组织的相关性分析 用mCRPC检测醋酸阿比特龙或苯扎鲁胺治疗前后的疗效。 我们的数据提供了强有力的证据，表明AR治疗耐药集中在p38α/Snail/PD-L1压力上- 可塑性轴，可作为治疗靶点以改善前列腺癌的临床结果。整体而言 本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 对患有转移性、激素治疗抵抗的前列腺癌的男性近期受益。

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.