Inhibiting Multiple Molecular Targets for Preventing Non-Melanoma Skin Cancer

描述（由申请人提供）：越来越多的证据表明，高度侵袭性皮肤肿瘤的发生可能需要不同基因座的多个突变，关键调控基因的过度表达或抑制可协同影响癌症的发生。太阳紫外线B（UVB）可诱导鸟氨酸脱羧酶（ODC）和环氧合酶-2（考克斯-2）的表达和活性。ODC是多胺合成的限速酶，多胺对所有细胞的生长和分化都是必需的。考克斯-2表达导致皮肤中的前列腺素（PGs），特别是PGE 2的合成增强。我们已经开发了基因工程小鼠模型，结合特定的药理学方法，以表明ODC和考克斯-2在小鼠皮肤中的过表达增强了非黑色素瘤皮肤癌（NMSC）的生长，并且下调ODC或考克斯-2仅部分减弱了这些肿瘤的生长。人鳞状细胞癌（SCC）和基底细胞癌（BCC）都过表达ODC和考克斯-2.我们和其他人已经表明，它们的过度表达是NMSC发病机制的基础。SCC显示其高表达，特别是在它们侵入正常组织的界面处。然而，在局部浸润性和转移性的基底细胞癌中，考克斯-2表达主要发生在基质细胞中，而ODC表达也相对不那么突出。在这个项目中，我们将测试的假设，这两种途径可以合作的NMSC的发病机制，其时间和空间的调节决定了肿瘤表型和恶性表型的进展。由于增强的考克斯-2产生的PGE 2和ODC依赖性多胺的过度产生导致携带已知肿瘤抑制基因（包括表征NMSC的p53和ptch）突变的细胞的增殖、迁移和侵袭性增强，因此这些分子靶点的联合抑制可以提供一种全新的方法来化学预防这种肿瘤。我们还提出研究ODC和考克斯-2联合过表达导致侵袭性肿瘤表型发病的机制。预计这些研究中产生的信息可以迅速转化为临床试验，采用亚拉巴马大学医学中心唯一可用的高风险人群。

DESCRIPTION (provided by applicant): Accumulating evidence indicates that the development of highly invasive skin tumors may require multiple mutations at different loci and that over-expression or repression of key regulatory genes can cooperate to influence the development of cancer. Solar ultraviolet B (UVB) induces the expression and activities of ornithine decarboxylase (ODC) and cyclooxygenase-2 (COX-2). ODC is the rate limiting enzyme for synthesis of polyamines, which are essential for the growth and differentiation of all cells. COX-2 expression leads to enhanced synthesis of prostaglandins (PGs), particularly PGE2 in the skin. We have developed genetically engineered murine models coupled with specific pharmacological approaches to show that both ODC and COX-2 over-expression in murine skin enhances the growth of non-melanoma skin cancers (NMSCs), and that down-regulation of ODC or COX-2 attenuates the growth of these tumors only partially. Human squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) both over- express ODC and COX-2. We and others have shown that their over-expression underlies the pathogenesis of NMSCs. SCCs show their high expression particularly at the interface where they invade normal tissue. However, in BCCs, which are locally invasive and metastasize only rarely, COX-2 expression occurs primarily in stromal cells, whereas ODC expression is also comparatively less prominent. In this project we will test the hypothesis that both pathways can cooperate in the pathogenesis of NMSCs and that their temporal and spatial regulation determines the tumor phenotype and progression to a malignant phenotype. Since both augmented COX-2-generated PGE2 and ODC-dependent polyamine overproduction lead to enhanced proliferation, migration and invasiveness of cells carrying mutations in known tumor suppressor genes including p53 and ptch that characterize NMSCs, the combined inhibition of these molecular targets could provide an entirely novel approach to the chemoprevention of this neoplasm. We also proposed to investigate the mechanism by which combined over expression of ODC and COX-2 can lead to the pathogenesis of an invasive tumor phenotype. It is anticipated that the information generated in these studies could be quickly translated into clinical trials employing the uniquely available high risk population at the University of Alabama Medical Center.