# CYP11A1-derived secosteroids as therapeutic agents in UVB induced skin cancer

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2020 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 9868809
- **Project number:** 5I01BX004293-02
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** ANDRZEJ T SLOMINSKI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868809

## Citation

> US National Institutes of Health, RePORTER application 9868809, CYP11A1-derived secosteroids as therapeutic agents in UVB induced skin cancer (5I01BX004293-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9868809. Licensed CC0.

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