Modulation of host intrinsic immunity to reduce prostate cancer disparity

 描述(由申请人提供)：癌症健康差异是美国一个主要的公共卫生问题。即使考虑到社会经济因素，少数群体的总发病率也比总体人口高，结果也比总体人口差。前列腺癌是一种非裔美国人(AA)男性的发病率和死亡率高于白人的此类疾病。尽管社会经济因素在一定程度上可能是罪魁祸首，但可以理解的是，基因构成使AA男性更容易患侵袭性前列腺癌。遗传和表观遗传变化被称为致癌驱动因素，因为表观遗传编辑排除了宿主抗肿瘤反应的建立，这是肿瘤细胞清除所必需的。由DNA甲基转移酶(DNMT)催化的DNA甲基化是前列腺癌最典型的表观遗传学修饰，DNA甲基化的种族差异与癌症的预后和生存有关。因此，靶向DNMT以逆转表观遗传学改变是一个吸引人的治疗靶点，对于缩小AA男性和高加索人之间观察到的前列腺癌预后差异至关重要。脱氧胞苷类似物地西他滨的独特之处在于它可以被重新定位以用于DNMT的非细胞毒性消耗。我们研究了低剂量地西他滨在四氢尿苷(清华)存在时吸收增加的特点。清华与地他滨联合应用改变了其药理作用，促进了非细胞毒性DNMT1的耗竭。我们发现清华-地西他滨联合应用能显著抑制免疫活性小鼠前列腺癌TRAMP-C2的生长，CpG免疫疗法的加入进一步增强了抗肿瘤免疫。基于我们强大的初步数据，我们假设清华地西他滨指导的表观遗传疗法重振了宿主的固有免疫，并增强了疫苗诱导的抗肿瘤反应。由于DNA甲基化在AAS中普遍存在，并与更大的风险相关，DNMT缺失将激活荷瘤宿主的免疫反应，为免疫治疗诱导强大的抗肿瘤免疫提供机会。我们将测试清华地西他滨导向的DNMT去除、免疫调节和治疗性疫苗的组合，以确定1)表观遗传编辑对小鼠模型前列腺癌细胞生长的影响；2)清华地西他滨疫苗诱导的抗原特异性抗肿瘤免疫在早期和晚期去势抵抗前列腺癌完全消退中的作用机制。这个项目是新颖的，因为清华-地西他滨无毒结合免疫疗法的概念尚未在任何癌症类型中进行测试。这种联合治疗方法将显著抑制AA男性中常见的侵袭性前列腺癌的生长，并可能代表一种减少前列腺癌差异的新疗法。

 DESCRIPTION (provided by applicant): Cancer health disparities represent a major public health concern in the United States. Even when socioeconomic factors are accounted for, minority populations have higher overall incidence rates and worse outcomes than the overall population. Prostate cancer is one such disease with higher incidence and death rates in African American (AA) men than Caucasians. Although socioeconomic factors may be blamed to a certain extent, it is appreciated that the genetic composition makes AA men more susceptible to aggressive prostate cancer. Genetic and epigenetic changes are known as tumorigenic drivers because epigenetic editing precludes mounting of host antitumor response necessary for tumor cell clearance. DNA methylation, catalyzed by DNA methyltransferase (DNMT), is the best-characterized epigenetic modification in prostate cancer, and racial disparities in DNA methylation are associated with cancer prognosis and survival. Therefore, targeting of DNMT to reverse epigenetic alterations is an appealing therapeutic target, and vital to reduce the observed prostate cancer outcome gaps among AA men and Caucasians. The deoxycytidine analogue decitabine is unique in that it can be repositioned for non-cytotoxic depletion of DNMT. We characterized a low dose of decitabine with its increased absorption in the presence of tetrahydrouridine (THU). Combination of THU with decitabine changes its pharmacology, and facilitates non-cytotoxic DNMT1 depletion. We demonstrated that the THU-decitabine combination significantly inhibits the growth of TRAMP-C2 prostate tumors in immune competent mice, and the addition of CpG immunotherapy further enhanced antitumor immunity. Based on our strong preliminary data, we hypothesize that THU-decitabine directed epigenetic therapy revitalize the host intrinsic immunity and augment vaccine-induced antitumor response. Since DNA methylation is prevalent and relates to greater risk in AAs, DNMT depletion will invigorate the immune response of tumor-bearing host, providing an opportunity to immunotherapy inducing robust antitumor immunity. We will test the combination of THU-decitabine directed DNMT depletion, immune modulation and therapeutic vaccine to determine 1) the effect of epigenetic editing on prostate cancer cell growth in murine models; and 2) the effector mechanism of THU-decitabine guided vaccine- induced antigen-specific antitumor immunity in complete regression of early and advanced castration-resistant prostate cancer. This project is novel because the concept of a non-toxic THU-decitabine combination with immunotherapy has not been tested in any cancer type. This combinatorial approach will significantly attenuate the growth of aggressive prostate cancer as often presented in AA men, and may represent a novel treatment to reduce prostate cancer disparity.