Chemoprevention of metastatic colorectal cancer

转移性结直肠癌的化学预防

基本信息

批准号：
8688712
负责人：
Chendil Damodaran
金额：
$ 41.22万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8688712
关键词：
AKT Signaling Pathway AKT inhibition Affinity Animal Model Animals Apoptosis BCL2 gene Binding Biological Assay Biotin Cancer Etiology Cause of Death Cell Culture Techniques Cell Line Cell Proliferation Cells Cessation of life Chemoprevention Chemopreventive Agent Clinical Clinical Trials Colon Carcinoma Colonic Neoplasms Colorectal Cancer Data Development Diagnosis Disease Disseminated Malignant Neoplasm Docking E-Cadherin Epithelial Event Fluorouracil Goals Growth Human In Vitro Investigation Label Laboratories Large Intestine Carcinoma Lead Malignant Epithelial Cell Mediating Mesenchymal Modeling Molecular Neoplasm Metastasis Oral Oral Administration Patients Pattern Phenotype Phosphotransferases Polyps Pre-Clinical Model Prevention Proteins Proto-Oncogene Proteins c-akt Radiosurgery Regimen Relapse Research Personnel Role SW620 Sampling Signal Transduction Snails Staging Survival Rate Therapeutic Time Transcription factor genes Tumor Tissue Withania somnifera Woman Xenograft Model Xenograft procedure analog angiogenesis base cell growth chemotherapy dietary supplements high risk insight interest meetings men metastatic colorectal migration neoplastic cell novel novel strategies overexpression pre-clinical prevent public health relevance slug survivin tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Colon cancer metastasis remains the leading cause of death due to this disease. It is important to identify the cause of events, maneuvering it to a more advanced stage and metastasis. In the proposed study we have hypothesized that high level of AKT expression is CRC is responsible for developing an aggressive and metastatic disease by influencing epithelial-mesenchymal transitions (EMT) endowing cells with migratory and invasive phenotype, hence targeting AKT activation can prevent metastasis in CRC. To prove the hypothesis we have checked the status of AKT in CRC cell lines and patient samples revealing high expression of AKT. In our cell culture and colon cancer xenograft models we have shown that overexpression of AKT leads to aggressive cell and tumor growth, angiogenesis in tumors and EMT phenotype in tumor cells. The goal of the current project is to characterize and generate preclinical data on withaferin-A (WA) or ita potent analog as an oral agent for the prevention of colon cancer metastasis. To inhibit AKT signaling we have employed Withaferin-A (WA) an herbal molecule that overcomes AKT-mediated EMT in preclinical models of CRC. Based on these finding we hypothesize that CRC cells have adapted for the high-level of AKT expression to develop an aggressive phenotypes, hence targeting AKT activation can prevent the development of aggressive CRC growth by inhibiting epithelial mesenchymal transition (EMT). We have proposed to identify and synthesize more potent molecules derived from WA, which bind more strongly to AKT. These derivatives will be further characterized in cell culture and animal (metastatic xenograft and an APC, mimicking advanced and metastatic human CRC) models. Preventing colon cancer using potent biomolecules targeting AKT specifically is a novel approach and may have significant impact on high-risk patients. In addition for the first time we have shown that AKT accumulation is a critical step towards EMT and we have proposed to develop biotin-labeled compounds to target AKT specifically. Chemoprevention of CRC by using these novel potent compounds may have a significant impact in high-risk patients or clinically relapsing patients by inhibiting AKT- induced EMT signaling and hence metastasis.

描述（由申请人提供）：结肠癌转移仍然是由于这种疾病而导致的死亡原因。重要的是要确定事件的原因，将其操纵到更先进的阶段和转移。在拟议的研究中，我们假设高水平的Akt表达是CRC通过影响迁移和侵入性表型的细胞的上皮 - 间质转变（EMT）来发展侵略性和转移性疾病，因此靶向Akt激活可以防止CRC中的转移。为了证明假设，我们检查了AKT在CRC细胞系和患者样品中的状态，显示了Akt的高表达。在我们的细胞培养和结肠癌异种移植模型中，我们表明AKT的过表达导致侵袭性细胞和肿瘤生长，肿瘤中的血管生成和肿瘤细胞中EMT表型。当前项目的目的是表征和生成有关withaferin-A（WA）或ITA有效类似物作为预防结肠癌转移的口服剂的临床前数据。为了抑制AKT信号，我们使用了AFERIN-A（WA）一种草药分子，该分子在CRC的临床前模型中克服了Akt介导的EMT。基于这些发现，我们假设CRC细胞已适应高水平的Akt表达来发展侵袭性表型，因此靶向AKT激活可以通过抑制上皮间质转换（EMT）来防止攻击性CRC生长的发展。我们建议识别和合成从WA衍生的更有效的分子，该分子与Akt更强地结合。这些衍生物将在细胞培养和动物（转移性异种移植物和APC，模仿晚期和转移性人类CRC）模型中进一步表征。使用针对AKT的有效生物分子预防结肠癌是一种新型方法，可能对高危患者产生重大影响。此外，我们首次表明AKT积累是EMT的关键步骤，我们建议开发出生物素标记的化合物以专门靶向AKT。通过使用这些新型有效化合物对CRC的化学预防可能会对高危患者或临床复发患者产生重大影响，通过抑制Akt诱导的EMT信号传导和转移。