The Department of Biochemistry and Biophysics invites you to a seminar given by Dr. Arup Indra, Professor of Pharmaceutical Sciences at Oregon State University. Dr. Indra’s talk, “Novel CYP11A1-Derived Vitamin D Hydroxyderivatives for Melanoma Prevention and Therapy,” will be on Wednesday, Nov. 5 at 9 a.m. in ALS 4001.

Abstract: Ultraviolet B (UVB) radiation is a primary driver of melanomagenesis, causing mutagenic damage and promoting aggressive behavior in skin melanocytes. While vitamin D supplementation has been shown to inhibit melanoma development, this effect appears independent of classical 25(OH)D3 serum levels and canonical Vitamin D Receptor (VDR) activation. This research focuses on an alternative vitamin D activation pathway initiated by the enzyme CYP11A1, which produces non-calcemic hydroxyderivatives, including and its metabolites, collectively termed. These novel compounds exhibit potent antimutagenic, antioxidative, and anti-melanoma activities in skin cells and effectively inhibit metastaic murine melanomas in a genetically engineered model (GEM) and human melanoma transplanted into mice at pharmacological doses. Furthermore, we identified the aryl hydrocarbon receptor (AhR) as an alternative receptor for specific metabolites, such as 20(OH)D3 and 20,23(OH)D3, suggesting a dual receptor signaling mechanism. We also generated mice to specifically define the VDR's role in melanocyte homeostasis and photoprotection. We also generated mice to specifically define the VDR's role in melanocyte homeostasis and photoprotection.

We hypothesize that this novel, endogenously produced non-toxic and non-calcemic metabolites are superior candidates for melanocyte photoprotection, melanoma prevention, and therapy. The mechanism of action (MOA) involves interactions with VDR and/or AhR genomic binding sites. Our ongoing research will define the regulatory role and MOA of (OH)nD3 through two specific projects. Project 1 will define the role and MOA of the novel (OH)nD3 in Inhibiting melanomagenesis. We are determining the MOA by which selected hydroxy derivatives inhibit or reverse UVB-induced damage in human melanocytes and define their role in initiation, promotion, and progression in an established GEM model. The specific roles of VDR or AhR and alternative signaling pathways will be established using RNA sequencing, ATAC-seq and spatial transcriptomics. Project 2 will establish the therapeutic efficacy of (OH)nD3 in Human Melanoma Xenografts. We are determining the ability of hydroxyderivatives to inhibit tumor growth in both cell line-derived (CDX) and patient-derived (PDX) xenograft models, both alone and in combination with standard therapy like vemurafenib (VEM). The role of VDR and/or AhR in anti-melanoma activity and the MOA via spatial transcriptomics, spatial ATAC-seq and proteomics is also being established. This work promises to elucidate a fundamental, noncanonical mechanism for vitamin D action in the skin and will position as a compelling, nextgeneration preventative and therapeutic agent for melanoma.

Bio: Dr. Arup K. Indra is a Professor of Pharmaceutical Sciences at Oregon State University (OSU), holding key adjunct appointments in Biochemistry & Biophysics (OSU) and in Dermatology (OHSU). He is also an Affiliate Investigator at the Linus Pauling Institute (LPI) and a Member of the Knight Cancer Institute at OHSU. Dr. Indra’s foundational training includes a postdoctoral fellowship with Prof. Pierre Chambon (IGBMC, France) on transcriptional regulation and nuclear hormone signaling in skin disease. He later completed a sabbatical with Nobel Laureate Prof. Randy Schekman (UC Berkeley), focusing on the biogenesis and function of extracellular vesicles in intercellular signaling in the skin.

The Indra Laboratory investigates the mechanisms of novel Vitamin D metabolites and bioactive molecules for the prevention and therapy of metastatic skin cancers, including melanoma and rare cancers such as uveal melanoma. A secondary focus is understanding the critical crosstalk between epithelial, mesenchymal, and immune cells in the microenvironment of inflammatory skin diseases and pigmentation disorders. The laboratory's multidisciplinary and collaborative research approach is generously supported by funding from the NIH, DOD, and industry sponsors. This work utilizes advanced, cutting-edge models, including 3D bioprinted human skin, genetically engineered mouse (GEM) models, patient-derived xenografts (PDX), and organoid technology. Dr. Indra has held leadership roles in the Pan American Society of Pigment Cell Research, the Society of Investigative Dermatology, OSU-OHSU Cancer prevention and control initiative and the Global Hemp Innovation Center. He serves regularly on grant review panels for the NIH, DOD, and Welcome Trust, UK. He is driven by a passion for interdisciplinary, team-based science committed to basic and translational research that advances cancer prevention, therapy, and healthy aging.