Inhibiting Multiple Molecular Targets for Preventing Non-Melanoma Skin Cancer

抑制多分子靶点预防非黑色素瘤皮肤癌

• 批准号: 8115651
• 负责人: Mohammad Athar
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-04 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115651
• 关键词: 1-Phosphatidylinositol 3-Kinase; Alabama; Animals; Attenuated; Basal cell carcinoma; Cell Cycle Progression; Cell Survival; Cells; Chemoprevention; Chemopreventive Agent; Clinical Trials; Coupled; Coxibs; DL-alpha-Difluoromethylornithine; Data; Development; Diclofenac; Differentiation and Growth; Dinoprostone; Down-Regulation; Eflornithine; Engineering; Enzymes; FDA approved; Genes; Genetic; Growth; Human; In Vitro; Inbred HRS Mice; Individual; Inhibition of Apoptosis; Invaded; Lead; Lesion; MAP Kinase Gene; Malignant Neoplasms; Mediating; Medical center; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Molecular; Molecular Target; Mus; Mutation; Neoplasm Metastasis; Neoplasms; Neoplastic Cell Transformation; Normal tissue morphology; Nude Mice; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; PTGS2 gene; Pathogenesis; Pathway interactions; Phenotype; Play; Polyamines; Population; Prostaglandins; Proteins; Regulation; Regulator Genes; Repression; Role; Science; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinoma; Skin Neoplasms; Squamous Cell; Squamous cell carcinoma; Stromal Cells; Testing; Tetanus Helper Peptide; Topical application; Translating; Tumor Suppressor Genes; Universities; cancer cell; carcinogenesis; celecoxib; cell motility; chemical carcinogenesis; chemical genetics; combinatorial; cyclooxygenase 2; high risk; in vivo; inhibitor/antagonist; keratinocyte; malignant phenotype; migration; mouse model; mutant; novel strategies; prevent; research study; skin squamous cell carcinoma; tumor; tumor growth; ultraviolet; vector

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.

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展可能需要不同位点的多个突变，关键调控基因的过表达或抑制可以协同影响癌症的发展。太阳紫外线B （UVB）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，多胺是所有细胞生长和分化所必需的。COX-2的表达导致前列腺素（PGs）的合成增强，尤其是皮肤中的PGE2。我们开发了基因工程小鼠模型，结合特定的药理学方法，表明小鼠皮肤中ODC和COX-2的过表达都能促进非黑色素瘤皮肤癌（NMSCs）的生长，而ODC或COX-2的下调只能部分减弱这些肿瘤的生长。人类鳞状细胞癌（SCCs）和基底细胞癌（BCCs）都过表达ODC和COX-2。我们和其他人已经表明，它们的过度表达是NMSCs发病机制的基础。SCCs表现出高表达，特别是在侵入正常组织的界面处。然而，在很少发生局部侵袭和转移的bcc中，COX-2的表达主要发生在基质细胞中，而ODC的表达也相对不那么突出。在这个项目中，我们将检验这两种途径在NMSCs的发病机制中可以合作的假设，以及它们的时间和空间调节决定了肿瘤表型和向恶性表型的进展。由于cox -2生成的PGE2增强和odc依赖的多胺过度产生都会导致携带已知肿瘤抑制基因突变的细胞的增殖、迁移和侵袭性增强，这些基因突变包括NMSCs的p53和ptch，因此联合抑制这些分子靶点可能为这种肿瘤的化学预防提供一种全新的方法。我们还提出研究ODC和COX-2联合过表达导致侵袭性肿瘤表型发病的机制。预计在这些研究中产生的信息可以迅速转化为临床试验，利用阿拉巴马大学医学中心独特的高风险人群。