CARP-1: A Potential Therapeutic Agent for Breast Cancer

CARP-1：乳腺癌的潜在治疗剂

• 批准号: 10618778
• 负责人: Arun Kumar Rishi
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618778
• 关键词: 4T1; Adjuvant; Adriamycin PFS; Affect; Apoptosis; Binding; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer therapy; Cancer Etiology; Cell Cycle; Chemoresistance; Cisplatin; Clinic; Clinical Trials; Coupled; Cyprinus carpio; DNA; DNA Damage; Data; Development; Doxorubicin; Drug resistance; EGF gene; Effectiveness; Etoposide; Female; Gefitinib; Genotoxic Stress; Growth; Healthcare; Homeostasis; Human; IL2 gene; IL8 gene; In Vitro; Inflammatory; Interleukin-2; Knowledge; MEKs; Mediating; Military Personnel; Mission; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Mechanisms of Action; Neoadjuvant Therapy; Nuclear; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphoproteins; Phosphorylation; Phosphotransferases; Platinum Compounds; Poly(ADP-ribose) Polymerase Inhibitor; Prognosis; Proliferating; Publishing; Radiation therapy; Regulation; Reporting; Resistance; Role; Signal Transduction; Steroids; TNF gene; TP53 gene; Testing; Therapeutic; Therapeutic Agents; Thyroid Gland; Tissues; Topoisomerase II; Transducers; Tumor Suppression; Veterans; Water; Woman; Women' s Health; Work; acronyms; anaphase-promoting complex; chemotherapy; combat; cytokine; effective therapy; genotoxicity; hormone therapy; improved; in vivo; inhibitor; innovation; malignant breast neoplasm; mortality; mutant; novel; novel therapeutic intervention; p65; palliative; receptor; side effect; small molecule inhibitor; targeted treatment; therapy development; translational impact; treatment response; triple-negative invasive breast carcinoma; tumor; ubiquitin-protein ligase

Development of new and improved strategies for triple-negative breast cancer (TNBC) treatment is urgently needed since molecular complexity of TNBC together with therapy-associated side effects and emergence of drug-resistance often limit effectiveness of current therapies. CARP-1/CCAR1 is a ubiquitous, phospho-protein that can induce proliferation and apoptosis through multiple mechanisms. CARP-1 transduces chemotherapy (adriamycin, etoposide, or Iressa)-dependent inhibitory signaling, and co-activates Adriamycin (ADR)-induced p53. CARP-1 also co-activates cell-cycle regulatory anaphase-promoting complex (APC/C) E3 ubiquitin ligase and steroid/thyroid receptors. Here we report that CARP-1 interacts with ERKs, and binds with NEMO (NF-B Essential Modulator; NF-B-activating kinase IKK subunit ). Our preliminary and published studies revealed that ADR induced CARP-1 threonine627 phosphorylation, ERK activation, and canonical NF-B pathway that involved NEMO-CARP-1 binding. Importantly, inhibition of NEMO-CARP-1 binding diminishes NF-B activation (noted by phosphorylation of p65/RelA) by ADR but not by TNFα, interleukin (IL)2, or EGF. Further, SNI-1, a novel SMI of NEMO-CARP-1 binding, enhances ADR or Cisplatin inhibition of TNBC cells, diminishes levels of genotoxic stress (ADR or Cisplatin)-induced pro-inflammatory cytokines TNFα and IL8. SNI-1 enhances TNBC growth suppression by ADR or Cisplatin in vivo in 4T1 syngeneic tumor model. Hypothesis: DNA Damage-inducing drugs (ADR, Cisplatin) activate CARP-1-mediated canonical NF-B and ERK pathways. The rationale for this hypothesis include our preliminary and published studies that indicate inhibition of therapy-induced, canonical NF-B activation by disruption of NEMO-CARP-1 binding enhances efficacy of ADR and Cisplatin in vitro and in vivo. Moreover, ADR also induces CARP-1 phosphorylation and, since genotoxic therapy also activates ERKs, targeting of NEMO-CARP-1 binding together with ERK inhibitors will result in greater tumor suppression by ADR or Cisplatin. Thus, targeting of CARP-1/NEMO binding could permit us to overcome chemo-resistance in TNBCs without affecting other central functions of NF-B induced by TNFα, IL2, and/or EGF signaling necessary for host tissue homeostasis. We will conduct following three aims to test our hypothesis. Aim 1: To define role of CARP-1 in genotoxic chemotherapy-induced canonical NF-B survival pathway. SNI-1 inhibits therapy-induced NEMO phosphorylation. We will elucidate how SNI-1 inhibits DNA damage-induced, NEMO phosphorylation and canonical NF-B pathway. Aim 2: To investigate mechanism(s) by which CARP-1 interacts with ERKs. We will determine how targeting of ERKs in combination with SNI-1 enhances efficacy of genotoxic chemotherapy. Aim 3: To demonstrate targeting of CARP-1/NEMO-dependent canonical, NF-B signaling by water-soluble SNI-1 alone or coupled with targeting of ERKs by therapeutics currently in clinical trials/use, will result in superior TNBC tumor kill by genotoxic chemotherapy in vivo. Potential Impact on Veterans Health Care: The proposed studies will yield valuable knowledge of molecular mechanisms of action of genotoxic chemotherapies (ADR and Cisplatin) to permit effective treatment of TNBCs and their drug-resistant counterparts. Our discovery of SNI-1 and its potential to enhance efficacy of TNBC therapies to overcome therapy-induced resistance will have translational impact and are expected to facilitate development of novel and effective strategies to combat hard to treat breast cancers that will benefit female VA workforce, contribute to Veterans Health Care and further the VA mission.

