Chemoprevention of metastatic colorectal cancer

描述(申请人提供)：结肠癌转移仍然是导致本病死亡的主要原因。重要的是要确定事件的原因，并将其控制到更高级的阶段和转移。在拟议的研究中，我们假设AKT的高水平表达是结直肠癌发生侵袭性和转移性疾病的原因，通过影响上皮-间充质转化(EMT)赋予细胞迁移和侵袭性表型，因此靶向AKT激活可以预防结直肠癌的转移。为了证明这一假设，我们检查了AKT在CRC细胞系和患者样本中的状态，发现AKT高表达。在我们的细胞培养和结肠癌异种移植模型中，我们已经证明AKT的过表达导致侵袭性细胞和肿瘤生长，肿瘤血管生成和肿瘤细胞的EMT表型。当前项目的目标是描述和生成关于将黄曲霉毒素-A(WA)或ITA有效类似物作为预防结肠癌转移的口服药物的临床前数据。为了抑制AKT信号，我们在临床前的CRC模型中使用了Withaferin-A(WA)，这是一种草药分子，可以克服AKT介导的EMT。基于这些发现，我们假设大肠癌细胞已经适应了AKT的高水平表达而形成侵袭性表型，因此靶向AKT激活可以通过抑制上皮间充质转化(EMT)来防止侵袭性大肠癌的发展。我们已经提议从与AKT结合更强的Wa中鉴定和合成更有效的分子。这些衍生物将在细胞培养和动物模型(转移性异种移植和APC，模拟高级和转移性人类结直肠癌)中进一步表征。使用针对AKT的有效生物分子来预防结肠癌是一种新的方法，可能会对高危患者产生重大影响。此外，我们第一次证明了AKT的积累是通向EMT的关键一步，我们建议开发针对AKT的生物素标记化合物。使用这些新的有效化合物化学预防结直肠癌可能通过抑制AKT诱导的EMT信号从而抑制转移而对高危患者或临床复发患者产生重大影响。

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.