Inhibiting Multiple Molecular Targets for Preventing Non-Melanoma Skin Cancer

描述(申请人提供)：越来越多的证据表明，高侵袭性皮肤肿瘤的发展可能需要不同位点的多个突变，关键调控基因的过度表达或抑制可以协同影响癌症的发展。紫外线B(UVB)可诱导鸟氨酸脱羧酶(ODC)和环氧合酶-2(COX-2)的表达和活性。ODC是合成多胺的限速酶，多胺对所有细胞的生长和分化都是必不可少的。COX-2的表达促进了前列腺素(PGs)的合成，尤其是PGE2在皮肤中的合成。我们开发了结合特定药理学方法的基因工程小鼠模型，以表明ODC和COX-2在小鼠皮肤中的过度表达都会促进非黑色素瘤皮肤癌(NMSCs)的生长，而ODC或COX-2的下调只能部分抑制这些肿瘤的生长。人鳞状细胞癌(SCCs)和基底细胞癌(BCC)均过度表达ODC和COX-2。我们和其他人已经证明，它们的过度表达是NMSCs发病的基础。SCCs呈高表达，特别是在它们侵袭正常组织的界面上。然而，在局部侵袭和转移极少的基底细胞癌中，COX-2的表达主要发生在间质细胞，而ODC的表达也相对较少。在这个项目中，我们将检验这两条通路在NMSCs的发病机制中的协同作用，以及它们的时间和空间调节决定了肿瘤的表型和向恶性表型的进展。由于COX-2产生的PGE2和依赖于ODC的多胺的过度生产都会导致携带已知肿瘤抑制基因突变的细胞的增殖、迁移和侵袭力增强，这些基因突变是NMSCs的特征，因此联合抑制这些分子靶点可以为NMSCs的化学预防提供一种全新的方法。我们还建议研究ODC和COX-2联合过表达导致侵袭性肿瘤表型的发病机制。预计这些研究中产生的信息将很快转化为临床试验，使用阿拉巴马大学医学中心唯一可用的高危人群。 公共卫生相关性：在非黑色素瘤皮肤癌(NMSCs)的发病过程中，COX-2和ODC持续上调。然而，阻断这些分子靶点中的任何一个只会部分阻断NMSCs的发展。这项提议试图阻断这两个分子靶点，以消除人类最常见的癌症--NMSCs的发病机制。

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. PUBLIC HEALTH RELEVANCE: Both COX-2 and ODC are consistently up-regulated during pathogenesis of non- melanoma skin cancers (NMSCs). However, blocking either one of these molecular targets only partially blocks the development of NMSCs. This proposal attempts to block both of these molecular targets to abrogate the pathogenesis of the most common human cancer, NMSCs.