迫切需要开发新的和改进的三阴性乳腺癌（TNBC）治疗策略 由于 TNBC 的分子复杂性以及治疗相关的副作用和出现 耐药性常常限制当前疗法的有效性。 CARP-1/CCAR1 是一种普遍存在的磷蛋白 可以通过多种机制诱导增殖和凋亡。 CARP-1 转导化疗 （阿霉素、依托泊苷或易瑞莎）依赖性抑制信号传导，并共同激活阿霉素 (ADR) 诱导的 第 53 页。 CARP-1 还共同激活细胞周期调节后期促进复合物 (APC/C) E3 泛素连接酶 和类固醇/甲状腺受体。在这里，我们报告 CARP-1 与 ERK 相互作用，并与 NEMO (NF-βB) 结合 基本调制器； NF-βB 激活激酶 IKK 亚基 )。我们的初步和已发表的研究表明 ADR 诱导 CARP-1 苏氨酸 627 磷酸化、ERK 激活和经典 NF-κB 通路 涉及 NEMO-CARP-1 结合。重要的是，抑制 NEMO-CARP-1 结合会减少 NF-κB 激活 （通过 p65/RelA 的磷酸化注意到）受 ADR 影响，但不受 TNFα、白细胞介素 (IL)2 或 EGF 影响。此外，SNI-1， NEMO-CARP-1 结合的新型 SMI，增强 ADR 或顺铂对 TNBC 细胞的抑制，降低 基因毒性应激（ADR 或顺铂）诱导的促炎细胞因子 TNFα 和 IL8。 SNI-1 增强 TNBC 在 4T1 同基因肿瘤模型中，ADR 或顺铂体内生长抑制。 假设：DNA 损伤诱导药物（ADR、顺铂）激活 CARP-1 介导的经典 NF-κB 并 ERK 途径。这一假设的基本原理包括我们的初步和已发表的研究表明 通过破坏 NEMO-CARP-1 结合来抑制治疗诱导的典型 NF-κB 激活可增强 ADR 和顺铂的体外和体内疗效。此外，ADR 还诱导 CARP-1 磷酸化，并且， 由于基因毒性疗法也会激活 ERK，因此以 NEMO-CARP-1 与 ERK 抑制剂结合为目标 将导致 ADR 或顺铂更大的肿瘤抑制作用。因此，CARP-1/NEMO 结合的靶向可以 使我们能够克服 TNBC 的化疗耐药性，而不影响 NF-κB 诱导的其他中枢功能 通过宿主组织稳态所必需的 TNFα、IL2 和/或 EGF 信号传导。我们将进行以下三项工作 目的是检验我们的假设。 目标 1：确定 CARP-1 在基因毒性化疗诱导的经典 NF-κB 生存途径中的作用。 SNI-1 抑制治疗诱导的 NEMO 磷酸化。我们将阐明 SNI-1 如何抑制 DNA 损伤诱导的、 NEMO 磷酸化和经典 NF-κB 通路。 目标 2：研究 CARP-1 与 ERK 相互作用的机制。我们将确定如何定位 ERK 与 SNI-1 结合可增强基因毒性化疗的疗效。 目标 3：证明水溶性 CARP-1/NEMO 依赖的经典 NF-κB 信号传导的靶向性 单独使用 SNI-1 或与目前处于临床试验/使用中的针对 ERK 的疗法相结合，将导致 体内基因毒性化疗具有优异的 TNBC 肿瘤杀灭效果。 对退伍军人医疗保健的潜在影响：拟议的研究将产生有价值的分子知识 基因毒性化疗（ADR 和顺铂）的作用机制，可有效治疗 TNBC 及其耐药对应物。我们对 SNI-1 的发现及其增强功效的潜力 克服治疗引起的耐药性的 TNBC 疗法将产生转化影响，预计将 促进制定新颖有效的策略来对抗难以治疗的乳腺癌，这将受益 退伍军人管理局女性员工，为退伍军人医疗保健做出贡献，并进一步推进退伍军人事务部的使命。