Wei Li
The University of Tennessee Health Science Center, USA
Title: Discovery of novel tubulin inhibitors and their synergy with BRAF inhibitors for malignant melanoma
Biography
Biography: Wei Li
Abstract
Malignant melanoma is the most aggressive form of skin cancer and it is highly resistant to most existing therapies. Despite recent advances in both targeted therapy (e.g. BRAF inhibitors vemurafenib and dabrafenib; MEK inhibitor trametinib) and immunotherapy (ipilimumab; pembrolizumab), acquired drug resistance often develops quickly and the overall survival for malignant melanoma remains unsatisfactory. Chemotherapeutic drugs including tubulin inhibitors (e.g., paclitaxel or vinblastine) are used in treating malignant melanoma clinically, but their efficacy is often limited by the ABC-transporter mediated drug efflux and non-specific tissue distribution, leading to dose limiting toxicity. We have discovered several sets of novel tubulin inhibitors that: 1) target the colchicine binding site in tubulin and have broad spectrum of potent anticancer activity; 2) effectively circumvent major drug resistance mechanisms (P-gp, BCRP, and MRPs) that hinder the clinical efficacy with existing tubulin inhibitors; 3) are orally bioavailable and have excellent drug-like properties; 4) are efficacious against both drug sensitive and drug resistant melanoma tumors in vivo; and 5) have strong synergy with approved BRAF inhibitors for BRAF-resistant melanoma tumors. We have also developed nanoparticle formulations for these agents and showed that these targeted drug delivery approaches can significantly improve the anticancer efficacy for these tubulin inhibitors.
