Therapeutically targeting cancer cell motility

针对癌细胞运动性的治疗

• 批准号: 9206893
• 负责人: Raymond C. Bergan
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206893
• 关键词: Academia; Affect; Androgen Antagonists; Androgen Receptor; Antiandrogen Therapy; Binding; Binding Proteins; Biological; Biological Assay; Biology; Biophysics; Bone Development; CDC37 gene; Cancer Biology; Cause of Death; Cell physiology; Cells; Cellular biology; Characteristics; Chemicals; Client; Development; Distant; Distant Metastasis; Extracellular Matrix Proteins; Goals; Health; Heat shock proteins; Heat-Shock Proteins 90; Human; Individual; Injection of therapeutic agent; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Chaperones; Mus; Natural Products; Nature; Neoplasm Metastasis; Oral; Organ; Osteonectin; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phenotype; Phosphorylation; Phosphotransferases; Process; Property; Prostate; Proteins; Receptor Signaling; Regulatory Pathway; Resistance; Science; Signal Transduction; Site; Testing; Therapeutic; Toxicology; Treatment Efficacy; Veterans; Work; Xenograft Model; Xenograft procedure; base; bone; cancer cell; carcinogenesis; cell growth; cell motility; cell transformation; clinical efficacy; clinically relevant; cohort; design; experimental study; high risk; hormone therapy; improved; insight; man; mortality; nanomolar; novel; novel therapeutics; pre-clinical; preclinical toxicity; prostate cancer cell; prostate cancer model; public health relevance; receptor function; success; therapeutic candidate; therapeutic target

 DESCRIPTION (provided by applicant): Prostate cancer (PCa) mortality is caused by the formation of metastases. This is a major problem for US veterans. Processes that drive the development of metastases, such as increased cell motility, therefore represent high value therapeutic targets. All attempts to selectively therapeutically target cell motility and consequent metastasis have failed. We approached this intractable and important problem by designing a unique strategy that used small chemicals as highly refined probes to identify novel and important biological regulatory sites. This led us to synthesize the probe, KBU2046, which inhibits phosphorylation of Ser226 on HSP90β. Phosphorylation of Ser226 drives cell invasion and mediates KBU2046 anti-invasion efficacy. When administered orally, KBU2046 inhibits human PCa metastasis in mice at nM concentrations. Knowing that HSP90 chaperone action maintains androgen receptor (AR) in its functional state, we went on to demonstrate that KBU2046-mediated disruption of HSP90 function inhibits AR signaling and AR-driven cell growth. Finally, comprehensive preclinical toxicity and pharmacology studies all support that KBU2046, as a drug, will have a high potential for activity in humans. We hypothesize that our chemical probe strategy has identified modulation of HSP90β Ser226 phosphorylation as a novel and selective mechanism regulating metastatic progression, that KBU2046 efficacy is due, at least in part, to modulation of client protein binding to HSP90β, resulting in changes in Ser226 phosphorylation status, and that this strategy provides a viable pathway for inhibiting PCa metastasis in humans. Aim 1. Characterize the molecular mechanism by which KBU2046 affects client protein binding and Ser226 phosphorylation. KBU2046 does not directly inhibit kinase function. It alters binding of client proteins to HSP90β, and appears to do so through stabilization of the HSP90β/CDC37 heterocomplex. Studies will fully characterize KBU2046 induced changes in client protein binding to HSP90β, and will go on to assess how they affect Ser226 phosphorylation status and cell motility. Aim 2. Evaluate KBU2046 efficacy in clinically relevant human PCa murine xenograft models. Aim 2A examines whether KBU2046 enhances the efficacy of hormone therapy, and delays emergence of resistance to it. Experiments in Aim 2B build upon our recent finding that KBU2046 selectively suppresses osteonectin expression. Osteonectin is an extracellular matrix protein, which has been shown to drive metastasis in human PCa. We hypothesize that KBU2046 will disrupt PCa cell dissemination to bone, and will test this using an intra-cardiac injection model of metastasis. Impact. Studies will increase our understanding of the basic biology of cancer cell motility and metastasis, and will inform us of the optimal means to modulate it in humans.

 描述（由申请人提供）： 前列腺癌（PCA）死亡率是由转移的形成引起的。对于美国退伍军人来说，这是一个主要问题。因此，驱动转移发展的过程，例如增加的细胞运动性，代表了高价值治疗靶标。所有尝试选择性治疗靶向细胞运动和随之而来的转移的尝试都失败了。我们通过设计一种独特的策略来解决这个棘手而重要的问题，该策略将小型化学物质用作高度精制的问题来识别新颖而重要的生物学调节位点。这导致我们合成了探针KBU2046，该探针抑制了Ser226在HSP90β上的磷酸化。 Ser226的磷酸化驱动细胞侵袭并介导KBU2046抗侵入效率。当口服给药时，KBU2046抑制NM浓度小鼠中的人PCA转移。知道HSP90伴侣作用将雄激素受体（AR）保持在其功能状态，我们继续证明KBU2046介导的HSP90功能的破坏抑制了AR信号传导和AR驱动的细胞生长。最后，全面的临床前毒性和药物研究都支持KBU2046作为药物，在人类中的活动可能很高。我们假设我们的化学探测策略已确定HSP90βSer226磷酸化的调节是一种新颖的选择性机制调节转移性进展，KBU2046至少部分是由于调节客户蛋白与HSP90β的调节，从而使Ser226磷酸化状态的变化导致了对HSP90β的变化，以至于在磷酸化状态下的变化，以至于在磷酸化状态下，这是有效的，该策略是在这种情况下的变化。人类。 AIM 1。表征KBU2046影响客户蛋白结合和Ser226磷酸化的分子机制。 KBU2046不直接抑制激酶功能。它改变了客户蛋白与HSP90β的结合，并通过稳定Hsp90β/cdc37杂膜化而进行了结合。研究将充分表征KBU2046诱导的客户蛋白与HSP90β的结合变化，并将继续评估它们如何影响Ser26磷酸化状态和细胞运动。 AIM 2。评估KBU2046在临床相关的人PCA鼠类特电学模型中的有效性。 AIM 2A考试KBU2046是否增强了骑马疗法的有效性，并延迟了对其抗药性的出现。 AIM 2B中的实验基于我们最近的发现KBU2046选择性抑制骨蛋白酶的表达。 Osteonectin是一种细胞外基质蛋白，已证明可以在人PCA中驱动转移。我们假设KBU2046将破坏PCA细胞向骨骼的传播，并将使用转移的心内注射模型对其进行测试。影响。研究将增加我们对癌细胞运动和转移的基本生物学的理解，并将告知我们在人类中调节它的最佳手段。