Abstract
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.
Highlights
Melanoma is the most aggressive and deadly form of skin cancer with a median overall survival for advanced stage metastatic disease of less than 6 months [1]
These results indicate that 3D1 monoclonal antibody (mAb) treatment diminishes Nodal expression, as well as downstream phosphorylation of Smad2 and ERK1/2, and reduces Cyclin B1 while increasing p27 in melanoma cells and that similar effects can be observed in breast cancer cells
The cancer stem cell theory suggests that within this continuously mutating heterogeneous tumor population reside subsets of cancer cells with stem cell-like characteristics that include drug resistance, and which have the potential for disease relapse and metastatic spread
Summary
Melanoma is the most aggressive and deadly form of skin cancer with a median overall survival for advanced stage metastatic disease of less than 6 months [1]. Despite the questionable survival benefit of DTIC therapy compared to supportive care [3], this drug is still listed as a therapeutic option for advanced stage or metastatic melanoma [4]. For decades no new therapeutic agent has been approved for metastatic melanoma by the FDA until a recent study, which showed survival benefit of a monoclonal antibody targeting a regulatory checkpoint, CTLA-4, in T-cells [5] and led to the approval of ipilimumab in 2011. Of special note are recent studies showing that targeting both PD-1 and CTLA-4 together in patients with metastatic melanoma resulted in higher rates of objective response and significantly longer progressionfree survival than targeting CTLA-1 alone [12]. Continued follow-up will determine if this anti-immune checkpoint combinatorial approach will lead to increased overall survival
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
