RIPK2/MKK7/c-Myc Signaling as a Therapeutic Target in Prostate Cancer Metastasis

RIPK2/MKK7/c-Myc 信号传导作为前列腺癌转移的治疗靶点

• 批准号: 10686235
• 负责人: Wei Yang
• 金额: $ 49.2万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686235
• 关键词: Address; Androgen Antagonists; Binding; Cancer Patient; Cause of Death; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Clone Cells; Creativeness; Data; Databases; Deterioration; Development; Disease Progression; Distant Metastasis; Drug Targeting; Economic Burden; Ectopic Expression; Follow-Up Studies; Fostering; Goals; Growth; Health; High Prevalence; Impairment; In Vitro; Invaded; Investigation; Knock-out; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Messenger RNA; Metabolic Pathway; Metastatic Prostate Cancer; Metastatic/Recurrent; Mission; Molecular; Morbidity - disease rate; Mus; Neoplasm Metastasis; Nonmetastatic; Nuclear; Operative Surgical Procedures; Organ; Organoids; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Phosphorylation; Phosphotransferases; Positioning Attribute; Process; Prognosis; Protein Kinase Interaction; Public Health; Quality of life; RIPK1 gene; Radiation therapy; Research; Resistance; Risk; Signal Pathway; Signal Transduction; Testing; Therapeutic; Time; Tissue Microarray; Translating; United States; United States Food and Drug Administration; Work; Xenograft procedure; c-myc Genes; cancer type; castration resistant prostate cancer; clinically actionable; clinically relevant; constitutive expression; druggable target; improved; in vivo; inhibitor; innovation; men; mortality; multidisciplinary; multiple omics; new therapeutic target; novel; novel therapeutics; overexpression; phase III trial; pre-clinical; prevent; primary endpoint; prostate cancer cell; prostate cancer cell line; prostate cancer metastasis; prostate cancer progression; social; therapeutic target; tumor growth; tumor xenograft

RIPK2/MKK7/c-Myc Signaling as a Therapeutic Target in Prostate Cancer Metastasis ABSTRACT: Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality of PC, imposing significant social and economic burdens. Three recent phase III clinical trials (i.e., SPARTAN, PROSPER, and ARAMIS) unequivocally demonstrated that preventing or delaying PC metastasis provides strong clinical benefits, prolonging the median overall survival by 10-14 months. To keep up the momentum and further improve the metastasis-free survival (a strong surrogate of overall survival) of PC patients, there is an urgent unmet need to identify novel druggable targets in PC metastasis and delineate their mechanisms of action (MoAs). Through an integrated analysis of three clinical omics databases, we identified receptor-interacting protein kinase 2 (RIPK2) as a top druggable target candidate for PC metastasis. RIPK2 is amplified/gained in 65% of lethal metastatic castration-resistant PC and its mRNA overexpression is associated with disease progression and poor prognosis. RIPK2 knockout (RIPK2-KO) or treatment with a potent RIPK2 inhibitor (e.g., the FDA-approved ponatinib) significantly suppressed PC cell invasion and colony formation but not proliferation in vitro and reduced the metastasis of 22Rv1 cells by up to 92% in vivo. Mechanistically, distinct from the canonical NOD/RIPK2/NF-κB pathway, RIPK2 strongly regulates the stability and activity of c-Myc (a driver of PC metastasis), largely by binding and activating MKK7, which we identified as a novel direct c-Myc- S62 kinase. This noncanonical RIPK2/MKK7/c-Myc signaling pathway can be potently inactivated by RIPK2-KO or ponatinib and thus is a very promising drug target in PC metastasis. Here, our overall goal is to provide a strong scientific rationale for a clinical trial by testing a central hypothesis: RIPK2/MKK7/c-Myc signaling is associated with PC progression, metastasis, and poor prognosis in patients and is critical for RIPK2-dependent PC metastasis, and its inhibition is the primary (albeit not the only) MoA of ponatinib in suppressing PC metastasis. The PI has assembled an outstanding multi-disciplinary team to pursue three distinct but interrelated specific aims: 1) assess the clinical correlations and refine the molecular basis of RIPK2/MKK7/c-Myc signaling, 2) determine whether RIPK2-KO inhibits PC metastasis primarily by inactivating the MKK7/c-Myc signaling pathway, and 3) determine whether ponatinib impairs PC metastasis primarily by inactivating RIPK2/MKK7/c- Myc signaling and define RIPK2-independent MoAs of ponatinib in suppressing PC metastasis. If successful, the proposed studies will expose a novel Achilles’ heel for PC metastasis and reveal the major MoAs of RIPK2- KO and ponatinib in suppressing PC metastasis. They will provide valuable preclinical data to guide the development of a clinical trial repurposing ponatinib to substantially improve the clinical outcomes of patients at risk for metastatic PC. Given the high prevalence of RIPK2 and MYC co-amplification/gain in multiple cancer types, the MoAs uncovered by the proposed studies will have clinical implications beyond the PC space.

