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

Neuropilin-2 轴在多西紫杉醇耐药和前列腺癌骨转移中的作用

• 批准号: 9220727
• 负责人: Kaustubh Datta
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220727
• 关键词: Apoptosis; Automobile Driving; Autophagocytosis; Biochemical; Cancer Model; Cancer Patient; Cell Differentiation process; Cell Surface Receptors; Cell physiology; Cells; Cellular biology; Characteristics; Complex; Development; Disease; Endocytosis; Endosomes; Engineering; Epithelial; Goals; Growth Factor Receptors; Human; Lesion; Link; Malignant neoplasm of prostate; Mediating; Mesenchymal; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Molecular; Neoplasm Metastasis; Neuropilin-2; Osteoblasts; Osteoclasts; Process; Regulation; Resistance; Role; Semaphorins; Site; Stress; Survival Rate; Testing; Therapeutic; Treatment outcome; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; base; bone; bone cell; cancer cell; carcinogenesis; cell motility; chemotherapy; combat; docetaxel; effective therapy; experimental study; improved outcome; in vivo; inhibitor/antagonist; interest; late endosome; mouse model; new therapeutic target; novel; novel therapeutics; osteoblast differentiation; paracrine; prostate cancer cell; public health relevance; receptor; taxane; therapy resistant; tumor

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.

描述（由申请人提供）：本申请的长期目标是了解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骨转移并赋予对癌细胞的治疗抗性。转移性前列腺癌是致命的，并且对目前可用的治疗方法具有耐药性。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是一种生长因子受体，如VEGF-C、VEGF-A和信号蛋白3F。我们观察到NRP-2在人前列腺癌骨转移中的高表达，表明它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内吞作用方面具有新的功能。我们特别感兴趣的是探索NRP-2轴对内吞作用的调节与其在诱导自噬以促进转移性前列腺癌治疗抵抗中的作用之间的潜在联系。此外，我们观察到在PCa刺激后，骨细胞（成骨细胞和破骨细胞）中有活性的NRP-2轴。我们的初步结果表明骨内的NRP-2轴可以促进成骨细胞病变，这是前列腺癌骨转移的一个特征。因此，我们假设NRP-2轴在癌细胞和基质骨细胞中的激活不仅增强了前列腺癌的转移潜力，而且促进了成骨细胞病变。靶向NRP-2轴对前列腺癌骨转移患者的治疗具有重要意义。在本研究的目的1中，我们将确定NRP-2及其下游靶点WDFY-1如何调节转移性前列腺癌的内核体成熟过程。在Aim 2中，我们将描述nrp -2介导的自噬的分子机制及其对转移性前列腺癌多西他赛耐药的影响。在目标3中，NRP-2轴参与促进成骨细胞分化将在PCa细胞刺激后进行测试。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诱导的成骨细胞活性及其抑制破骨细胞功能中的作用。我们推测PCa诱导成骨细胞和破骨细胞的NRP-2轴累积促进成骨细胞转移。这一建议将阐明NRP-2轴在前列腺癌骨转移中的功能，并将评估该轴的治疗潜力。抑制这一靶点与已有的治疗方案（如多西他赛）相结合，将为伴有骨转移的前列腺癌患者提供生存益处。