Abstract A28: Eukaryotic initiation factor 4E phosphorylation in human malignant melanoma
Authors: Carter Julia H. , Spaulding Reed , Deddens James A. , Colligan Bruce M. , Lewis Grant , Pemberton Jackson O. , Graff Jeremy R. , Douglass Larry E. 
Published: July 2015

Abstract
Malignant melanoma continues to be a challenge both in terms of understanding the biologic mechanisms behind its behavior, as well as applying that information toward developing new therapeutic interventions. From 1992 through 2006, the incidence of malignant melanoma increased annually in the United States among non-Hispanic whites in all age groups, with death rates increased in patients 65 years and older. Approximately 70,000 new cases of invasive melanoma are anticipated in 2014. The need for better therapeutic strategies to combat these alarming statistics is paramount. While melanoma is a disease that primarily arises in the skin, it is a derivative of neural crest. During embryogenesis, an epithelial to mesenchymal transition occurs in order to form these cells. Once formed, these neural crest cells migrate to various locations in the body and differentiate into cells of the central and peripheral nervous system, medullary cells of the adrenal glands, various craniofacial connective tissues, and melanocytes. The histopathologic progression in melanocytic transformation is described by Chin, et al., (1998) as follows: (1) Normal skin has an even distribution of dendritic melanocytes throughout the basal layer; (2) Benign proliferation of melanocytes - in a nevus, nevoid melanocytes are organized into uniform nests of cells; (3) Melanocyte dysplasia - a dysplastic nevus has irregular and bridging nests of cells consisting of large atypical melanocytes; (4) In-situ melanoma, radial growth phase (RGP) - single dysplastic cells are present in the epidermis (Pagetoid spread); (5) Malignant melanoma, the vertical growth phase (VGP). Breslow thickness, the thickness of the melanoma from the most superficial nucleated layer, the granular layer, to the deepest level of invasion, has a strong predictive value in the prognosis of patients with non-metastatic melanomas. In our present study of 75 FFPE archived surgical specimens from 52 melanoma patients, we examined immunohistochemically detected cytoplasmic and nuclear expression of eukaryotic translation initiation factor 4E (eIF4E) and phosphorylated eIF4E in the four major subtypes of cutaneous melanoma (superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma and acral lentiginous melanoma), as well as in benign nevi, in relation to clinical outcome. Although the importance of activation of eIF4E through phosphorylation for cell proliferation and transformation in cultured cells and animal models of epithelial derived carcinomas has been documented, the role of eIF4E phosphorylation in transformation and histopathologic progression of melanocytes to melanomas has not previously been reported. We find that both eIF4E and phosphorylated eIF4E are increased in all major subtypes of human cutaneous malignant melanomas relative to benign dermal nevi. Importantly, in a subset of these specimens, nuclear phosphorylated eIF4E is significantly increased in nodular and metastatic melanomas compared to superficial spreading melanomas (P = 0.02). Survival analyses indicate that increased nuclear phosphorylated eIF4E is significantly associated with reduced survival (P = 0.0019, 3.994 Hazard Ratio). Since it has recently been reported (Konicek, et al., 2011) that inhibition of eIF4E phosphorylation with an orally bioavailable inhibitor of MAPK-interacting kinases (MNK) reduces lung metastases in the B16 mouse melanoma model, the present data may point to a novel cancer therapeutic strategy for treatment of human malignant melanoma, namely inhibition of eIF4E phosphorylation.
Citation Format: Julia H. Carter, Reed Spaulding, James A. Deddens, Bruce M. Colligan, Grant Lewis, Jackson O. Pemberton, Jeremy R. Graff, Larry E. Douglass. Eukaryotic initiation factor 4E phosphorylation in human malignant melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A28.