Pim 1 Protein Kinase in Regulating Stromal Cell Biology in Prostate Cancer

 描述(申请人提供)：前列腺癌(Pca)上皮细胞与周围的肿瘤间质微环境有着至关重要的相互作用，这种反馈关系刺激了Pca的进展和转移。PCa间质由激活的肌成纤维细胞组成，产生生长、血管生成、迁移因子和细胞外基质，所有这些都有助于肿瘤的侵袭性。破坏这种相互依赖的肿瘤间质-上皮相互作用会显著抑制肿瘤生长并阻止转移。南卡罗来纳医科大学卡夫实验室的研究人员发现，已知在前列腺癌中升高的PIM1丝氨酸-苏氨酸蛋白在人类前列腺基质细胞中显著增加，并在控制成纤维细胞生物学中发挥重要作用。在正常的前列腺成纤维细胞系中，增加PIM1激酶的水平会导致这些正常细胞转分化为激活的肌成纤维细胞，随后PDGF受体的增加和多种刺激肿瘤生长的因子的分泌也会增加。此外，这些PIM激活的肌成纤维细胞能够显著刺激人前列腺上皮细胞的生长和迁移。这些令人兴奋的结果导致了一个独特的假设，即激活的PIM1激酶在前列腺成纤维细胞的转分化过程中发挥着重要作用，可能控制前列腺癌的生长和迁移。这一假设表明，卡夫实验室提供的I期试验中的小分子PIM抑制化合物有可能中断这种上皮：间质反馈关系，并阻止这些肿瘤的生长。评估这一假说的具体目标是：1)确定新分离的癌症相关成纤维细胞中PIM1的增加是否驱动和部分生长和迁移因子，以及这是否可以被阻断PIM激酶的药物抑制；以及2)在动物模型中检测过表达PIM1的前列腺肌成纤维细胞是否能够诱导上皮细胞恶性肿瘤和肿瘤生长。拟议的研究设计将利用一种新的糖蛋白标记程序，该程序使用“点击”化学来测量基质分泌组，并在小鼠身上进行肾被膜下重组试验。这些研究将使用阿斯利康和基因泰克开发的新型小分子PIM抑制剂，这些药物正进入临床用于癌症治疗。这些研究将显著增加对PIM1在前列腺癌成纤维细胞活性中作用的理解，并为使用PIM抑制剂作为一种潜在的阻断间质的方法提供理论基础：上皮相互作用抑制前列腺癌生长。

 DESCRIPTION (provided by applicant): Prostate cancer (PCa) epithelial cells have a critically important interaction with the surrounding tumor stromal microenvironment, and this feedback relationship stimulates PCa progression and metastasis. PCa stroma is composed of activated myofibroblasts that produce growth, angiogenesis, migration factors, and extracellular matrix, all of which contribute to tumor invasiveness. Disrupting this mutual-dependency tumor stromal-epithelial interaction leads to marked inhibition of tumor growth and blocks metastasis. Investigators in the Kraft laboratory at the Medical University of South Carolina have discovered that the PIM1 serine-threonine protein, known to be elevated in prostate cancer, is significantly increased in human prostate stromal cells and plays an important role in controlling fiibroblast cell biology. Increasing the level of PIM1 kinase in a normal prostate fibroblast cell line leads t the transdifferentiation of these normal cells to activated myofibroblasts, followed by the increase in the PDGF receptor and secretion of multiple factors that play a critical role in stimulating tumor growth. Further, these PIM activated myofibroblasts are capable of markedly stimulating the growth and migration of human prostate epithelial cells. These exciting results lead to the unique hypothesis that activated PIM1 kinase plays an important role in transdifferentiation of prostate fibroblast cells potentially controlling prostate cancer growth an migration. This hypothesis suggests that small molecule PIM inhibitory compounds in phase I trials and available to the Kraft laboratory have the potential to interrupt this epithelial:stroma feedback relationship and block the growth of these tumors. The specific aims will evaluate this hypothesis by: 1) determining whether increases in PIM1 in freshly isolated cancer associated fibroblasts drive and section of growth and migration factors and whether this can be inhibited by drugs which block the PIM kinase; and 2) examining whether PIM1 overexpressing prostate myofibroblasts are capable of induced epithelial cell malignancy and tumor growth in animal models. The proposed study design will make use of a novel glycoprotein labelling procedure that employs "click" chemistry to measure the stromal secretome, and a subrenal capsular recombination assay in mice. These studies will employ novel small molecule PIM inhibitors developed by AstraZeneca and Genentech that are entering the clinic for cancer therapy. These studies will markedly increase the understanding of the role of PIM1 in prostate cancer fibroblast activity and develop the rationale for using PIM inhibitors as a potential method of interrupting stromal:epithelial interaction inhibiting prostate tumor growth.