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

描述(由申请人提供)：我们最近产生了实验数据，证实CXCR6/CXCL16轴是前列腺癌(PCA)的治疗靶点。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有所上升。高死亡率与恶性细胞向包括骨骼在内的各种组织扩散密切相关。近10%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。为了满足这一未得到满足的医疗需求，我们的团队正在积极探索通过抑制趋化因子受体来调节肿瘤细胞运输和转移的化学生物学、药物化学和治疗意义。本R03申请描述了MLPCN HTS就绪研究计划，该计划符合我们实验室的兴趣和专业知识。这项建议的主要目的是使用高通量筛选方法来识别选择性抑制CXCR6的小分子拮抗剂探针。我们的团队打算解决一个关键的假设：CXCR6/CXCL16轴对PCa细胞转移和随后的骨侵袭有重要作用。一种小分子拮抗剂将阻止癌细胞的转移，从而调节转移事件和疾病向骨骼的进展。我们提供的支持数据证实了CXCR6/CXCL16轴在PCa肿瘤进展、侵袭和增殖中的作用。因此，获得药理上可用的小分子拮抗剂最终将使我们能够研究与疾病相关的模型，并允许更无缝地转化为临床应用。 公共卫生相关性：前列腺癌(PCA)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有所上升。高死亡率与恶性细胞向包括骨骼在内的各种组织扩散密切相关。在被诊断为前列腺癌的患者中，近10%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继发性骨骼肿瘤。我们的目标是发现新的化学探针分子，通过受体拮抗来阻断由CXCR6受体驱动的信号通路。这最终将作为一种潜在的治疗手段来阻止PCa疾病的进展和随后的骨侵袭。

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. PUBLIC HEALTH RELEVANCE: Prostate cancer (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 secondary skeletal tumor involvement. We are targeting the discovery of novel chemical probe molecules that block the signaling pathways driven by the CXCR6 receptor through receptor antagonism. This ultimately has utility as a potential therapeutic means to halt PCa disease progression and subsequent bone invasion.