Chen et al. Page 2835

Ibrutinib is an irreversible tyrosine kinase inhibitor that targets Bruton's tyrosine kinase (BTK) as well as ErbB family kinases. Chen and colleagues found that ibrutinib potently inhibited the activity of ErbB kinases and the growth of HER2 overexpressing cells similarly as ErbB-targetted inhibitors in clinic. Compare to ErB inhibitors, the dual activity toward TEC and ErbB family kinases was unique to ibrutinib. In addition, it was shown that the anti-tumor effects of ibrutinib in breast cancer models are at clinically achievable levels. Since TEC kinases modulate several types of tumor accessory cells, the utility of ibrutinib's unique inhibitory spectrum is worthy of further exploration.

Gebreyohannes and Schöffski et al. Page 2845

Advanced/metastatic gastrointestinal stromal tumors (GIST), driven mainly by KIT or PDGFRA mutations, are treated with tyrosine kinase inhibitors (TKI) such as imatinib. However, the development of resistance remains to be a major clinical challenge. Gebreyohannes, Schöffski and colleagues showed the in vivo activity of cabozantinib, a novel small molecule multi-targeted TKI, in three GIST patient-derived xenograft models, characterized by different KIT mutations and sensitivity to standard TKI. Cabozantinib decreased or stabilized tumor burden, mainly through the inhibition of cell proliferation and tumor vascularization. Moreover, the effect observed was significantly better than the one obtained with imatinib.

Thomas et al. Page 2946

T cell immunoglobulin mucin-1 (TIM-1) is highly up-regulated in renal cell carcinoma and ovarian clear cell carcinoma. To exploit the expression of TIM-1 on these malignancies, the Celldex Therapeutics team developed CDX-014, which is an antibody drug conjugate comprised of a fully-human monoclonal antibody directed against an epitope of TIM-1, conjugated to the cytotoxic agent MMAE. Preclinical studies with this ADC demonstrated in vitro and in vivo efficacy against a variety of TIM-1 expressing cell lines and tumor models. With the successful completion of IND-enabling studies, activities are on-going to advance CDX-014 in clinical studies in renal cell carcinomas and other TIM-1 expressing tumors.

Uitdehaag et al. Page 3097

122 anti-cancer agents were profiled in proliferation assays with cancer cell lines from diverse tumor tissues. For 38 compounds this is the first comparative profiling study. Good correlations were observed with other cell panels. Curve fitting led to a large source of variation. Hierarchical clustering revealed common mechanisms of action. Nine clusters, including EZH2, BET and TTK inhibitors, have not been reported before. The lack of clustering of several Aurora and PI3K inhibitors could be explained by differences in biochemical selectivity. The study shows that cell line profiling is an excellent tool for the unbiased classification of anti-proliferative compounds.