Tea Pemovska (2015)

Studies of axitinib and axitinib drug combinations as BCR-ABL1(T315I)-selective therapies for drug-resistant CML and Ph+ ALL

Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland

We have recently shown that the renal cancer drug axitinib exhibits potent, leukemia-selective responses in CML and Ph+ ALL patient samples harboring the T315I mutation ex vivo and in vivo (Pemovska et al. Nature, 2015). In addition, we observed that two week treatment of a CML patient with a T315I mutation resulted in a 5-fold reduction of T315I transcript levels in the blood marrow, suggesting that axitinib can produce meaningful responses in patients. In this follow up study the aim is to characterize the vulnerability profile of axitinib in terms of drug resistance and identify combinatorial strategies to overcome it. To identify whether prolonged exposure of BCR-ABL1(T315I)-driven cells to axitinib leads to the selection of resistance mutation we will perform an accelerated cell-based mutagenesis assay. If resistance occurs, cells will be expanded and the entire ABL1 kinase domain will be sequenced to uncover the possible mutation switch. The axitinib resistant cells will then be subjected to combinatorial treatment of axitinib with other ABL1 approved inhibitors as well as inhibitors of BCR-ABL1 downstream effector signals to identify synergistic activity. Given the ABL1(T315I)-selective activity of axitinib, it is conceivable that T315I-negative clones might be selected in response to axitinib treatment in vivo. In addition, in patients not all blast cells might be T315I positive that may render axitinib ineffective. To address this, this study will also test combinations of axitinib with either other ABL1 inhibitors or inhibitors of downstream effector signals (e.g. MEK, PI3K, SMO) in cells derived from T315I positive CML/Ph+ ALL patients. We expect that drug combinatorial approaches with axitinib as a backbone should provide a more complete clonal coverage and consequently more effective treatment of the leukemia.