My main research involves the use of dietary constituents to inhibit the growth and progression of cancer, and elucidating the molecular mechanisms and pathways involved in malignant progression and chemotherapeutic resistance. My early studies involved the use of ascorbic acid (vitamin C) to inhibit the progression of melanoma and potentially augment chemotherapeutic response by enhancing regulation of the Hypoxia Inducible Factor 1 alpha (HIF1-a) transcription factor. HIF-1α has been implicated as a key player in the development and progression of melanoma as well as several other cancer types. Tumor tissues of various types have been found to be ascorbate depleted when compared to normal surrounding tissue, and in conjunction, often expressed elevated levels of HIF-1α. My lab has documented the ability of physiological concentrations of ascorbic acid to reduce both the protein expression and activity of HIF-1α and subsequently inhibit the invasive potential of metastatic melanoma cells. These findings provide evidence that ascorbate, as a critical cofactor for prolyl- and asparginyl-hydroxylase enzymes (PHD and FIH), which regulate the stability and transcriptional activity of HIF1-a, may play an important role in the regulation of aberrant expression and activity of HIF-1α in melanoma cells. By documenting evidence for the efficacy of ascorbic to impede an aggressive malignant phenotype, this work can potentially change the traditional course of therapy for individuals with melanoma or other cancer types with aberrant HIF-1α. I am also interested in the use of other natural compounds (capsaicinoids) and phytochemicals (quercetin) as adjuvant or potentially preventative cancer therapy. Presently, I am involved in investigating the use of these compounds in lung and ovarian cancer, which have a higher prevalence in the Appalachian region (compared to melanoma), allowing more opportunity to translate the use of natural compounds to improve the clinical outcomes of cancer patients.
My research in the field of melanoma also lead to a unique collaborative investigation to determine the molecular identity and mechanism of the serum borne factor causing Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP). BDUMP is an ocular paraneoplastic disorder which causes the benign proliferation of melanocytes in the uveal tract of the eye along with exudative retinal detachment and rapid cataract formation, resulting in blindness. My earliest published work involved the development of an in vitro melanocyte bioassay for detecting the presence of the circulating melanocyte elongation and proliferation (CMEP) factor in patient serum. My findings were the first reported in vitro investigations and clearly demonstrated the presences of a circulating melanocyte-selective stimulating factor responsible for BDUMP syndrome. In addition, published collaborative studies have also identified that this syndrome is not limited to ocular melanocytes, but can affect dermal melanocytes as well, which has likely been historically overlooked. We have made significant progress in identifying the putative mechanism of the BDUMP factor, pinpointing the molecular identity and signaling mechanism which appears to plays a key role in BDUMP syndrome pathology (publication in preparation). Our confirmation that BDUMP syndrome is initiated by a circulating serum factor has contributed to improving therapy interventions. The implementation of plasmapheresis has proven to have beneficial effects in stabilizing the progression of ocular melanocytic lesions and reversing exudative retinal detachment to improve visual acuity, if the condition is caught early. On-going studies involve the proteomic analysis of our collection of BDUMP patient samples (vs controls) to identify potential protein factors that are unique to BDUMP to definitively identify the CMEP factor. By confirming the identity and mechanism of the CMEP factor, our goal is to develop a diagnostic assay to improve the accuracy and speed of patient diagnosis and find more suitable and sustainable therapeutic options. These studies also have much broader implications in melanocyte biology, which may translate to understanding the mechanisms of several other poorly understood melanocytic pathologies.
