CARP-1: A Potential Therapeutic Agent for Breast Cancer

CARP-1：乳腺癌的潜在治疗剂

• 批准号: 10356047
• 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/10356047
• 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; Couples Therapy; 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; NF-kappa B; Neoadjuvant Therapy; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphoproteins; Phosphorylation; Phosphotransferases; Platinum Compounds; Prognosis; 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; p65; palliative; receptor; side effect; small molecule inhibitor; targeted treatment; therapy development; translational impact; treatment response; treatment strategy; 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.

紧急开发了三阴性乳腺癌（TNBC）治疗的新策略和改进的策略 由于TNBC的分子复杂性以及治疗相关的副作用以及出现 抗药性通常会限制当前疗法的有效性。 Carp-1/CCAR1是无处不在的磷酸蛋白 这可以通过多种机制诱导增殖和凋亡。鲤鱼1转导化疗 （阿霉素，依托泊苷或IRESSA）依赖性抑制信号，并共激活阿霉素（ADR）诱导的 p53。 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/甲状腺接收器。在这里，我们报告Carp-1与Erks相互作用，并与Nemo（NF-B）结合 基本调制器； NF-B激活激酶IKK亚基）。我们的初步和发表研究揭示了 ADR诱导鲤鱼1苏氨酸627磷酸化，ERK激活和规范的NF-B途径 涉及NEMO-CARP-1结合。重要的是，抑制NEMO-CARP-1结合减少NF-B激活 （通过ADR对p65/rela的磷酸化注意，而不是TNFα，白介素（IL）2或EGF。此外，Sni-1，a Nemo-CARP-1结合的新型SMI，增强了TNBC细胞的ADR或顺铂抑制作用，可降低 遗传毒性应激（ADR或顺铂）诱导的促炎细胞因子TNFα和IL8。 SNI-1增强了TNBC 4T1合成肿瘤模型中ADR或顺铂在体内抑制的生长抑制。 假设：诱导DNA损伤的药物（ADR，顺铂）激活了鲤鱼1介导的规范NF-B和 ERK路径。该假设的基本原理包括我们的初步和发表的研究，表明 通过破坏Nemo-CARP-1结合增强功能，抑制治疗诱导的典型NF-B激活 ADR和顺铂在体外和体内的功效。此外，ADR还诱导了鲤鱼1磷酸化，并且 由于遗传毒性疗法还激活了ERK，因此与ERK抑制剂一起靶向Nemo-CARP-1结合 ADR或顺铂会导致更大的肿瘤抑制。那是carp-1/nemo结合的靶向 允许我们在不影响NF-B的其他中心功能的情况下克服TNBC中的化学抗性 由TNFα，IL2和/或EGF信号传导，用于宿主组织稳态。我们将跟随三个 旨在检验我们的假设。 目标1：定义鲤鱼1在遗传毒性化学疗法诱导的典范NF-B存活途径中的作用。 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损伤引起的， NEMO磷酸化和规范NF-B途径。 目标2：研究鲤鱼1与ERK相互作用的机制。我们将确定如何定位 ERK与SNI-1结合增强了遗传毒性化疗的效率。 目标3：证明靶向鲤鱼-1/NeMo依赖性规范，NF-B信号通过水溶性 单独使用SNI-1或与目前在临床试验/使用中的治疗中对ERK的靶向，将导致 遗传毒性化学疗法在体内通过遗传毒性化学疗法杀死的上升。 对退伍军人卫生保健的潜在影响：拟议的研究将产生有价值的分子知识 遗传毒性化学疗法（ADR和顺铂）的作用机理，以有效治疗 TNBC及其耐药的对应物。我们发现SNI-1及其提高效率的潜力 克服治疗诱导的抗性的TNBC疗法将产生翻译影响，预计将 促进制定新颖有效的策略，以抗击难以治疗的乳腺癌，这将受益 女性VA劳动力，为退伍军人卫生保健和VA任务做出了贡献。