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 耐药性通常限制了目前治疗的有效性。CARP-1/CCAR 1是一种普遍存在的磷酸化蛋白， 可以通过多种机制诱导细胞增殖和凋亡。CARP-1转导化疗 （阿霉素，依托泊苷，或易瑞沙）依赖性抑制信号，并共激活阿霉素（ADR）诱导的 第53页。CARP-1还共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-κ B B）结合， 必需调节剂; NF-κ B活化激酶IKK亚基（IKK）。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-κ B B通路， 涉及NEMO-CARP-1结合。重要的是，NEMO-CARP-1结合的抑制减少了NF-κ B B活化 （通过p65/RelA的磷酸化来观察），但不通过TNFα、白细胞介素（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，降低了TNBC细胞的ADR或顺铂水平， 遗传毒性应激（ADR或顺铂）诱导的促炎细胞因子TNFα和IL 8。SNI-1增强TNBC 在4 T1同基因肿瘤模型中通过ADR或顺铂的体内生长抑制。 假设：DNA损伤诱导药物（ADR，顺铂）激活CARP-1介导的经典NF-κ B B， ERK通路。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-κ B B活化， 阿霉素与顺铂体内外疗效比较此外，ADR还诱导CARP-1磷酸化， 由于基因毒性疗法也激活ERK，因此NEMO-CARP-1结合与ERK抑制剂一起靶向 将导致ADR或顺铂的更大肿瘤抑制。因此，CARP-1/NEMO结合的靶向作用可以 使我们能够克服TNBC中的化学抗性，而不影响NF-κ B B诱导的其他中枢功能。 通过宿主组织稳态所必需的TNFα、IL 2和/或EGF信号传导。我们将开展以下三项活动 旨在验证我们的假设。 目的1：明确CARP-1在遗传毒性化疗诱导的经典NF-κ B B存活通路中的作用。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， NEMO磷酸化和经典NF-κ B B通路。 目的2：研究CARP-1与ERK相互作用的机制。我们将决定如何瞄准 ERK与SNI-1联合增强遗传毒性化疗的疗效。 目的3：证明通过水溶性重组蛋白靶向CARP-1/NEMO依赖的典型NF-κ B B信号传导。 SNI-1单独或与目前在临床试验/使用中的治疗剂靶向ERK结合，将导致 体内遗传毒性化疗对TNBC肿瘤具有出色的上级杀伤作用。 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， 遗传毒性化疗（ADR和顺铂）的作用机制，以有效治疗 TNBC及其耐药对应物。我们对SNI-1的发现及其增强抗肿瘤药物疗效的潜力 克服治疗诱导的耐药性的TNBC疗法将产生转化影响，预计 促进开发新的和有效的战略，以打击难以治疗的乳腺癌， 退伍军人事务部的女性劳动力，有助于退伍军人保健和进一步的退伍军人事务部使命。