Modulation of host intrinsic immunity to reduce prostate cancer disparity

 描述（由申请人提供）：癌症健康差异代表了美国的一个主要公共卫生问题。即使考虑到社会经济因素，少数民族人口的总体发病率也高于总人口，结果也更差。前列腺癌是一种这样的疾病，在非洲裔美国人（AA）男性中的发病率和死亡率高于高加索人。虽然社会经济因素可能在一定程度上受到指责，但应该认识到，遗传组成使AA男性更容易患上侵袭性前列腺癌。遗传和表观遗传变化被称为致瘤驱动因素，因为表观遗传编辑排除了肿瘤细胞清除所必需的宿主抗肿瘤反应的增加。由DNA甲基转移酶（DNMT）催化的DNA甲基化是前列腺癌中最具特征的表观遗传修饰，DNA甲基化的种族差异与癌症预后和生存相关。因此，靶向DNMT以逆转表观遗传学改变是一个有吸引力的治疗靶点，并且对于减少AA男性和高加索人之间观察到的前列腺癌结果差距至关重要。脱氧胞苷类似物地西他滨的独特之处在于其可以被重新定位用于DNMT的非细胞毒性消耗。我们的特点是低剂量的地西他滨的吸收增加的存在下，四氢尿苷（THU）。THU与地西他滨的组合改变其药理学，并促进非细胞毒性DNMT 1消耗。我们证明了THU-地西他滨组合显著抑制了免疫活性小鼠中TRAMP-C2前列腺肿瘤的生长，并且CpG免疫疗法的添加进一步增强了抗肿瘤免疫。基于我们强有力的初步数据，我们假设THU-地西他滨定向的表观遗传疗法恢复宿主固有免疫并增强疫苗诱导的抗肿瘤应答。由于DNA甲基化在AA中普遍存在并且与更大的风险相关，因此DNMT去除将增强荷瘤宿主的免疫应答，为诱导强大的抗肿瘤免疫的免疫治疗提供了机会。我们将测试THU-地西他滨引导的DNMT耗竭、免疫调节和治疗性疫苗的组合，以确定1）表观遗传编辑对鼠模型中前列腺癌细胞生长的影响;和2）THU-地西他滨引导的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性前列腺癌的完全消退中的效应机制。该项目是新颖的，因为无毒THU-地西他滨与免疫疗法组合的概念尚未在任何癌症类型中进行测试。这种组合方法将显著减弱AA男性中经常出现的侵袭性前列腺癌的生长，并可能代表减少前列腺癌差异的新治疗。

 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.