[1642] Morphoproteomics Provides Correlates of Chemoresistance, Metastatic Potential, Insulin-Like Growth Factor and c-Met Signaling in Uveal Melanoma with Therapeutic Implications.

Robert E Brown, Jamie Buryanek. University of Texas- Medical School, Houston

Background: Uveal melanoma has a propensity to metastasize to the liver and to be chemoresistant (systemic therapies produced a response rate of <1% in one large study).Insulin-like growth factor(IGF)-1 receptor (R)and c-Met are expressed in uveal melanoma and are significantly associated with metastatic disease and death. Moreover, these are receptors for IGF-1 and hepatocyte growth factor ligands, which are produced by the liver.The majority of uveal melanomas expressed activated MET protein in one study, and the blocking of MET reduced uveal melanoma cell proliferation and migration. Targeting IGF-1R and c-Met has been proposed as a therapeutic option in uveal melanoma.
Design: Three(3)patients with uveal melanoma with metastatic disease(two with metastasis to the liver) were the subject of this study. Representative sections were analyzed using a comprehensive morphoproteomic profile(Brown, RE.Arch Pathol Lab Med. 2009;133:568-79). This included a specific focus on chemoresistant and metastasis-associated protein analytes and on molecules linking IGF-1R and c-Met signaling in uveal melanoma, in an attempt to provide therapeutic opportunities.
Results: The anti-apoptotic protein, Bcl-2 was expressed in the cytoplasm of all tumor cells (up to 3+ on a scale of 0 to 3+) with concomitant and correlative expression of CD44 and heat shock protein(Hsp)90 on their plasmalemmal aspect and in their cytoplasmic compartment, respectively. Fatty acid synthase [FAS] expression(up to 2 to 3+) in the cytoplasm was evident in the vast majority of the tumor cells in each case.
Conclusions: Bcl-2 expression provides one explanation for the chemoresistance of uveal melanoma. Because CD44 and Hsp90 contribute to its expression, these present therapeutic opportunities. CD44 is associated with metastasis in melanoma. FAS represents a bridge between IGF-1R and c-Met, being induced at the genomic level by the former and also involved in the expression of c-Met tyrosine kinase. Inhibition of IGF-1R causes regression and attenuates invasion of uveal melanoma cells. Inhibition of FAS retards growth and induces apoptosis of melanoma cells and suppresses c-Met receptor kinase expression. The constellation of findings from our study raises the following therapeutic opportunities in uveal melanoma based on their reported actions: Valproic acid to downregulate CD44 and thereby, Bcl-2; 17-AAG to inhibit Hsp90 and also downregulate Bcl-2; Metformin to inhibit both IGF-1R signaling and FAS expression.
Category: Ophthalmic

Wednesday, March 2, 2011 1:00 PM

Poster Session VI # 284, Wednesday Afternoon

 

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