Abstract A213: Topical PHT-427, a dual AKT/PDPK1 PH domain inhibitor, for treatment of primary and metastatic skin cancer.

Epicutaneous (topical) therapy with molecularly targeted agents is an attractive modality for treatment of basal cell carcinoma (BCC), early UVB induced squamous cell carcinoma (SCC) and cutaneous metastatic disease (CMD) associated with metastatic breast cancer. There is evidence that Akt and PDKP1 play complimentary yet independent roles in PI3K pathway signaling associated with driving the growth of BCC, UVB induced SCC, and breast CMD. Both Akt and PDPK1 possess a pleckstrin homology (PH) domain, a highly conserved three-dimensional superfold with a high affinity for binding phosphatidylinositol-3-phosphates, causing Akt and PDPK1 to translocation to the plasma membrane where Akt is activated. Through reiterative molecular docking and structure refinement using a proprietary computational platform, we have identified PHT-427 as an agent that binds to the PH domains of Akt and PDPK1, inhibiting their activity. PHT-427 has antitumor activity when administered orally but importantly also following epicutaneous administration. We evaluated the antitumor potential of epicutaneous PHT-427 against CMD in an intradermal breast xenograft model and in an early UVB induced skin cancer model in mice. For the CMD investigation MCF-7 human breast cancer (mutant PIK3CA) was injected intradermally in the flank of female nu/nu mice. Groups of 5 mice were treated twice a day for 10 days with vehicle or 0.1ml PH-427 (50 mg/mL) applied to a 1 cm patch of skin over the tumor. The mice were euthanized 4 hr after the last application and blood, tumor and overlying skin were removed for analyzes. Topical PHT-427 produced 89% inhibition of tumor growth (3/5 no measurable tumor) with no change in body weight or skin toxicity and inhibited targets in skin and tumor. Levels of PHT-427 by HPL-MS were detected in the skin at the site of application, in tumor and in plasma. To evaluate the activity PHT-427 in early UVB induced skin cancer female SKH-1 hairless mice were exposed to UVB irradiation to induce Akt and the production of skin tumors. The mice were treated epicutaneously with PHT-427 or vehicle 3 times a week for 4 weeks at which point animals were sacrificed and skin, tumors and blood were obtained. In this study topical PHT-427 significantly reduced tumor incidence, tumor burden and tumor multiplicity. Following treatment with PHT-427 80% of mice were tumor free and those with tumors averaged fewer than 1 per mouse and those were 1mm in size. There was no change in body weight and no apparent skin toxicity. Thus, topical application of PHT-427 can deliver active drug to skin and tumor, inhibiting AKT and PDPK1, both of which drive the PI3K pathway important in UVB induced SCC and breast CMD, with significant inhibition of tumor growth without adverse effects on normal skin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A213.