Role of Oncogenic Kinase Pim-1 in Prostate Cancer

描述(由申请人提供)：对于雄激素消融治疗失败的晚期前列腺癌(即去势抵抗前列腺癌)，有公认的临床需要确定新的分子治疗靶点。此外，在异种移植模型中具有明显活性的抗癌药物在临床上经常失败，这使得在本土动物模型中测试候选药物势在必行。这项研究计划的主要目标是开发致癌的丝氨酸-苏氨酸激酶PIM1激酶作为前列腺癌的治疗靶点。PIM1与c-myc共表达，并以一种激酶依赖的方式显著增强c-myc驱动的前列腺癌的发生。值得注意的是，PIM1在肿瘤中是由缺氧和多西紫杉醇治疗诱导的，多西紫杉醇是晚期去势抵抗前列腺癌患者的一种常见但基本上无效的选择。低氧和多西紫杉醇诱导的PIM1促进前列腺癌细胞存活和治疗耐药。因此，PIM1可能是前列腺癌的一个有价值的治疗靶点。为了测试这一概念，我们开发了新的本土前列腺癌小鼠模型，用于测试新型PIM1激酶抑制剂在治疗前列腺癌和逆转治疗耐药方面的有效性。我们还在前列腺上皮细胞中发现了新的候选PIM1相互作用蛋白。在已鉴定的蛋白质中，有一种MYC转录辅因子和一种前列腺干细胞标记/调节因子。我们假设PIM1通过磷酸化参与调节MYC转录活性和干细胞功能的关键底物来促进前列腺癌的发生，并且靶向PIM1激酶活性是治疗表达MYC/PIM1的前列腺癌的有效策略。我们将通过三个目标来解决这些假设。在第一个目标中，我们将阐明MYC和PIM1在前列腺癌中协同作用的机制基础。在第二个目标中，我们将研究PIM1在调节干细胞更新中的作用。在第三个目标中，我们将在体内测试新型PIM1激酶抑制剂治疗前列腺癌和逆转耐药的疗效。这些研究将为我们提供对PIM1在前列腺癌中作用机制的新见解，并严格测试新的PIM1激酶抑制剂在治疗前列腺癌和逆转治疗耐药方面的有效性。

DESCRIPTION (provided by applicant): There is a recognized clinical need to identify new molecular therapeutic targets for advanced prostate cancers that have failed androgen ablation therapy (i.e. castration-resistant prostate cancer). Furthermore, the frequent failure in the clinial setting of cancer drugs with demonstrable activity in xenograft models makes the testing of drug candidates in autochthonous animal models imperative. The overarching goal of this research program is to develop the oncogenic serine-threonine kinase PIM1 kinase as a therapeutic target in prostate cancer. PIM1 is coexpressed with c-MYC and dramatically enhances c-MYC-driven prostate tumorigenesis in a kinase-dependent manner. Notably, PIM1 is induced in tumors by hypoxia and by treatment with docetaxel, a common but largely ineffective option for patients with advanced castration-resistant prostate cancer. PIM1 induction by hypoxia and docetaxel promotes prostate cancer cell survival and therapeutic resistance. Therefore PIM1 may represent a valuable therapeutic target in prostate cancer. To test this notion, we have developed new autochthonous mouse models of prostate cancer for testing the efficacy of novel PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance. We have also identified novel candidate PIM1-interacting proteins in prostate epithelial cells. Among the proteins identified are a MYC transcriptional cofactor and a prostate stem cell marker/regulator. We hypothesize that PIM1 promotes prostate tumorigenesis by phosphorylating key substrates involved in regulating MYC transcriptional acivity and stem cell function and that targeting PIM1 kinase activity is an effective strategy to treat MYC/PIM1- expressing prostate cancer. We will address these hypotheses via three aims. In the first aim, we will elucidate the mechanistic basis for cooperativity between MYC and PIM1 in prostate cancer. In the second aim, we will investigate the role of PIM1 in regulating stem cell renewal. In the third aim, we will test the efficacy of novel PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance in vivo. These studies should to provide us with novel insights into the mechanisms of PIM1 function in prostate cancer and rigorously test the effectiveness of new PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance.