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Inosine monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the production of guanine nucleotides via the de novo synthesis pathway. There are two mammalian IMPDH isoforms: type I and type II. AVN-944 is a small molecule, selective inhibitor of both IMPDH isoforms that inhibits proliferation of a wide range of hematologic and epithelial tumor cell types. To guide dose escalation and monitor patient response to AVN-944 in clinical trials, we have identified a set of 19 marker genes with altered expression as a consequence of IMPDH inhibition and depletion of guanine nucleotide pools. This study evaluated the gene expression signature in eight ex vivo drug-treated Acute Myelogenous Leukemia (AML; n=2), Acute Lymphoblastic Leukemia (ALL; n=4) and Chronic Lymphocytic Leukemia (CLL; n=2) clinical isolates. Expression of the biomarker set, assayed by quantitative PCR analysis, shows the 19 gene signature is altered after 2 and 6 hour incubation with 1.0 uM AVN-944, in agreement with changes in these 19 genes in cancer cell lines, including the AML cell line KG-1. Additionally, analysis of global gene expression microarray data from ex vivo treated patient samples clearly demonstrate that gene ontology categories affected in cell lines are also affected in patient samples and include nucleotide biosynthesis, the apoptotic cascade, energy production and metabolism, and cellular proliferation. Genes involved in cell cycle control and in the purine biosynthetic pathway in particular are down-regulated by AVN-944. Interestingly, global gene expression analysis differentiates each malignancy; however, gene expression responses to AVN-944 treatment are consistent across cancer types, suggesting broad therapeutic potential for AVN-944 in multiple cancers. The gene signatures observed in primary leukemia samples are the foundation for building predictors of response to AVN-944, and may also enable patient enrichment strategies in clinical trials.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]