The overall objective of this proposal is to determine whether systemic treatment with the biologic agent, interferon a2a, will modulate the molecular, immunologic, histopathologic, and clinical features of atypical nevi, which are the known precursors and risk markers of malignant melanoma. In the setting of familial melanoma, the presence of atypical nevi is associated with a nearly 100% risk of developing primary melanoma by age 70. Likewise, in the case of sporadic melanomas, between 40-60% of them develop from preexisting atypical nevi. Furthermore, patients with a clinical history of primary melanoma and two or more atypical nevi are at an 8-fold greater risk of developing a second primary melanoma. Thus, in light of the rising incidence and mortality rate of melanoma, it is not only imperative to find and implement strategies that will help cure patients with metastatic disease but also to prevent the progression of atypical nevi to malignant melanoma. We recently demonstrated that direct gene targeting of bFGF/FGFR-1 in human melanomas causes their growth arrest and regression as a result of blocked melanoma proliferation and intratumoral angiogenesis. In addition, we documented expression of these two genes in the dermal nevocytic and stromal compartments of atypical nevi. The results of recent clinical trials provided evidence that IFNa has a significant therapeutic impact on metastatic melanoma, leading in 1995 to an FDA approval of IFNa as the first agent for adjuvant therapy of high-risk melanoma. While IFNa is known to be a potent antiviral, antiproliferative and immunomodulating agent, recent studies have shown that IFNa also functions as a strong angiogenesis inhibitor by blocking bFGF mRNA and protein in human malignancies. Given these findings, we propose to determine whether the biological, histopathological and clinical features of melanoma precursor lesions can be modulated by systemic treatment with low-dose IFNa-2a in patients who have a clinical history of melanoma and multiple atypical nevi.
|Moschos, Stergios J; Jukic, Drazen M; Athanassiou, Charalambos et al. (2010) Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues. Hum Pathol 41:1286-98|