It is unclear what response would be expected with dasatinib or nilotinib in a study population that included both second and third line setting patients. Myelosuppression and pleural effusions are serious adverse events that EPO906 Epothilone B have been seen with dasatinib, and myelosuppression and liver dysfunction, with nilotinib.21, 24, 25 These events were observed infrequently with INNO 406. The safety profile of INNO 406 is therefore unique, offering a potential advantage in the treatment of patients who have developed toxicities during treatment with other Bcr Abl TKIs. Of note, a planned central evaluation of ECGs during the first cycle of INNO 406 therapy revealed only 1 patient with a QTc 500 msec, this patient, who had an elevated QTc at baseline, entered the study with a waiver.
Mutational analysis revealed mutations prior to the start of INNO 406 in 22 of the 49 patients analyzed. Among these were 4 patients who had T315I mutations, which are known to confer resistance to imatinib, dasatinib, and nilotinib. None of the 4 patients with T315I mutations responded to INNO 406. PXD101 Outcomes of CML treatment have improved dramatically since the introduction of imatinib mesylate. The rising incidence of imatinib resistance and intolerance has resulted in the need for alternative agents. Nilotinib, dasatinib, and bosutinib are second generation TKIs that have been developed to overcome imatinib resistance.11, 12 All 3 agents have similar efficacy with slightly different adverse effect profiles.
There is a need for additional agents that are more potent than both imatinib and the existing second generation TKIs. As patients are being treated longer, they are more commonly cycling through different treatment regimens. This study demonstrates that INNO 406 is tolerated at a dose of 240 mg BID. Lower dose schedules may also be equally effective and deserve further evaluation. Further studies are needed to better evaluate the efficacy of INNO 406 in patients who have developed resistance to or intolerance of imatinib and/or other TKIs. Abstract Prediction of drug action in human cells is a major challenge in biomedical research. Additionally, there is strong interest in finding new applications for approved drugs and identifying potential side effects.
We present a computational strategy to predict mechanisms, risks and potential new domains of drug treatment on the basis of target profiles acquired through chemical proteomics. Functional protein protein interaction networks that share one biological function are constructed and their crosstalk with the drug is scored regarding function disruption. We apply this procedure to the target profile of the second generation BCR ABL inhibitor bafetinib which is in development for the treatment of imatinib resistant chronic myeloid leukemia. Beside the well known effect on apoptosis, we propose potential treatment of lung cancer and IGF1R expressing blast crisis. Introduction Biomedical research is changing towards a systems pharmacology view of drug action. In parallel, chemical proteomics, a postgenomic version of classical drug affinity purifications which use is growing rapidly, has been deve