Effects of a novel Nodal-targeting monoclonal antibody in melanoma

• Published in: Oncotarget Vol. 6; no. 33; pp. 34071 - 34086
• Main Authors: Strizzi, Luigi, Sandomenico, Annamaria, Margaryan, Naira V, Focà, Annalia, Sanguigno, Luca, Bodenstine, Thomas M, Chandler, Grace S, Reed, David W, Gilgur, Alina, Seftor, Elisabeth A, Seftor, Richard E B, Khalkhali-Ellis, Zhila, Leonardi, Antonio, Ruvo, Menotti, Hendrix, Mary J C
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 27-10-2015
• Subjects: Animals; Antibodies, Monoclonal - immunology; Breast Neoplasms - pathology; Cell Line, Tumor; Cyclin B1 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p27 - biosynthesis; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases - biosynthesis; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Imidazoles - pharmacology; Melanoma - pathology; Mice; Nodal Protein - antagonists & inhibitors; Nodal Protein - blood; Nodal Protein - immunology; Oximes - pharmacology; Priority Research Paper; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Smad2 Protein - biosynthesis; Surface Plasmon Resonance; Nodal; cancer; antibody; therapy; ELISA
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6049

Nodal is highly expressed in various human malignancies, thus supporting the rationale for exploring Nodal as a therapeutic target. Here, we describe the effects of a novel monoclonal antibody (mAb), 3D1, raised against human Nodal. In vitro treatment of C8161 human melanoma cells with 3D1 mAb shows reductions in anchorage-independent growth and vasculogenic network formation. 3D1 treated cells also show decreases of Nodal and downstream signaling molecules, P-Smad2 and P-ERK and of P-H3 and CyclinB1, with an increase in p27. Similar effects were previously reported in human breast cancer cells where Nodal expression was generally down-regulated; following 3D1 mAb treatment, both Nodal and P-H3 levels are reduced. Noteworthy is the reduced growth of human melanoma xenografts in Nude mice treated with 3D1 mAb, where immunostaining of representative tumor sections show diminished P-Smad2 expression. Similar effects both in vitro and in vivo were observed in 3D1 treated A375SM melanoma cells harboring the active BRAF(V600E) mutation compared to treatments with IgG control or a BRAF inhibitor, dabrafenib. Finally, we describe a 3D1-based ELISA for the detection of Nodal in serum samples from cancer patients. These data suggest the potential of 3D1 mAb for selecting and targeting Nodal expressing cancers.