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.

迫切需要开发新的和改进的三阴性乳腺癌治疗策略