A Dual AKT/PDPK1 Inhibitor for Actinic Keratosis and Skin Cancer Prevention

Skin cancer is the most common cause of cancer in the US. About 16% of skin cancers are squamous cell carcinoma (SCC), which is the most aggressive type of non-melanoma skin cancer. Actinic keratoses (AKs) are a dysplastic epidermal lesion that often appear prior to SCC and may be precursor lesions of invasive SCC. Although the rate of AK transformation to SCC is 1 to 10% over a 10-year period, it is not possible to predict which of these early lesions will progress to SCC, thus treatment of all AK lesions is medically necessary to minimize the risk of progression to malignant skin cancer. In addition, in immuno¬suppressed patients, there is up to a 250-fold increased rate of conversion of AK lesions to SCC. Current treatments available for AK utilize fairly toxic agents such as cryotherapy, surgical excision, oral bexarotene, and topical cytotoxic agents such as 5-fluorouracil, diclofenac, imiquimod, and ingenol mebutate. Thus, there is a need for clinical studies that examine the long-term effects of non-toxic topical AK treatment as a component of a chemopreventive strategy for reducing the conversion of AK to non-melanoma skin cancers in immuno¬compromised patients. PHT-427 is a small molecule dual inhibitor of the pleckstrin homology (PH)-domains of AKT and PDPK1, both important drivers of skin cancer carcinogenesis. PHT-427?s lipophilicity allows skin penetration when applied topically; concentrations in skin can be 10,000-fold higher than in plasma, leading to local AKT and PDPK1 inhibition. Topical PHT-427 has been shown to inhibit UVB-induced carcinogenesis in mouse models of AK with low toxicity; PHT-427 has exhibited a maximally tolerated dose (MTD) following daily oral administration greater than 400 mg/kg, with no evidence of skin irritation in mice or rats upon repeated topical administration at 150 mg/kg/dose. The mild toxicity profile separates PHT-427 from the irritant treatments currently being used for AK. These features suggest that PHT-427 could be an ideal candidate for long-term treatment to prevent the development of skin cancer in patients with precancerous AK, particularly in immunosuppressed patients, who are prone to develop AK and nonmelanoma skin cancer. The main objectives of this Task Order RFP are to develop a topical formulation of PHT-427 suitable for use in human patients and perform in vitro and in vivo IND-enabling toxicology studies to facilitate translation to human clinical trials.