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）通路的激活是头颈部癌变的早期事件。因此，人们对靶向EGFR进行化学预防的兴趣增加。然而，考虑到肿瘤分子信号传导的冗余，单独抑制EGFR信号传导不太可能抑制肿瘤细胞的增殖。 OSCC的恶性进展。在这方面，具有有利的安全性特征的天然化合物或营养补充剂特别有吸引力地用作潜在的“生物佐剂”， 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抑制剂厄洛替尼的化学预防功效。EGFR途径的两个主要下游效应涉及MAPK-Erk和PI 3 K-Akt途径的活化，其关键地参与细胞存活、增殖和血管生成。骨化三醇以半胱天冬酶依赖性方式诱导MEK裂解，并且还降低Erk和Akt的磷酸化，这是其活化所必需的。因此，我们的假设是，用骨化三醇（或维生素D）联合厄洛替尼靶向这些相互作用的信号通路将更有效地预防口腔癌。目前工作的重点是进行全面的临床前研究，这种机制驱动的化学预防潜力， 口腔癌使用致癌物和PDX模型，拟议的研究计划将评估化学预防功效（目标1和2），并剖析口腔癌对该组合方案的反应所涉及的分子机制（目标3）。积极的结果将为使用维生素D3与厄洛替尼联合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.