Noncalcemic Vitamin D-Hydroxy Derivatives as Preventive and Therapeutic Agents in UVB-Induced Melanoma
Abstract
Two of the Fiscal Year 2020 (FY20) Melanoma Research Program (MRP) Focus Areas: (1) Prevention of melanoma initiation factors (e.g., ultraviolet radiation UVR) and (2) Therapeutic Prevention (e.g., interruption of disease progression, recurrence) will be addressed by the current research project. The proposed research fully responds to the FY20 MRP Challenge Statement by hypothesis-driven studies on prevention of melanomagenesis induced by UVR at each step of development including initiation and promotion. In addition, it also involves studies on therapeutic prevention/attenuation of metastatic melanoma (defined as tumor progression) by novel active vitamin D derivatives using patient-derived orthotopic xenograft (PDOX) models of melanoma. Research has shown that both active-duty military personnel and Veterans are more likely to develop skin cancer compared to general American population due to unprotected exposure to ultraviolet B (UVB), because of the unique nature the military Service, training. or exercise. In addition, UVB is a full carcinogen responsible for melanoma development. Melanoma is the most aggressive form of skin cancer and is a significant clinical problem due to its recalcitrance; resistance develops within a few months, leading to death of the patients. This calls for new preventive and therapeutic approaches to inhibit UVB-induced initiation and promotion of melanoma and to attenuate or prevent development of the metastatic disease. The recent research has identified vitamin D receptor (VDR) and novel vitamin D-derivatives that are non-toxic, and economical with limited side effects, as preventive or therapeutic targets for melanoma. Furthermore, the use of classical active form of vitamin D (calcitriol) is limited due to its toxicity following systemic use. The above barrier has been removed by discovery of new alternative pathway of vitamin D3 metabolism initiated by CYP11A1 to produce 20-hydroxyvitamin D3 (20(OH)D3) that shows anti-oxidative, anti-mutagenic, and anti-melanoma activities. Therefore, the following hypothesis is formulated: novel, non-toxic and endogenously produced 20(OH)D3, defined also as a natural product, can serve as an excellent candidate for prevention of UVB-induced melanoma initiation, promotion, and prevention of melanoma progression, with mechanism of action including interactions with genomic binding site of VDR (G-VDR) and possible activity on retinoic acid related orphan receptors (ROR alpha and gamma). The above hypothesis will be tested through realization of two following aims: Aim 1: Testing the hypothesis that non-calcemic 20(OH)D3 will prevent UVB-induced melanoma initiation and promotion in a well- established Braf^V600E melanoma model via VDR: Subaim 1a: Testing the ability of 20(OH)D3 to prevent melanoma initiation and promotion in vivo; Subaim 1b: Testing the hypothesis that 20(OH)D3 activates VDR dependent target gene expression that promote UVB-induced melanoma prevention. Aim 2: Testing the efficacy of non-calcemic 20(OH)D3 in prevention/attenuation of metastatic diseases using patient-derived orthotopic xenograft (PDOX) models of melanoma: Subaim 2a: Testing the in vivo efficacy of 20(OH)D3 in PDOX mouse models of human metastatic melanoma; Subaim 2b: Testing the mechanism of action (MOA) of 20(OH)D3 in PDOX models. The most efficient methods of melanoma management involve prevention, early diagnosis, and surgical excision when the disease is localized to the skin. Moreover, we do not have a rational strategy to treat patients at high risk for metastatic disease without a pathological proof of metastases. Therefore, defining new targets such as VDR and new endogenously produced non-toxic compounds that are economical, and identified as natural products, with preventive and therapeutic potential, are urgently needed. Following preliminary data support the project, CYP11A1-derived active forms of vitamin D (1) inhibits prolif
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210691
Entities
People
- Arup Indra
Organizations
- Oregon State University
- United States Army