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Novel AKT PH domain inhibitors to prevent skin cancer

新型 AKT PH 域抑制剂可预防皮肤癌

基本信息

批准号：
7937893
负责人：
Emmanuelle Joelle Meuillet
金额：
$ 7.28万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-24 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7937893
关键词：
1-Phosphatidylinositol 3-Kinase Actinic keratosis Animal Model Apoptosis Applications Grants Area Basal cell carcinoma Binding Biological Markers Cancer Model Cancer cell line Cell Proliferation Cell Survival Cell membrane Cell model Cells Chemoprevention Chemopreventive Agent Chronic Clinical Computer Simulation Data Detection Exhibits Growth Health Human Hyperplasia In Vitro Lipid Binding MEKs Malignant Neoplasms Measures Molecular Molecular Target Mus Mutation PH Domain PTEN gene Pathway interactions Phorbol Esters Prevention Prevention approach Prevention strategy Primary Prevention Protective Clothing Protein Isoforms Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Risk Role Signal Pathway Signal Transduction Skin Skin Cancer Skin Carcinogenesis Skin Carcinoma Skin Neoplasms Squamous cell carcinoma Staging Stratified Epithelium Stratum Basale Sun Exposure Sunscreening Agents Testing The Sun Topical application Tumor Suppressor Proteins Ultraviolet Rays United States Work Xenograft Model Xenograft procedure base cancer cell cancer diagnosis carcinogenesis in vivo inhibitor/antagonist keratinocyte melanoma mouse model novel overexpression platelet protein P47 pre-clinical prevent skin cancer prevention small hairpin RNA success therapeutic target tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Recent advances in our understanding of the molecular basis of carcinogenesis have led to the identification of potential molecular targets that could be used to prevent the progression of early skin cancer. While a number of agents have been tested in skin cancer prevention studies, very few have been directed against molecular targets known to be involved in skin carcinogenesis. AKT (protein kinase B) is a pleckstrin homology (PH) lipid binding domain containing, serine/threonine kinase that is a key component of the phosphatidylinositol-3-kinase (PI3K) cell survival signaling pathway that is activated in many skin cancers. AKT activity increases in parallel with the phorbol ester induced promotion stages of mouse skin carcinogenesis while constitutively active AKT in the basal layer of the mouse stratified epithelia induces an increase in epidermal proliferation leading to alterations in epidermal differentiation and hyperplasia. Ultraviolet light B (UVB) is capable of inducing AKT activation and xenografted cells that overexpress myristoylated-AKT develop faster and form bigger tumors compared to cells that express normal levels of AKT. Finally loss of the tumor suppressor, PTEN which leads to the constitutive activation of AKT occurs 10-30% of melanoma frequently concurrent with activating mutations of B-Raf. Taken together, these data provide evidence for a critical role for AKT in skin carcinogenesis and skin tumor progression. Thus, AKT represents an attractive molecular target for skin cancer prevention. We have developed a novel inhibitor of AKT (PH4) that binds to the pleckstrin homology domain of AKT thus preventing its binding to PI-(3,4,5)P3 in the plasma membrane and subsequent AKT activation. PH4 inhibits AKT activity at low micromolar concentrations and exhibits good systemic anti-tumor activity in xenografts models. Recently, we have found that PH4 is able to prevent UVB-induced AKT activation and expression in HaCaT keratinocytes cells and in the skin of the SKH-1 mouse model. Moreover, the compound is lipophilic and we have found that it readily penetrates the skin in mice when applied topically, and significantly decreases AKT levels. Thus, the hypothesis upon which our work is based on is that the topical use of a novel lipophilic AKT inhibitor will provide an effective chemotherapeutic strategy for the prevention of non-melanoma skin cancers. The objectives of the proposed studies are: 1) to investigate the role of AKT and its isoforms in NMSCs, 2) to investigate the activity of the novel AKT inhibitor PH4 in cellular models of skin cancer and 3) to investigate the chemopreventive effects of PH4 in the UVB-induced skin SKH-1 mouse model.

描述(由申请人提供)：在我们对致癌的分子基础的理解方面的最新进展导致了潜在的分子靶点的确定，这些分子靶点可以用来防止早期皮肤癌的进展。虽然许多药物已经在皮肤癌预防研究中进行了测试，但很少有药物针对已知的与皮肤癌发生有关的分子靶点。AKT(蛋白激酶B)是一种含有丝氨酸/苏氨酸激酶的Pleckstrin同源(PH)脂结合结构域，是磷脂酰肌醇-3-激酶(PI3K)细胞生存信号通路的关键组成部分，在许多皮肤癌中被激活。AKT活性与佛波酯诱导的小鼠皮肤癌变促进阶段平行增加，而小鼠复层上皮基底层的AKT活性增加，导致表皮增殖增加，导致表皮分化和增殖的改变。紫外线B(UVB)能够诱导AKT激活，与表达正常水平AKT的细胞相比，过度表达肉豆蔻酰化AKT的异种移植细胞发展更快，形成更大的肿瘤。最后，导致AKT结构性激活的肿瘤抑制因子PTEN的缺失经常发生在10-30%的黑色素瘤中，并伴有B-Raf的激活突变。综上所述，这些数据为AKT在皮肤癌发生和皮肤肿瘤进展中的关键作用提供了证据。因此，AKT是预防皮肤癌的一个有吸引力的分子靶点。我们开发了一种新的AKT抑制剂(PH4)，它能与AKT的pleckstrin同源结构域结合，从而阻止其与质膜上的PI-(3，4，5)P3结合并随后激活AKT。PH4在低微摩尔浓度下抑制AKT活性，并在异种移植模型中表现出良好的全身抗肿瘤活性。最近，我们发现PH4能够阻止UVB诱导的AKT在HaCaT角质形成细胞和SKH-1小鼠模型皮肤中的激活和表达。此外，该化合物是亲脂性的，我们发现，当局部使用时，它很容易渗透到小鼠皮肤，并显著降低AKT水平。因此，我们工作所基于的假设是，局部使用一种新型的亲脂性AKT抑制剂将为预防非黑色素瘤皮肤癌提供一种有效的化疗策略。本研究的目的是：1)研究AKT及其异构体在NMSCs中的作用；2)研究新型AKT抑制剂PH4在皮肤癌细胞模型中的活性；3)研究PH4对UVB诱导的皮肤SKH-1小鼠模型的化学预防作用。