Towards personalized medicine: Utilizing biomarkers to track response of the inosine monophosphate dehydrogenase (IMPDH) inhibitor AVN944 patient samples from a Phase I clinical trial in AML and evaluation of a patient stratification signature.

A58 AVN944 is an orally bioavailable inhibitor of inosine monophosphate dehydrogenase 1 and 2 (IMPDH). IMPDH2 is highly up regulated and required for the de novo production of guanine nucleotides in many malignancies, including hematologic cancers. AVN944 has been in a repeat-dose, dose escalation trial in patients with advanced hematologic cancers including AML, CLL, Multiple Myeloma, and lymphomas. In addition to the objective of defining the maximum tolerated dose and repeat dose pharmacology of AVN944 (given bid for 21 days on a 28 day cycle), we have examined a comprehensive set of pharmacodynamic biomarkers. We have isolated peripheral blood samples from all patients in this trial both before and after receiving AVN944. These samples have been used to determine the effects of the drug on GTP pools and IMPDH enzyme activity, and to correlate these changes to the genetic response of the circulating cells using gene expression detection technologies. Examination of the behavior of these genes in patient samples from this phase I trial show a dynamic response of subsets of these genes depending on 1) the type of malignancy, 2) the predominant cell type in the peripheral blood, 3) the dose of AVN944 received, and 4) the number of treatment cycles completed. Perturbation of biomarkers in these samples relate directly to cellular pathways and functions dependent upon IMPDH activity and include guanine nucleotide biosynthesis, purine and pyrimidine biosynthesis, mitochondrial functions, metabolic pathways and energy production, cell proliferation and the apoptotic cascade. Increasing doses resulted in increases in the number of genes changing per individual, and/or an increase in the magnitude of change in a gene-dependent manner. These genetic markers, correlated with biochemical effects of the drug on protein function and guanine nucleotide levels, can be used as important biomarkers in selecting the optimal dose for additional studies with this drug and for enriching for patients most likely to respond to the drug.