Probing the CXCR6/CXCL16 Axis: Targeting Prevention of Prostate Cancer Metastasis

探索CXCR6/CXCL16轴：靶向预防前列腺癌转移

• 批准号: 8330241
• 负责人: Gregory Paul Roth
• 金额: $ 5.38万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330241
• 关键词: Address; American; Antibodies; Binding; Biological Assay; Biological Factors; Biology; CXCR6 gene; Cancer Etiology; Cell Line; Cells; Cessation of life; Chemicals; Chemotaxis; Collection; Coupled; Critical Pathways; Cyclic AMP; Data; Development; Diagnosis; Disease; Disease Progression; Doctor of Philosophy; Event; Filtration; Fractionation; Human; In Vitro; LNCaP; Laboratories; Laboratory Research; Libraries; Malignant neoplasm of prostate; Mediating; Medical; Medical Research; Membrane; Metastatic Neoplasm to the Bone; Methods; Michigan; Modeling; Morbidity - disease rate; Neoplasm Metastasis; Patients; Pharmaceutical Chemistry; Prevention; Prostate; Protocols documentation; Provider; PubChem; Quinine; Receptor Inhibition; Research; Research Institute; Risk; Role; Scheme; Screening procedure; Signal Pathway; Therapeutic; Tissues; United States National Institutes of Health; Universities; VCaP; assay development; base; bone; bone invasion; cancer cell; chemokine receptor; clinical application; design; expectation; high throughput screening; interest; material transfer agreement; men; mortality; neoplastic cell; novel; programs; radioligand; receptor; skeletal; small molecule; therapeutic target; trafficking; tumor; tumor progression

DESCRIPTION (provided by applicant): We have recently generated experimental data that validates the CXCR6/CXCL16 axis as a prostate cancer (PCa) therapeutic target. PCa is the second leading cause of cancer death in American men and its morbidity has increased globally in recent years. The high mortality rate is closely associated with the spread of malignant cells to various tissues including bone. Nearly 10% of patients whose conditions are diagnosed as PCa initially present with bone metastasis and almost all patients who die of prostate cancers have skeletal involvement. Identifying new mechanisms that control bone metastasis is of great consequence to facilitate the design of therapeutics aimed at decreasing metastatic risk and/or its complications. To address this unmet medical need, our team is actively engaged in exploring the chemical biology, medicinal chemistry, and therapeutic significance of modulating tumor cell trafficking and metastasis via chemokine receptor inhibition. This R03 application describes an MLPCN HTS-ready research program which is within the interests and expertise of our laboratories. The primary objective of this proposal is to use high throughput screening methods to identify small molecule antagonist probes that selectively inhibit CXCR6. Our team intends to address a key hypothesis: The CXCR6/CXCL16 axis significantly contributes to PCa cell metastasis and subsequent bone invasion. A small molecule antagonist would block cancer cell trafficking; hence mediate a metastatic event and disease progression to bone. We demonstrate supporting data that validates the role of the CXCR6/CXCL16 axis in PCa tumor progression, invasion, and proliferation. Thus, access to pharmacologically available small molecule antagonists will ultimately enable our studies in disease relevant models and allow for a more seamless translational advance to clinical applications.

描述（由申请人提供）：我们最近生成了验证CXCR 6/CXCL 16轴作为前列腺癌（PCa）治疗靶点的实验数据。前列腺癌是美国男性癌症死亡的第二大原因，近年来其发病率在全球范围内增加。高死亡率与恶性细胞扩散到包括骨在内的各种组织密切相关。近10%的被诊断为前列腺癌的患者最初出现骨转移，几乎所有死于前列腺癌的患者都有骨骼受累。确定控制骨转移的新机制对于促进旨在降低转移风险和/或其并发症的治疗方法的设计具有重要意义。为了解决这一未得到满足的医疗需求，我们的团队正在积极探索化学生物学，药物化学以及通过趋化因子受体抑制调节肿瘤细胞运输和转移的治疗意义。该R 03应用程序描述了MLPCN HTS就绪研究计划，该计划在我们实验室的兴趣和专业知识范围内。该提案的主要目的是使用高通量筛选方法来鉴定选择性抑制CXCR 6的小分子拮抗剂探针。我们的团队打算解决一个关键假设：CXCR 6/CXCL 16轴显著有助于PCa细胞转移和随后的骨侵袭。小分子拮抗剂将阻断癌细胞运输;因此介导转移事件和疾病进展至骨。我们证明了支持性数据，证实了CXCR 6/CXCL 16轴在PCa肿瘤进展、侵袭和增殖中的作用。因此，获得可利用的小分子拮抗剂将最终使我们能够在疾病相关模型中进行研究，并允许更无缝地转化为临床应用。