RIPK2/MKK7/C-MYC信号作为前列腺癌转移的治疗靶标 摘要：尽管前列腺癌（PC）疗法进展，但遥远的转移仍然是主要原因 PC的发病率和死亡率，施加了巨大的社会和经济伯恩斯。三个最近的三期临床 试验（即Spartan，Prosper和Aramis）明确证明了防止或延迟PC 转移提供了强大的临床益处，将中位总生存期延长了10-14个月。保持 提高动量并进一步改善PC的无转移生存期（对整体生存的强大替代） 患者，紧急未满足的需要识别PC转移中的新型可药物靶标并描绘它们 作用机理（MOAS）。通过对三个临床OMIC数据库的综合分析，我们确定了 受体相互作用蛋白激酶2（RIPK2）是PC转移的最高吸毒靶标候选。 Ripk2是 在65％的致命转移性castration-PC及其mRNA过表达中得到扩增/获得 疾病进展和预后不良。 RIPK2敲除（RIPK2-KO）或用潜在RIPK2处理 抑制剂（例如，FDA批准的Ponatinib）显着抑制了PC细胞浸润和菌落形成，但 不能在体外增殖，并使22RV1细胞的转移减少了92％的体内。机械上，不同 从规范的点头/RIPK2/NF-κB途径中，RIPK2强烈调节C-MYC的稳定性和活性（a PC转移的驱动力很大 S62激酶。 RIPK2-KO可能会灭活这种非规范RIPK2/MKK7/C-MYC信号通路 或Ponatinib，因此是PC转移中非常有前途的药物靶标。在这里，我们的总体目标是提供 通过测试中心假设来进行临床试验的强大科学原理：RIPK2/MKK7/C-MYC信号是 与患者的PC进展，转移和预后不良相关，对于RIPK2依赖性至关重要 PC转移及其抑制是抑制PC的​​主要（尽管不是唯一的）MOA 转移。 PI组装了一个出色的多学科团队，以购买三个不同但相互关联 具体目的：1）评估RIPK2/MKK7/C-MYC信号传导的临床相关性并完善分子基础 2）确定RIPK2-KO是否通过灭活MKK7/C-MYC信号来抑制PC转移原发性 途径和3）确定Ponatinib是否通过灭活Ripk2/MKK7/C-来损害PC转移的主要 MYC信号传导并定义了Ponatinib的RIPK2无关MOA，以抑制PC转移。如果成功， 拟议的研究将使PC转移的新型阿喀琉斯高跟鞋揭露Ripk2-的主要MOAS脚跟 - KO和Ponatinib抑制PC转移。他们将提供有价值的临床前数据，以指导 开发将Ponatinib重新利用的临床试验大大改善了患者的临床结果 转移PC的风险。考虑到多个癌症中RIPK2和MYC共扩张/增益的高流行率 拟议研究发现的MOA类型将具有PC空间以外的临床意义。