Anas Cahill posted an update 1 week, 2 days ago
Last, SUGAR-MGH could be employed to identify genetic variants that differentially influence the responses to the two pharmacological challenges. Given the different time scales of the interventions, this approach would require that a chosen glipizide Ro 67-7476 phenotype be normalized across all participants and compared against a similarly normalized metformin phenotype. For this hypothetical example, there would be 85% power to detect an effect difference of 0.45 between the two endpoints for a variant with minor allele frequency of 5% in the SUGAR-MGH cohort. For a variant with a 20% minor allele frequency, there would be 85% power to detect an effect difference of 0.26. Given the large number of potential questions that can be tested using SUGAR-MGH, appropriate statistical thresholds, correcting for the number of hypotheses tested, must be used to limit false positive findings. In summary, the SUGAR-MGH cohort illustrates a paradigm for the construction of a pharmacogenetic resource in humans, which is free of the uncontrolled nature of retrospective clinical datasets, achievable at a local site with an investigator-initiated award, and simple enough to enable the recruitment of a large cohort with excellent retention rates and short duration. The receptor tyrosine kinase fms-like tyrosine kinase 3 is expressed at high levels on malignant blasts in 70% to 100% of cases of acute myeloid leukemia and is mutated, most commonly by internal tandem duplication, in 20 to 30 percent of AML cases in different series. FLT3-ITD mutations result in constitutive FLT3 signaling and, clinically, are associated with short disease-free survival following chemotherapy. FLT3 signaling may also be activated in AML cells by autocrine stimulation by FLT3 ligand. Diverse kinase inhibitors inhibit signaling by both FLT3-ITD and wild-type FLT3. However first-generation inhibitors, including lestaurtinib, midostaurin, tandutinib sorafenib and sunitinib, lack optimal potency, selectivity and pharmacokinetic properties, resulting in limited activity and/or problematic toxicities, and have produced limited single-agent therapeutic benefit, mainly consisting of transient decreases in blasts. The single randomized trial of a first-generation FLT3 inhibitor, lestaurtinib, in conjunction with chemotherapy reported to date did not demonstrate clinical benefit. The second-generation bis-aryl urea FLT3 inhibitor quizartinib has excellent kinase selectivity and pharmacokinetic properties inhibits FLT3-ITD and wild-type FLT3 at 0.1 and 0.5 mM, respectively, in vivo and has shown favorable tolerability and single-agent activity in phase I and II trials. Of note, the dose-limiting toxicity of quizartinib is prolongation of the QT interval, which occurred in 38% and 6% of patients receiving continuous daily doses of 300 and 200 mg, respectively. Following completion of early-phase clinical testing, quizartinib will be tested in combination with chemotherapy. The ATP-binding cassette proteins ABCB1 and ABCG2 are drug efflux proteins that are frequently expressed on AML cells. Their substrates include anthracyclines, mitoxantrone and other drugs used to treat AML, and their expression on AML cells is associated with inferior treatment outcomes. Co-administration of inhibitors of ABCB1 and ABCG2 drug efflux activity has the potential to sensitize AML cells to chemotherapy drugs that are substrates of these proteins. Unfortunately, however, clinical trials of ABCB1 inhibitors did not in fact demonstrate clinical benefit. One of the possible reasons is lack of inhibition of ABCG2. The first-generation FLT3 inhibitors, including midostaurin, lestaurtinib, tandutinib, sorafenib and sunitinib, are substrates and/or inhibitors of ABCB1 and ABCG2. Of note, in one recent study a significant positive correlation was found between FLT3-ITD and ABCG2 overexpression, and DFS was shortest in patients with AML with both FLT3-ITD and ABCG2 overexpression. These data suggest that co-inhibition of FLT3 and of ABCG2 might be beneficial. Since neutropenia caused by disease and/or therapy is frequent in AML patients, antibiotics and antifungals are commonly coadministered with AML therapy. Some of the antibiotic and antifungal agents prescribed to AML patients are ABCG2 and/or ABCB1 substrates and may also prolong the QT interval. Coadministration of drugs and FLT3 inhibitors with ABCG2 and/or ABCB1 interactions may alter pharmacokinetics and/or pharmacodynamics of either or both drugs. We sought to characterize interactions of quizartinib with ABCB1 and ABCG2. Inhibition of these transport proteins on the surface of AML cells by quizartinib would result in sensitization to ABC protein substrate chemotherapy drugs, and co-inhibition of FLT3 and ABCG2 could improve outcomes. However, quizartinib inhibition of ABCG2 on intestinal mucosal cells could result in increased absorption and altered pharmacokinetics of coadministered therapeutic agents that are ABC protein substrates, including drugs that cause QT prolongation, with consequent potential for enhancing cardiotoxicity.