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.
The purpose of this grant application is to develop a novel inhibitor targeting AKT for the prevention of non-melanoma skin cancers (NMSC). Recent studies have suggested that over-expressed AKT is a therapeutic target for the prevention of NMSC. We propose that the topical use of a lipophilic AKT inhibitor will provide an effective chemotherapeutic strategy for the prevention of NMSC. We have developed such a novel compound using in silico screen and early testing to demonstrate strong anti- tumor activity in various cancer models. We also show that the compound is able to inhibit UVB-induced AKT activation, the leading pathway causing skin cancer growth. We propose to better understand the role of AKT in NMSC and to test the compound in skin keratinocytes and cancer cell lines as well as animal models in which AKT levels have been modulated. The UVB-induced skin cancer animal model (SKH-1) will also be used to test the effects of the novel AKT inhibitor.
| Lucero-Acuña, Armando; Jeffery, Justin J; Abril, Edward R et al. (2014) Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer. Int J Nanomedicine 9:5653-65 |
| Meuillet, E J (2011) Novel inhibitors of AKT: assessment of a different approach targeting the pleckstrin homology domain. Curr Med Chem 18:2727-42 |
