Ras Dependent Human Cutaneous Neoplasia

描述（由申请人提供）：虽然皮肤基底细胞癌（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，与人类鳞状细胞癌有关。我们的实验室最近开发了一个人类鳞状细胞癌模型，使用Ras和细胞周期蛋白依赖性激酶4 （CDK4）来创建恶性表皮细胞群，准确地模仿自然发生的人类鳞状细胞癌。这种转化仅由两种基因定义的元素驱动，代表了一个理想的系统，它可以实现促进对Ras驱动的人类表皮瘤变的特定机制的更全面理解的主要目标。首先，将通过单独激活每个信号通路来确定三个主要Ras下游效应臂在CDK4驱动表皮瘤变中的相对贡献。已知可激活Raf、PI3K或RalGDS通路的组成型活性Ras突变体将在人角质形成细胞中与CDK4一起表达，并移植到免疫缺陷小鼠身上，研究其对表皮生长和分化的影响。单个通路也将在有限的组合中被激活，因为多个效应臂可能协同作用以复制完全转化的侵袭性SCC。其次，个体Ras效应臂的必要性将通过对Ras信号通路中特定成分的遗传和药理学阻断进一步确定。这将确定潜在治疗干预的关键点。最后，利用小组织穿透多肽的新技术将被开发出来，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，我们希望能够确定Ras驱动表皮瘤变的具体机制，以促进对人体组织肿瘤发生的理解，并指导未来针对皮肤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.