Inactivation of genes which control cell proliferation and cell death contribute to the establishment and maintenance of malignant phenotypes. Two mechanisms by which gene transcription are inhibited are methylation of cytosine residues in promoter regions, and removal of acetyl groups from histones, maintaining a chromatin structure which is not permissive for transcriptional initiation. Optimal re-expression of silenced genes in malignant cells in vitro has recently been accomplished through sequential application of DNA methyltransferase inhibitors (MeTI) and histone deacetylase inhibitors (HDI). The clinical research proposed in this application is designed to exploit this strategy for the treatment of malignancies. Two planned Phase I clinical trials at The Johns Hopkins Oncology Center (JHOC) will study the feasibility of combining the MeTI 5-azacytidine (AC) with the HDI sodium phenylbutyrate (PB). One trial will focus on patients with hematologic malignancies (HM), the other on non-hematologic malignancies (non-HM). The research proposed in this application uses the two trials as platforms to determine whether the clinical administration of 5AC plus PB leads to the re-expression of genes important in maintaining the malignant phenotype.
In Specific Aim 1, the optimum dose and schedule of 5AC administration for inhibition of DNA MeT and decreased methylation of targeted promoters will be investigated. Different dosing and scheduling schemata of 5AC will be employed in the two trials to enable determination of the optimal regimen of 5AC administration for MeTI.
Specific Aim 2 determines the extent of histone acetylation in response to a variety of dosing schedules of PB. The administration of PB will differ significantly between the two trials. In each trial, acetylation of histones from PBMC will be studied at a variety of time points following PB administration to determine the extent and duration of induced histone acetylation.
Specific Aim 3 examines the impact of clinical administration of 5AC plus PB on the expression of targeted genes, both specific cancer-targeted genes, and several non-malignancy associated surrogate genes.
Specific Aim 4 will investigate the molecular response rate for gene re-expression. Following successful completion of dose and schedule determination, both trials will accrue an additional cohort of patients at a uniform dosage and schedule with continuing determination of correlative laboratory endpoints. This will enable determination of the """"""""molecular response rate"""""""" to this therapy and preliminary exploration of correlation between these molecular endpoints and clinical response.
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