CELL-TARGETED RGD-SUNITINIB MOLECULAR CONJUGATES IMPAIR TUMOR GROWTH OF MELANOMA

Abstract

Despite progress in the clinical management of advanced-stage melanoma with different treatmentoptions available, mainly based on targeted therapy and immunotherapy, many concerns still existdealing with the observed overall toxicity. Effective dosing regimens and the insurgence of resistancemechanisms lead to tumor relapse and progression to a metastatic disease with incredibly aggressivefeatures. Given the involvement of multiple, yet strictly related biological targets and signaling cascadesin the metastatic melanoma disease, the combination therapy has become the standard-of-care treatment,in both small molecule-based (e.g. vemurafenib+cobinetinib in BRAFV600E/K-mutant disease) andantibody-based therapies (e.g. ipilimumab+nivolumab), with the primary goal to improve clinical benefitwhile overcoming the insurgence of drug resistance and compensating mechanisms often observed usingtargeted monotherapy. In these cases, however, off-organ (and possible synergistic) toxicity remains astill unsolved issue. Thus, the creation of new molecular conjugates which combine the ability to targetmelanoma cells using recognition of specific surface-exposed receptors, enter melanoma cells via receptormediatedendocytosis, and modulate key intracellular targets and signaling pathways, is an appealingapproach toward enhanced drug efficacy at lowered drug dosage and increased safety window.