Dr. D’Orazio is a physician scientist by training who combines an active clinical practice in pediatric hematology/oncology with NIH-funded research in inherited cancer syndromes, focusing on melanoma susceptibility. His training and expertise center around skin biology and molecular processes involved in UV-mediated mutagenesis and carcinogenic transformation.
Dr. D’Orazio obtained Ph.D. training in Immunology with Dr. Joan Stein-Streilein at the University of Miami, studying the effects of superantigens on natural kiler (NK) cells, publishing three first-authored works:
As an MD/PhD student, he then finished medical school before completing training in Pediatrics at the Massachusetts General Hospital in Boston. After spending an extra year as Chief Resident in Pediatrics, Dr. D’Orazio joined the fellowship program in Pediatric Hematology-Oncology at Boston Children’s Hospital and Dana-Farber Cancer Institute. As part of his fellowship training, Dr. D’Orazio joined the laboratory of Dr. David E. Fisher, a melanocyte biologist interested in molecular mechanisms of melanoma development. In Dr. Fisher’s laboratory, Dr. D’Orazio developed a humanized fair-skinned mouse model based on a single gene defect in the melanocortin-1 receptor (MC1R), the melanocytic cell surface receptor that, upon binding to its cognate ligand melanocyte stimulating hormone (MSH), stimulates production of the second messenger cAMP and subsequent production of pigment. Using that animal model, Drs. D’Orazio, Fisher and co-workers found that UV-dependent pigmentation (tanning of the skin) depended on MC1R function. Furthermore, they discovered that in MC1R-defective animals incapable of tanning (that approximate the fair-skinned, UV-sensitive human condition), topical application of a pharmacologic adenylate cyclase activator (forskolin) rescued robust epidermal melanin deposition that was highly protective against acute and chronic UV damage (including carcinogenesis). Their work, published in Nature in September, 2006, established MC1R as a critical mediator of epidermal UV responses. Further work from the Fisher laboratory (on which Dr. D’Orazio was a contributor) demonstrated that initiation of the MC1R signaling cascade in the skin occurs through p53 induction in UV-exposed keratinocytes. UV-mediated DNA damage in the keratinocyte subsequently leads to production of MSH from the keratinocyte compartment of the skin, and consequent up-regulation of melanocytic pigment production through the MC1R signaling cascade.
Dr. D’Orazio came to University of Kentucky in October, 2004 as Assistant Professor of Pediatrics. His laboratory has continued to investigate the role of the MC1R and downstream cAMP-dependent signaling pathways in protecting melanocytes from malignant transformation. He has focused on MC1R signaling because loss-of-function polymorphisms of MC1R (which affect millions of Americans) are associated with at least a four-fold increased lifetime melanoma risk and a much higher risk of other UV-induced skin cancers such as squamous cell and basal cell carcinomas which together account for the great majority of all cancers diagnosed annually in the United States. Since becoming independent, Dr. D’Orazio and his coworkers have reported that topical cAMP stimulation is both effective and well-tolerated in their unique murine model. Furthermore, their laboratory has become proficient in the isolation, purification and expansion of primary melanocytes and keratinocytes from the mice, facilitating mechanistic cellular studies. The D’Orazio laboratory has published several papers making use of the K14-Scf transgenic murine system, reporting that topical cAMP stimulation promotes melanin deposition in the skin and promotes epidermal thickening and UV protection.
Recently, the D’Orazio laboratory has focused on the role of MC1R on melanocyte genome stability. They expanded the murine model by incorporating albinism-causing tyrosinase mutations to remove MC1R-dependent pigment effects to isolate other MC1R-dependent effects on melanocytes. They found that mutagenic UV-induced photodimers were cleared more rapidly in the skin when MC1R was functional. They confirmed that MC1R-enhanced DNA repair occurred in melanocytes and that this observation extended to human melanocytes. They recently reported that MC1R signaling impacts nucleotide excision DNA repair by a novel and direct PKA-mediated phosphorylation of ATR on Ser435, an amino acid residue previously not known to affect ATR's function. Rather than activate ATR to promote Chk1 phosphorylation and cell cycle arrest, Ser435 phosphorylation by PKA promotes ATR's physical association with xeroderma pigmentosum complement group A (XPA) protein and directs XPA to sites of UV damage in the nucleus to accelerate repair of photodamage. PKA-mediated phosphorylation of ATR on Ser435, stimulated either by MSH-MC1R interactions or pharmacologically by forskolin-mediated adenylyl cyclase activation, accelerated repair of UV photodamage and robustly protects against UV-induced mutagenesis. Their findings were recently published in Molecular Cell:
Though his interest in small molecule-induced pigmentation (sunless tanning) continues, Dr. D’Orazio is currently focused on the molecular mechanisms by which MC1R signaling pathway enhances UV resistance in melanocytes by inducing repair of UV-induced DNA damage. The laboratory’s current research interests are to:
The intent of the D’Orazio research group is to use the information gathered from their studies to develop novel melanoma-preventive therapies based on MC1R signaling pharmacologic replacement in high-risk MC1R-defective melanoma-prone individuals.
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