Impact of Vitamin D on the Chemopreventive Efficacy of Erlotinib against Oral Cancer

 描述(由申请人提供)：表皮生长因子受体(EGFR)途径的激活是头颈部癌症发生的早期事件。因此，人们越来越有兴趣将EGFR作为化学预防的靶点。然而，考虑到肿瘤分子信号的冗余性，仅抑制EGFR信号不太可能抑制 口腔鳞癌的恶性进展。在这方面，具有良好安全性的天然化合物或营养补充剂尤其具有吸引力，可用作潜在的 癌症预防。为此，我们的新方法涉及使用营养补充剂维生素D3(或其活性代谢物骨化三醇)作为生物佐剂，以增强EGFR抑制剂Erlotinib的化学预防效果。EGFR通路的两个主要下游效应涉及MAPK-Erk和PI3K-Akt通路的激活，这两个通路在细胞生存、增殖和血管生成中起关键作用。骨化三醇以caspase依赖的方式诱导MEK的裂解，并降低ERK和Akt的磷酸化，这是激活ERK和Akt所必需的。因此，我们的假设是，以骨化三醇(或维生素D)与厄洛替尼联合作用于这些相互作用的信号通路将在预防口腔癌方面更有效。目前的工作重点是对这种机械驱动的抗病毒药物的化学预防潜力进行全面的临床前调查。 口腔癌。利用致癌物和PDX模型，拟议的研究计划将评估化学预防效果(目标1和2)，并剖析口腔癌对这种联合方案反应的分子机制(目标3)。阳性结果将为联合使用维生素D3和厄洛替尼预防口腔癌铺平道路。

 DESCRIPTION (provided by applicant): Activation of the epidermal growth factor receptor (EGFR) pathway is an early event in head and neck carcinogenesis. As a result, there has been increased interest in targeting EGFR for chemoprevention. However, given the redundancy in molecular signaling of tumors, it is unlikely that inhibition of EGFR signaling alone would inhibit malignant progression of OSCC. In this regard, natural compounds or nutritional supplements with favorable safety profiles are particularly attractive for use as potential 'bio-adjuvants' for cancer prevention. To this end, our novel approach involves the use of the nutritional supplement, Vitamin D3 (or its active metabolite calcitriol) as a bio-adjuvant to enhance the chemopreventive efficacy of the EGFR inhibitor, Erlotinib. Two of the main downstream effects of the EGFR pathway involve activation of the MAPK- Erk and the PI3K-Akt pathways that are critically involved in cell survival, proliferation and angiogenesis. Calcitriol induces cleavage o MEK in a caspase-dependent manner and also decreases phosphorylation of Erk and Akt, that is necessary for their activation. It is therefore our hypothesis that targeting these interacting signaling pathways with calcitriol (or vitamin D) in combination with Erlotinib will be more effective in preventing oral cancer. The focus of the present work is to conduct a comprehensive preclinical investigation into the chemopreventive potential of this mechanistically-driven against oral cancer. Using carcinogen and PDX models, the proposed research plan will evaluate the chemopreventive efficacy (Aim 1 and 2) and dissect the molecular mechanisms (Aim 3) involved in the response of oral cancers to this combination regimen. Positive results would pave the way for use of vitamin D3 in combination with Erlotinib for the prevention of oral cancer.