CARP-1: A Potential Therapeutic Agent for Breast Cancer

CARP-1：乳腺癌的潜在治疗剂

• 批准号: 8598030
• 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: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598030
• 关键词: Adriamycin PFS; Adverse effects; Antibodies; Apoptosis; Apoptotic; Attenuated; BRCA1 gene; BRCA2 gene; Binding; Biological Assay; Breast; Breast Cancer Cell; Breast Cancer Treatment; Breast Carcinoma; Cancer Cell Growth; Caspase; Cell Cycle; Cell Death; Cell Line; Cell Survival; Cells; Development; Disease; Dose; Drug Kinetics; Drug resistance; Effectiveness; Epidermal Growth Factor Receptor; Epitopes; Estrogen Receptors; Etoposide; Family member; Fluorescence Polarization; Gefitinib; Goals; Growth; Healthcare; Human; In Vitro; Intravenous; Investigation; Knowledge; Laboratories; Lead; MAPK14 gene; MCF10A cells; MCF7 cell; Malignant Neoplasms; Maps; Mission; Mitotic; Molecular; Molecular Target; Mus; New Agents; Nuclear; Oncogenic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Progesterone Receptors; Protein p53; Proteins; Proteome; Reagent; Resistance; Resistance development; Retinoic Acid Receptor; Risk Factors; SCID Mice; Signal Transduction; Tail; Tamoxifen; Testing; Therapeutic; Therapeutic Agents; Transducers; Tumor Suppressor Proteins; Ubiquitin; Veins; Veterans; Woman; Work; Xenograft Model; Xenograft procedure; Yeasts; acronyms; analog; anaphase-promoting complex; base; cancer cell; cancer therapy; caspase-9; cell growth; cellular transduction; chemotherapy; combat; cyclin B1; design; drug development; expectation; fighting; genetic regulatory protein; high throughput screening; human MAPK14 protein; in vivo; inhibitor/antagonist; innovation; insight; loss of function; malignant breast neoplasm; mimetics; multicatalytic endopeptidase complex; mutant; novel; outcome forecast; prevent; protein function; response; small molecule; small molecule libraries; stress activated protein kinase; therapeutic target; treatment strategy; tumor; ubiquitin-protein ligase; upstream kinase; yeast two hybrid system

DESCRIPTION (provided by applicant): The molecular complexity of breast cancers and therapy-associated side effects often limit effectiveness of many therapies, warranting the development of new agents for specific molecular targets while minimizing the off-target effects. Our goal is to develop novel, safer, and effective human breast cancer (HBC) therapies by exploiting functions of an apoptosis regulatory protein CCAR1/CARP-1. CARP-1 functions to transduce cell growth as well as chemotherapy (adriamycin, etoposide, or Iressa)-dependent inhibitory signaling. CARP-1 expression correlates inversely with HBC tumor grades. A yeast-two-hybrid (Y2H) screen revealed that CARP- 1 binds with the E3 ubiquitin ligase subunit anaphase promoting complex (APC)-2 protein. Following mapping of the interacting epitopes of CARP-1 and APC-2, we developed a fluorescence polarization assay (FPA) and screened a chemical library to identify small molecule inhibitors (SMIs) of CARP-1:APC-2 binding. The lead SMI termed CARP-1 Functional Mimetic (CFM)-4, inhibits HBC growth in vitro and in vivo. CFM-4 also attenuates growth of tamoxifen (TAM) or adriamycin (ADR)-resistant HBC cells but does not suppress growth of the non-tumorigenic and immortalized MCF-10A cells. CFM-4 binds with CARP-1, leads to increased CARP- 1 levels, activates pro-apoptotic p38 mitogen-activated protein kinase (MAPK), caspases-9 and 3, and apoptosis. CFM-4 induces loss of mitotic cyclin B1 and Cdc20 proteins, possibly through caspase-dependent but ubiquitin proteasome pathway (UPP)-independent mechanism(s). Hypothesis: CARP-1, a peri-nuclear phospho-protein, functions to regulate HBC cell growth and apoptosis, and is a key regulator of ADR signaling. We further hypothesize that CFM-4 stimulation of CARP-1 levels will provide a novel mechanism for treating breast and other cancers. Objectives: Our long-term objective is to elucidate mechanisms of CARP-1-dependent HBC growth inhibition, and to exploit this knowledge to develop agents for targeting of HBC. The rationale for this objective is based on the facts that loss of tumor suppressor p53 promotes development of aggressive HBCs and that resistance to ADR continues to be a problem. Since CARP-1 regulates HBC growth inhibition by ADR and is a co- activator of p53, the CFMs that bind and elevate CARP-1, activate pro-apoptotic p38 MAPK and caspases, and suppress Cdc20 and cyclin B1 levels have potential to target HBCs including those that have mutant p53 as well as have resistance to ADR or TAM. We will test our hypothesis by pursuing the following objectives. (1) To investigate molecular mechanism(s) of p38 activation, and the extent to which CARP-1 binding with p38 regulates HBC growth in the presence of CFM-4 or ADR. (2) To elucidate mechanism(s) of CARP-1-dependent activation of caspases-9 and -3, and determine the extent to which activated caspases target Cyclin B1 in the presence of CFM-4. (3) To conduct pharmacokinetic (PK) profiling and to demonstrate the anti-tumor activities of CFM(s) in mouse xenograft models of HBC. Potential Impact on Veterans Health Care: This investigation will facilitate development of strategies to prevent/combat breast cancer that will benefit women in the VA workforce, contribute to Veterans Health Care and further the mission of the VA.

描述（由申请人提供）：