CCR: combination of drugs can effectively fight against melanoma!

April 27, 2018 / bioin / - in the past decade, due to the approval of several new therapies (such as BRAF and MEK inhibitors), patients with advanced or metastatic melanoma can have a longer cancer free time, but most patients will eventually develop drug resistance and tumor recurrence A team of scientists from Moffett cancer research center are exploring how melanoma can be resistant to BRAF inhibitors in an attempt to find new strategies that are more effective They tested whether the combination of targeted heat shock protein 90 (Hsp90) and BRAF inhibitor vimofinil is a safe and more effective treatment strategy The relevant research results were published in clinical cancer research recently BRAF protein is an important regulator of cell survival and growth, so it is a potential target for tumor control Almost half of the patients with melanoma will carry the BRAF gene mutation Currently, two drugs targeting the mutation BRAF, vimofinil and darafinil, have been approved for the treatment of patients who carry the BRAF mutation and cannot be surgically removed or have been transferred These drugs improve patient survival and are often used in combination with MEK inhibitors, but it is very common that drug resistance eventually occurs Moffett researchers have published a preclinical study in the past showing that the Hsp90 inhibitor xl888 can overcome the resistance of melanoma cells to vimofinib The team quickly carried out experiments in mice and initiated a phase 1 clinical trial to evaluate the effect of xl888 combined with vermopheni on melanoma patients to determine the optimal dose The researchers treated 21 melanoma patients with BRAF mutations who could not be surgically removed or metastasized with an incremental dose of xl888 in combination with vimofinib They reported data for 20 of them, and the results showed that 75% of patients responded to the combination therapy, including 3 patients responding fully and 12 patients responding partially The median progression free survival was 9.2 months and the mean overall survival was 34.6 months The toxicity of combination therapy can be controlled The most common advanced adverse events are diarrhea, headache, fatigue and skin toxicity, which are easily treated or removed Six patients experienced visual problems, but all were resolved after the drug was discontinued The researchers also found that the combination of xl888 and vimofinib could alter the expression patterns of many proteins up-regulated by Hsp90, which means that the therapy works on patients as expected "Our research is very encouraging, but we need further research to evaluate the efficacy of the combination of xl888 and BRAF inhibitors and MEK inhibitors, and to find out the biomarkers that inhibit the change of HSP 90." Dr Keiran S Smalley, director of the center of excellence for melanoma and skin cancer, Donald A Adam, Moffett "Perhaps the most important thing about this study is that it is a model for Moffett research center from scientific research to clinical research, bringing the findings of our laboratory to clinical practice to change the prognosis of patients." Reference: Zeynep Eroglu et al, combined BRAF and HSP90 initiation in patients with unresponsive BRAFV600E mutant melanoma, clinical cancer research (2018) Doi: 10.1158/1078-0432.ccr-18-0565