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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）：我们对致癌作用的分子基础的理解的最新进展已经导致了可用于预防早期皮肤癌进展的潜在分子靶点的鉴定。虽然在皮肤癌预防研究中已经测试了许多药剂，但很少有药剂针对已知参与皮肤癌发生的分子靶点。AKT（蛋白激酶B）是一种含有普列克底物蛋白同源性（PH）脂质结合结构域的丝氨酸/苏氨酸激酶，其是在许多皮肤癌中被激活的磷脂酰肌醇-3-激酶（PI 3 K）细胞存活信号传导途径的关键组分。AKT活性的增加与佛波酯诱导的小鼠皮肤癌发生的促进阶段平行，而在小鼠分层上皮的基底层中的组成型活性AKT诱导表皮增殖的增加，导致表皮分化和增生的改变。紫外线B（UVB）能够诱导AKT活化，与表达正常水平AKT的细胞相比，过表达肉豆蔻酰化AKT的异种移植细胞发育更快并形成更大的肿瘤。最后，导致AKT组成性激活的肿瘤抑制因子PTEN的丧失在10-30%的黑素瘤中经常与B-Raf的激活突变同时发生。总之，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代表了皮肤癌预防的有吸引力的分子靶标。我们已经开发了一种新的AKT抑制剂（PH 4），其结合AKT的普列克底物蛋白同源结构域，从而防止其结合质膜中的PI-（3，4，5）P3和随后的AKT活化。PH 4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PH 4能够阻止UVB诱导的HaCaT角质形成细胞和SKH-1小鼠模型皮肤中的AKT活化和表达。此外，该化合物是亲脂性的，我们发现当局部应用时，它很容易渗透小鼠的皮肤，并显著降低AKT水平。因此，我们的工作所基于的假设是，局部使用新型亲脂性AKT抑制剂将为预防非黑色素瘤皮肤癌提供有效的化疗策略。所提出的研究的目的是：1）研究AKT及其亚型在NMSC中的作用，2）研究新型AKT抑制剂PH 4在皮肤癌细胞模型中的活性，以及3）研究PH 4在UVB诱导的皮肤SKH-1小鼠模型中的化学预防作用。