Membrane proteins and their interactions play central roles in a variety of cellular processes including nutrient uptake, signaling and cell-cell communication. Many cancers, neurological, metabolic and immune disorders can be attributed to the abnormal function of membrane proteins. All of these membrane proteins either contain one or several transmembrane (TM) strands and/or undergo some degree of oligomerization. Thus, stabilization or disruption of these protein-protein interactions is therefore of great interest for the modulation of protein function within the cell. In this context, TM domains of neuropilin-1 receptor (NRP1) and human epidermal growth factor receptor (HER2) are particularly studied in our laboratory to develop anti-cancer therapies based on the interference of the TM domains. Antitumor effects of TM peptides targeting NRP1 or HER2 has been proved in glioblastoma (Nasarre et al., 2010) and breast cancer (Arpel et al., 2016) respectively. In addition, HER2 has been proved to reduce metastasis in a metastatic model of breast cancer (Arpel et al., 2014). Moreover, NRP1 expression has been detected by immunostaining in tumor specimens obtained from patients with prostate, lung, pancreatic, colon carcinoma and melanoma.
In order to expand the therapeutic applications of these TM peptides, we evaluated its anti-tumoral activity in melanoma in an orthotopic allograft model in nude mice (B16F10 cell line).
Our results show, that a local administration of MTP-NRP1 (1µg/kg, 3x/week) significantly reduces tumor development after 11 days of treatment. These results concur with the dT/dC% value at day 13 (18,3%) indicating that the treatment is efficiently impacting the tumor volume after this period. The application of the RECIST criteria identified 7.1% of mice presenting stable disease while 78,6% exhibited partial response. However 14.3% of mice were non responders to the treatment.
Hence, current work is conducted to analyze by gene array profiling the differences in NRP1 and other cancer promoting receptors between responder and non-responder populations. This is a prerequisite to decide whether MTP-NRP1 could be developed in this indication, particularly by associating it to another drug in the non-responding population.
Clinical trial identification
Legal entity responsible for the study
INSERM U1109, “Microenviromental Niche in Tumorigenesis and Targeted Therapy” MN3T lab, Labex Medalis, University of Strasbourg, France.
Labex Medalis, University of Strasbourg, France.
All authors have declared no conflicts of interest.