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：原位癌需要细胞运动才能形成侵入性原发性前列腺癌（PCA）。抑制 运动将拦截侵入性癌症的形成。到目前为止，不可能选择性地抑制 运动。我们发现了一个精确的表演一流的代理KBU2046。它有选择地抑制运动性，具有 一个宽阔的治疗窗口，导致我们发现迄今未知的监管途径，以此为目标 途径，在GLP级别IND促进研究中表现良好，并打开了新的高价值创新概念 用于预防癌症。研究支持KBU2046是一种有效癌症的假设 通过一种新型机制运行的拦截剂，它调节的途径将具有 抑制侵入性癌症发展的高潜力，进而具有致命的潜力。 目标1。识别和验证KBU2046的药理学结合位点。在硅，生物物理和生化 研究表明，KBU2046在Hsp90β和Cdc37和Cdc37和Cdc37和 有选择地降低与RAF1的约束。使用基于KBU2046的光合链接探针和蛋白水解 靶向嵌合体（Protac），与化学蛋白质方法和生物信息学分析相结合，研究 将识别并验证细胞环境中的KBU2046结合位点。 AIM 2。表征RAF1调节人前列腺细胞运动性的信号传导途径。我们 显示KBU2046在RAF1的激活图案上降低了Ser338的磷酸化，下游调节 运动性通过一种新的途径介导，其中Raf1与肌动蛋白结合蛋白L-形成复合物 Plastin（LCP1），而质谱仪（MS）蛋白质组学 /生物信息学分析表明了主要影响 在细胞运动蛋白上。研究将检查这种途径在AT风险的人类前列腺细胞中，将使用RAF1 主动/非活动构建体，类似地工程师LCP1构建体，通过正交分析的探测信号传导， 使用MS对蛋白质特征的概况影响，并将检查单个途径成员在细胞中的作用 运动性和KBU2046轻松。 目标3。评估临床相关模型的人类疾病模型中的靶向基序。在appipcap转基因中 模型，PTEN和p53的代码可诱导原位→侵入性→转移性PCA。它支持治疗 与原位病变发展后的相对于之后，使我们能够检查预防和拦截效率， 分别用于抑制侵入性癌的形成。使用前列腺快速尸检中的原代细胞 程序（RAP），我们显示了对KBU2046的机械相关响应能力。原代细胞和结果 类器官为检查临床相关模型的有效性提供了独特的机会。快速盖和说唱 组织将在分子和功能水平上询问，以检查KBU2046的作用。 影响。研究人员试图推进细胞运动是重要癌症的创新概念 预防截断目标。它适用于许多癌症类型。