Military personnel are unavoidably exposed to high doses of ultraviolet radiation (UVR) during training or exercise, or when deployed to locations with high solar radiation. Therefore, our veterans are particularly vulnerable to a lifetime development of skin cancers such as squamous and basal cell carcinomas, because of an excessive exposure to UVR that is inevitable due to the requirements and nature of military service. UVB is also required for vitamin D3 (D3) production in the skin, which supplies >90% of the body’s requirement for this prohormone. Due to the toxic (calcemic) effects, therapeutic uses of 1,25(OH)2D3 at pharmacological doses are severely limited. We discovered an alternative pathway that starts by the action of CYP11A1, rate limiting enzyme of steroidogenesis, to produce 20(OH)D3 with its further hydroxylation producing several (OH)nD3 metabolites. All of them express biological activities that are affected by cell lineage and position of hydroxyl group. 20(OH)D3 and its metabolites are present in the epidermis, adrenals and in human serum with majority of other metabolites also detectable in vivo. These secosteroids demonstrate biological potency equal or higher than that of 1,25(OH)2D3. Some of them are noncalcemic/nontoxic at supra-pharmacological doses. They induce keratinocyte differentiation, and initial experiments indicate that they have radio-protective and anti-skin cancer properties. Therefore, our hypothesis is that novel CYP11A1-derived vitamin D hydroxyderivatives can prevent and reverse UVB induced skin cancerogenesis and act as anti-cancer compounds. The hypothesis will be tested in two specific aims. Specific Aim 1: We will define the preclinical efficacy of CYP11A1-derived D3-hydroxyderivatives and determine their mechanism of action against UVB-induced epidermal skin cancers. In its Subaim 1 we will define the relative efficacy of 20(OH)D3 and its downstream (OH)nD3 metabolites against immortalized or malignant human and murine epidermal keratinocytes. In its Subaim 2 we will define the mechanism of action of selected (OH)nD3 derivatives. Specific Aim 2: We will test preclinical efficacy of 20(OH)D3 and the two most potent (OH)nD3 derivatives against UVB-induced cancer in the Ptch+/-/SKH-1 murine model. The expected outcome is to provide the proof that selected CYP11A1-derived secosteroids can attenuate or reverse UVB induced pathology acting as “guardians” against photocarcinogenesis. We will also define the mechanism of action for its anti-cancerogenic effects and establish similarities and differences for topical application prior to or after UV exposure. The final goal is to use topically or intra-muscularly optimal noncalcemic secosteroids to protect or treat current and future military personnel against UVB induced skin cancer before it is too late.