Ras Dependent Human Cutaneous Neoplasia

描述(申请人提供)：尽管皮肤基底细胞癌(BCC)和鳞状细胞癌(SCC)是美国最常见的癌症，但驱动人类表皮转化的具体机制尚不清楚。RAS是人类癌症中最常见的突变原癌基因，已被认为与人类鳞癌有关。我们实验室最近开发了一种人鳞状细胞癌模型，使用RAS和细胞周期蛋白依赖性激酶4(CDK4)来创建准确模拟自然发生的人鳞状细胞癌的恶性表皮细胞群。这种转化仅由两个基因定义的元件驱动，并代表了一个理想的系统，通过它来实现更完整地了解RAS导致人类表皮肿瘤的具体机制这一主要目标。首先，将通过单独激活每个信号通路来确定Ras下游三个主要效应臂在CDK4驱动表皮肿瘤形成中的相对贡献。已知的激活Raf、PI3K或RalGDS通路的结构性活性RAS突变体将与CDK4一起在人角质形成细胞中表达，并移植到免疫缺陷小鼠身上，在那里将检测对表皮生长和分化的影响。单独的通路也将在有限的组合中被激活，因为多个效应器手臂可能协同作用，以复制完全转化的侵袭性SCC。其次，通过遗传和药物阻断RAS信号通路中的特定成分，将进一步确定单个RAS效应臂的必要性。这将为潜在的治疗干预确定关键点。最后，将开发利用小组织穿透性多肽的新技术，以特异性地相互作用并抑制人类表皮中RAS信号通路的关键成分。在资助期结束时，我们希望确定RAS驱动表皮肿瘤的具体机制，以促进对人类组织肿瘤发生的理解，并指导未来针对皮肤癌和其他组织癌症的靶向分子治疗的发展。

DESCRIPTION (provided by applicant): Although cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in the US, specific mechanisms driving human epidermal transformation are not well understood. Ras is the most commonly mutated proto-oncogene in human cancer and has been implicated in human SCC. A model for human SCC has recently been developed in our laboratory employing Ras and cyclin dependent kinase 4 (CDK4) to create a malignant epidermal cell population that accurately mimics naturally occurring human SCC. This transformation is driven by only two genetically defined elements, and represents an ideal system with which to accomplish the primary goal of advancing a more complete understanding of specific mechanisms mediating Ras driven human epidermal neoplasia. First, the relative contribution of each of the three major Ras downstream effector arms in driving epidermal neoplasia with CDK4 will be identified by activating each signaling pathway individually. Constitutively active Ras mutants known to activate either the Raf, PI3K, or RalGDS pathways will be expressed with CDK4 in human keratinocytes and grafted onto immunodeficient mice where effects on epidermal growth and differentiation will be examined. Individual pathways will also be activated in limited combinations as multiple effector arms may act in concert to reproduce the completely transformed invasive SCC. Second, the necessity of individual Ras effector arms will be defined further through both genetic and pharmacologic blockade of specific components in the Ras signaling pathways. This will identify key points for potential therapeutic intervention. Finally, new technologies utilizing small tissue penetrating polypeptides will be developed to interact specifically and inhibit critical components of the Ras signaling pathway in human epidermis. At the end of the funding period, we hope to have defined specific mechanisms through which Ras drives epidermal neoplasia to advance an understanding of human tissue tumorigenesis and to guide development of future targeted molecular therapies for cancers of the skin and other tissues.