Identification of Glycomic Alterations During Melanoma Metastasis
Abstract
This application addresses research in one of the Fiscal Year 2017 Peer Reviewed Cancer Research Program Topic Areas (Melanoma) and the Focus Area “Gaps in cancer prognosis and treatment” as directed by Congress. Scientific Objective and Rationale: Skin cancer is the most common type of cancer, and melanoma is its most deadly form. With a relatively early age of onset compared to other cancers, melanoma has a high impact in terms of “life years lost.” The most devastating complication of melanoma is spread to other organs (i.e., liver, lung, brain), a phenomenon called metastasis. Although promising new therapies have been recently approved, many tumors are not responsive or become resistant after initial responses. Therefore, in order to develop new and more therapies, there is an imperative need to understand better how these small tumors (measured at millimeters at diagnosis) become able to reach and adapt to distant organs. Unfortunately, it is currently not possible for physicians to predict which patients with melanoma are the ones most likely to eventually develop metastasis. Proteins in the cell membrane often acquire sugar modifications, which shape the interactions between a tumor cell and its environment. For instance, these sugar branches modify the recognition of tumor cells by the immune system. We will identify sugar modifications characteristic of tumors capable of metastasizing as potential markers and determinants of melanoma aggressive behavior. For that, we will use a technique developed by Dr. Lara K. Mahal and only available at her laboratory. The advantage of this technology is the ability to examine multiple sugars simultaneously in an unbiased and automated manner. Applicability of the Research: Melanoma that is confined to the skin is surgically removed without additional treatment. However, many melanomas diagnosed at an early stage go on to recur and spread throughout the body. The current staging system is insufficient in its ability to predict which patients will undergo a more aggressive disease course. Detection of specific sugars in the surface of melanoma cells from tumors that metastasize (absent from those that do not) may allow identifying patients at higher risk of dying of melanoma, who could potentially benefit from novel adjuvant therapies. In Aim 1, we will define and test the ability of a set of sugar modifications to predict melanoma metastasis. We will also identify sugar changes characteristic of melanoma tissues isolated from various distal organs (lymph node, brain, soft tissue), which may be required for adaptation to those organs. In Aim 2, we will assess if inhibiting the enzymes responsible for those sugar modifications can impair melanoma dissemination, particularly to the brain, and the mechanisms mediating these effects. In sum, our studies can benefit both early diagnosed and advanced patients by subclassifying high-risk patients for intense surveillance or additional treatment and by uncovering novel therapeutic targets against metastatic melanoma. Relevance to Active Duty Service Members, Veterans, and Other Military Beneficiaries: Novel prognostic markers may allow identifying active duty Service members diagnosed with primary melanoma who may be at higher risk of developing metastasis, and subject them to a more intensive surveillance and aggressive treatment. Service members or Veterans diagnosed with advanced melanoma might benefit from novel treatment modalities that bypass the emergence of resistance or the toxicity associated to currently approved therapies. Overall, our studies might eventually improve the outcomes of active members, Veterans, and their relatives afflicted by melanoma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810498
Entities
People
- Eva Hernando-monge
Organizations
- Grossman School of Medicine
- United States Army