Neuropilin-2 Axis in Docetaxel Resistance and Prostate Cancer Bone Metastasis

描述(由申请人提供)：这项提案的长期目标是了解Neuropilin-2(NRP-2)抑制剂作为治疗转移性前列腺癌(PCa)的新疗法的潜力。我们将专门研究NRP-2轴如何促进前列腺癌的骨转移，并赋予肿瘤细胞治疗耐药性。转移性前列腺癌是致命的，对目前可用的治疗方法具有抵抗力。通过全面了解参与这一过程的分子参与者，可以实现对转移性疾病的有效治疗。NRP-2是生长因子受体，如血管内皮生长因子C、血管内皮生长因子A和信号素3F。我们观察到NRP-2在人前列腺癌骨转移中的高表达，提示其具有转移特异性作用。我们的初步结果表明，NRP-2在维持前列腺癌细胞的内吞作用方面具有新的功能。我们特别感兴趣的是探索转移性前列腺癌中NRP-2轴对内吞作用的调节与其在诱导自噬以促进治疗抵抗中的作用之间的潜在联系。此外，我们观察到在Pca的刺激下，骨细胞(成骨细胞和破骨细胞)中有一个活跃的NRP-2轴。我们的初步结果表明，骨中的NRP-2轴可以促进成骨细胞的损害，这是PCa骨转移的特征。因此，我们假设NRP-2轴在癌细胞和基质中的骨细胞中的激活不仅增强了PCa的转移潜能，而且促进了成骨细胞的病变。靶向NRP-2轴对于治疗前列腺癌骨转移患者将是重要的。在这项拟议研究的目标1中，我们将确定NRP-2及其下游靶点WDFY-1如何调控转移性PCa的内体成熟过程。在目标2中，我们将描述NRP-2介导的自噬的分子机制及其在转移性前列腺癌多西紫杉醇耐药中的意义。在目标3中，将在PCA细胞刺激下测试NRP-2轴在促进成骨细胞分化中的作用。我们还将确定破骨细胞中的NRP-2轴是否被PCA激活。因此，这些实验将揭示NRP-2轴在PCA诱导的成骨细胞活动中的作用及其参与抑制破骨细胞的功能。我们推测，PCA诱导的成骨细胞和破骨细胞中的NRP-2轴累积促进了成骨细胞的转移。这项建议将阐明NRP-2轴在前列腺癌骨转移中的作用，并将评估该轴的治疗潜力。抑制这一靶点，结合已有的治疗方案，如多西紫杉醇，应该会为前列腺癌骨转移患者提供生存益处。

DESCRIPTION (provided by applicant): The long term objective of this proposal is to understand the potential of Neuropilin-2 (NRP-2) inhibitors as novel therapies against metastatic prostate cancer (PCa). We will specifically investigate how NRP-2 axis promotes PCa bone metastasis and confers therapy resistance to cancer cells. Metastatic PCa is lethal and is resistant to currently available therapies. Effective treatment against the metastatic disease can be achieved through a comprehensive understanding of the molecular players involved in this process. NRP-2 is a receptor for growth factors such as VEGF-C, VEGF-A, and semaphorin 3F. We have observed a high expression of NRP-2 in human PCa bone metastases suggesting it has a metastasis-specific role. Our preliminary results suggested a novel function of NRP-2 in maintaining endocytosis in PCa cells. We are particularly interested in exploring the potential link between the regulation of endocytosis by the NRP-2 axis and its role in inducing autophagy to facilitate therapy resistance in metastatic prostate cancer. Moreover, we observed an active NRP-2 axis in bone cells (osteoblasts and osteoclasts) following its stimulation of PCa. Our preliminary results indicated that the NRP-2 axis in bone can promote osteoblastic lesions, a characteristic of PCa bone metastasis. We therefore hypothesize that the activation of NRP-2 axis in both the cancer cells and the bone cells in stroma enhances not only the metastatic potential of PCa but also promotes osteoblastic lesions. Targeting the NRP-2 axis will be important to treat prostate cancer patients with bone metastasis. In Aim 1 of this proposed study, we will determine how NRP-2 and its downstream target, WDFY-1, regulates the process of endosome maturation in metastatic PCa. In Aim 2, we will delineate the molecular mechanisms of NRP-2-mediated autophagy and its implications for docetaxel resistance in metastatic prostate cancer. In aim 3, the involvement of NRP-2 axis in promoting differentiation of osteoblastic cells will be tested following stimulation by PCa cells. We will also determine whether NRP-2 axis in osteoclasts is activated by PCa. These experiments will therefore reveal the role of NRP-2 axis in PCa-induced osteoblastic activity and its involvement in inhibiting osteoclast function. We speculate that PCa induced NRP-2 axis in osteoblast and osteoclast cumulatively promotes osteoblastic metastasis. This proposal will elucidate the function of the NRP-2 axis in prostate cancer bone metastases and will evaluate the therapeutic potential of this axis. The inhibition of this target in combination with established treatment options such as docetaxel should offer a survival benefit for prostate cancer patients with bone metastasis.