CM-728 as a novel and potential new compound for metastatic ccRCC treatment.

2019 edition

Jazmine Arévalo

Clear cell renal cell carcinoma (ccRCC) is the most prevalent and lethal histological subtype of renal cell carcinoma (RCC) because of its asymptomatic phenotype associated with chemotherapy and radiotherapy resistance. If ccRCC is detected at early stages, partial or radical nephrectomy is the first-line treatment increasing survival in 65% of patients. Conversely, if detection occurs in advanced metastatic stage, drugs like Sunitinib are used as first-line treatment although less than 50% of cases respond to therapy. Tyrosine kinase inhibitors (TKIs), such as Sunitinib, prevent activation of signal transducers and activators of transcription (i.e. STAT3) but, molecular heterogeneity between tumors precede the scarcity of their effectiveness. Furthermore, abnormal STAT3 activation has been correlated with poor prognosis and overall survival of ccRCC patients. Because of the insufficient and partial effective metastatic first-line treatments available to date, CEAMED SA developed the compound CM-728, a fused quinone that acts as a specific STAT3 inhibitor. Therefore, the aim of this work was: a) to determine the effect of CM-728 on human ccRCC derived cell lines (769-P, 786-O) and non-tumoral renal cell lines (HK2, RPTEC); b) to analyze the effect of CM-728 upon STAT3 activation and, c) to compare it with first-line treatment Sunitinib and AG490 (a potent JAK/STAT pathway inhibitor). Our results showed that ccRCC cell lines were more sensitive in a time-dose-dependent manner to CM-728 than to Sunitinib and AG490, demonstrating that CM-728 is a powerful STAT3 inhibitor and, therefore, a potential new compound for metastatic ccRCC treatment.