Preventing invasive prostate cancer

预防侵袭性前列腺癌

• 批准号: 10566591
• 负责人: Raymond C. Bergan
• 金额: $ 53.58万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566591
• 关键词: 3-Dimensional; Achievement; Actin-Binding Protein; Address; Adhesions; Affect; Affinity; Animals; Autopsy; Binding; Binding Sites; Biochemical; Bioinformatics; Biological; Biological Assay; Biological Markers; Biophysics; Blood; CDC37 gene; Calorimetry; Canis familiaris; Carcinoma in Situ; Cause of Death; Cell physiology; Cells; Chromans; Clinical; Complex; Coupled; Data; Development; Disease; Engineering; Heat-Shock Proteins 90; Human; Image; In Situ; In Situ Lesion; In Vitro; Individual; Intercept; Intervention; Invaded; Journals; Knowledge; L-Plastin; LCP1 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Modeling; Molecular; Movement; Mus; Nature; Neoplasm Metastasis; Organoids; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Phosphorylation; Prevention; Prostate; Protac; Proteins; Proteome; Proteomics; Proto-Oncogenes; Rattus; Regulation; Regulatory Pathway; Research Personnel; Risk; Role; Safety; Signal Pathway; Signal Transduction; Specificity; System; TP53 gene; Testing; Therapeutic; Tissues; Titrations; Toxicokinetics; Transgenic Model; Treatment Efficacy; bone; cancer cell; cancer invasiveness; cancer prevention; cancer type; cell motility; cell type; chemoproteomics; clinically relevant; efficacy evaluation; human disease; human model; in silico; inhibitor; innovation; kinase inhibitor; luminescence; mass spectrometer; member; monomer; novel; pharmacologic; predictive modeling; prevent; programs; prostate cancer cell; tool

Abstract: Cell motility is required for in situ cancer to form invasive primary prostate cancer (PCa). Inhibiting motility would intercept formation of invasive cancer. Until now it has not been possible to selectively inhibit motility. We have discovered a precision acting first-in-class agent, KBU2046. It selectively inhibits motility, has a wide therapeutic window, has led us to uncover heretofore unknown regulatory pathways, targets those pathways, performs well in GLP grade IND enabling studies, and opens up new high value innovative concepts for cancer prevention-interception. Studies support the hypothesis that KBU2046 is an effective cancer interception agent that operates through a novel mechanism, and that it and the pathways it modulates will have high potential for inhibiting the development of invasive cancer, which in turn has lethal potential. Aim 1. Identify and validate KBU2046’s pharmacologic binding site. In silico, biophysical and biochemical studies suggest that KBU2046 binds at the protein-protein interface between HSP90β and CDC37 and selectively decreases binding to Raf1. Using KBU2046-based photo-crosslinkable probes and proteolysis targeting chimeras (PROTACs), coupled to chemo-proteomic approaches and bioinformatic analysis, studies will identify and validate KBU2046 binding sites in the cellular milieu. Aim 2. Characterize the signaling pathway by which Raf1 regulates the motility of human prostate cells. We show KBU2046 decreases phosphorylation of ser338 on Raf1’s activation motif, that downstream regulation of motility is mediated through a novel pathway wherein Raf1 forms a complex with the actin binding protein, L- plastin (LCP1), while mass spectrometer (MS) proteomic / bioinformatic analysis demonstrates primary effects on cell motility proteins. Studies will examine this pathway in at risk human prostate cells, will use Raf1 active/inactive constructs, similarly engineer LCP1 constructs, probe signaling through orthogonal analytics, profile effects on protein signature using MS, and will examine the role of individual pathway members on cell motility and KBU2046 efficacy. Aim 3. Evaluate targeting motiliy in clinically relevant models of human disease. In the RapidCaP transgenic model, codeletion of Pten and p53 induces in situ→invasive→metastatic PCa. It supports treatment before versus after development of in situ lesions, allowing us to examine prevention and interception efficacy, respectively, for inhibiting formation of invasive cancer. Using primary cells from our prostate rapid autopsy program (RAP), we show mechanistically relevant responsiveness to KBU2046. Primary cells and resultant organoids provide a unique opportunity to examine efficacy in clinically relevant models. RapidCaP and RAP tissues will be interrogated at molecular and functional levels to examine effects of KBU2046. Impact. Investigators seek to advance the innovative concept that cell motility is an important cancer prevention-interception target. It has applicability to many cancer types.

摘要：原位癌形成侵袭性原发性前列腺癌（PCa）需要细胞运动。 迄今为止，还无法选择性地抑制侵袭性癌症的形成。 我们发现了一种精准作用的一流药物 KBU2046，它选择性地抑制运动。 一个广泛的治疗窗口，使我们发现了迄今为止未知的调控途径，针对那些 途径，在 GLP 级 IND 支持研究中表现良好，并开辟新的高价值创新概念 研究支持 KBU2046 是一种有效的癌症的假设。 通过一种新颖机制运作的拦截剂，并且它及其调节的途径将具有 抑制侵袭性癌症发展的潜力很大，而侵袭性癌症又具有致命的潜力。 目标 1. 在计算机、生物物理和生物化学中识别并验证 KBU2046 的药理学结合位点。 研究表明，KBU2046 结合在 HSP90β 和 CDC37 之间的蛋白质-蛋白质界面上，并且 使用基于 KBU2046 的光交联探针和蛋白水解选择性减少与 Raf1 的结合。 靶向嵌合体（PROTAC），结合化学蛋白质组学方法和生物信息学分析、研究 将识别并验证细胞环境中的 KBU2046 结合位点。 目标 2. 表征 Raf1 调节人类前列腺细胞运动的信号通路。 显示 KBU2046 降低 Raf1 激活基序上 ser338 的磷酸化，从而下游调节 运动性是通过一种新的途径介导的，Raf1 与肌动蛋白结合蛋白 L- 形成复合物 塑蛋白 (LCP1)，而质谱仪 (MS) 蛋白质组学/生物信息学分析显示主要效应 研究将使用 Raf1 检测处于危险的人类前列腺细胞中的这一通路。 活性/非活性结构，类似地设计 LCP1 结构，通过正交分析探测信号， 使用 MS 分析对蛋白质特征的影响，并将检查各个途径成员对细胞的作用 活力和 KBU2046 功效。 目标 3. 评估 RapidCaP 转基因临床相关模型中的靶向运动。 模型中，Pten和p53的共缺失诱导原位→侵袭性→转移性PCa，支持之前的治疗。 与原位病变发生后相比，使我们能够检查预防和拦截功效， 分别用于抑制侵袭性癌症的形成，使用来自我们的前列腺快速尸检的原代细胞。 程序（RAP），我们显示了对 KBU2046 原代细胞和所得结果的机械相关反应。 类器官为检查临床相关模型的功效提供了独特的机会。 将在分子和功能水平上对组织进行检查，以检查 KBU2046 的效果。 研究人员寻求推进细胞运动是一种重要癌症的创新概念。 它适用于许多癌症类型。