Deepa Sampath, Ph.D. University of Texas MD Anderson Cancer Center

NEW DRUGS

Chromatin Modulation as a Therapeutic Strategy for CLL

Grant Awarded in 2008

Abstract:

Certain cancers such as CLL are characterized by a slow accumulation of cells that display enhanced survival. These cells do not divide. Therefore, agents that require active DNA replication or cell division are ineffective against this disease. My project focuses on the development of a new class of agents, the histone deacetylase inhibitors (HDACI), for the treatment of leukemias.

HDACIs work by acetylating proteins so that genes synthesize (or transcribe) new RNAs. Generally speaking, the production of these RNAs is suppressed in CLL. When CLL cells are exposed to LBH589, an HDACI, there is an increased level of protein modification on genes and these RNAs are now re-expressed. They in turn control the activity of other proteins which induce cell death. LBH589 also inhibits the transcription of genes needed for the survival of CLL cells. These features make LBH589 an ideal drug to target CLL cells.

Our hypothesis is that because of these DNA independent actions of LBH589, quiescent (non-dividing) CLL lymphocytes will undergo death. We hope to understand the mechanism of action of this agent in leukemia cells that are freshly obtained from blood of patients with CLL. These data will help in the development of HDACIs as a drug for the treatment of CLL. We will compare all our data in CLL lymphocytes with normal lymphocytes. We will obtain blood from CLL patients and healthy donors, as permitted under a protocol approved by the Institutional Review Board (IRB). We also have an IRB approved phase I protocol to use LBH589 for patients with leukemias including CLL.

Useful definitions:
Acetylation: Protein modification that allows for the synthesis of new gene products.