Guillermo Garcia-Manero, M.D. University of Texas MD Anderson Cancer Center

GENETICS

Epigenetic and therapeutic profiling of chronic lymphocytic leukemia

Grant awarded in 2005

Abstract:

Gene silencing, or the inactivation of genes, is often associated with cancer. Often, the addition of methyl groups to specific regions on the gene results in gene silencing. Gene silencing inactivates genes that are important for cell function. We are working in the laboratory to identify subsets of patients with specific DNA methylation (alterations) which may predict specific prognoses. DNA methylation can be reversed and we are studying drugs that have proven reversal activity in myeloid leukemias. Understanding methylation alterations in CLL may allow the selective use of these relatively non-toxic therapies.

Based on these concepts, we propose to:
1-Develop an epigenetic/genetic profile of patients with chronic lymphocytic leukemia (CLL).
2-Develop systems to test the molecular effects of hypomethylating agents on CLL cells.
3-Develop clinical trials based on information derived from #1 & #2 using hypomethylating agents in patients with CLL.

We will analyze a set of untreated CLL samples for both gene specific and global methylation. The data generated will be compared to known prognostic alterations in CLL such as IgVH mutational status, FISH analysis, and expression of ZAP-70 and CD38.

CLL cells will be epigenetically profiled prior to treatment. Two different drugs with hypomethylating activity, 5-aza-2'-deoxycytidine and 5-azacytidine, will be given and the cells will be analyzed for methylation changes and cell kill dynamics. This data will then be used to develop a phase I clinical trial of one of these two agents. The data generated by aims #1-3 will be used to develop a final methylation classification of CLL and to introduce the use of hypomethylating agents for the treatment of CLL patients.