Tris DBA palladium is an orally available inhibitor of GNAQ mutant uveal melanoma in vivo
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Elgilda Musi1, Gary K. Schwartz1,2, Jae Hyuk Yoo3, Shannon J. Odelberg3,4,6, Dean Y. Li3,5,6,7, Michael Y. Bonner8, Ponniah Selvakumar9, Shikha Rao8, Linda C. Gilbert8,10, Justin Elsey8 and Jack L. Arbiser8,10
1 Department of Medicine, Columbia University Medical Center, New York, New York, USA
2 Herbert Irving Comprehensive Cancer Center, Columbia University College of Medicine, New York, New York, USA
3 Department of Medicine, Program in Molecular Medicine, University of Utah, Salt Lake City, Utah, USA
4 Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah, USA
5 Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA
6 Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah, USA
7 Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA
8 Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia, USA
9 Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
10 Veterans Affairs Medical Center, Decatur, Georgia, USA
|Jack L. Arbiser,||email:||firstname.lastname@example.org|
Keywords: melanoma; chemotherapy
Received: April 09, 2019 Accepted: June 05, 2019 Published: July 09, 2019
Uveal melanoma is a rare but often lethal malignancy and is the leading cause of death due to an ophthalmic condition. Uveal melanoma is often diagnosed at a late stage and has a strong propensity to hepatic metastasis. Recently, the most common driver mutations in uveal melanoma have been identified, predominantly in the G-proteins GNAQ. This pattern differs from that of cutaneous melanoma in which Braf and Nras predominate. There are no current clinically used agents that target GNAQ mutations, unlike the use of Braf inhibitors in cutaneous melanoma. We tested the novel agent Tris DBA palladium and found that it was markedly more effective against GNAQ mutant melanomas than wild type uveal melanomas. Given that ARF6 has recently been discovered as a node in GNAQ mutations, we evaluated the efficacy of Tris DBA palladium on ARF6 signaling and found that it was effective in inhibiting ARF6 activation. Finally, Tris DBA palladium was orally effective against GNAQ mutant melanoma in vivo. Tris DBA Palladium deserves further evaluation as a systemic agent for uveal melanoma.
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