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：
7788398
负责人：
Emmanuelle Joelle Meuillet
金额：
$ 7.27万
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 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7788398
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）：我们对癌变分子基础的理解的最新进展导致鉴定了可用于防止早期皮肤癌进展的潜在分子靶标。尽管在皮肤癌预防研究中已经测试过许多药物，但很少有人针对已知参与皮肤癌变的分子靶标。 Akt（蛋白激酶B）是含有丝氨酸/苏氨酸激酶的脂质同源性（pH）脂质结合结构域，是磷脂酰氨基醇3-激酶（PI3K）细胞存活信号通路的关键成分，在许多皮肤癌中都被激活。 Akt活性与佛波酯诱导的小鼠皮肤致癌促进阶段并联，而在小鼠分层上皮分层的基础层组成型活性AKT则诱导表皮增殖的增加，从而改变表皮分化和增生和增生。与表达正常AKT水平的细胞相比，紫外线B（UVB）能够诱导Akt激活和异种移植细胞，使肉豆蔻酰化-Akt过表达的细胞发展得更快，并且形成更大的肿瘤。最后，导致Akt的本构激活的PTEN的损失发生在10-30％的黑色素瘤与B-RAF激活突变同时同时发生。综上所述，这些数据为AKT在皮肤致癌和皮肤肿瘤进展中的关键作用提供了证据。因此，AKT代表了预防皮肤癌的有吸引力的分子靶标。我们已经开发了一种新型AKT（PH4）的抑制剂，该抑制剂与Akt的Pleckstrin同源性结构域结合，从而阻止了质膜中其与PI-（3,4,5）P3的结合，并随后的Akt激活。 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能够防止HACAT角化形成细胞和SKH-1小鼠模型的皮肤中UVB诱导的AKT激活和表达。此外，该化合物是亲脂性的，我们发现它在局部应用时很容易穿透小鼠的皮肤，并显着降低了AKT水平。因此，我们的工作基于的假设是，新型亲脂性AKT抑制剂的局部使用将为预防非黑质膜皮肤癌的有效化学治疗策略提供。拟议研究的目标是：1）研究AKT及其在NMSC中的同工型的作用，2）研究新型Akt抑制剂PH4在皮肤癌的细胞模型和3）中研究PH4在UVB诱导的皮肤SKH-SKH-1小鼠模型中的化学抗化作用。