Varsha Gandhi, Ph.D. University of Texas MD Anderson Cancer Center

THERAPY/ PROGNOSTIC

Transcription Inhibition to Target CLL

Grant awarded in 2005

Abstract:

Chronic lymphocytic leukemia (CLL) is characterized by disrupted cell death pathway rather than increased rate of proliferation. Because these cells do not divide they do not synthesize DNA or go through cell replication. Hence agents that are DNA replication- or cell division-directed do not work well for this disease. We are focusing on developing chemotherapy that is not directed to DNA. Studies from my group have reported that chlorinated adenosine (8-Chloro-adenosine, 8-Cl-Ado) kills human myeloma and leukemia cell lines. When these cells are treated with 8-Cl-Ado, the cellular energy, i.e. ATP, declines. Also, by incorporating it into RNA (a transmitter of genetic information from gene to protein), this agent inhibits transcription of genes needed for survival of CLL cells. These features make 8-Cl-Ado an ideal drug to target CLL cells.

Our hypothesis is that because of these actions, which are DNA independent, quiescent CLL lymphocytes will undergo death. We plan to understand metabolism and mechanism of action of this agent in leukemia cells that are freshly obtained from peripheral blood of CLL patients. We will compare all our data in CLL lymphocytes with normal lymphocytes. We have IRB-approved LAB protocols to get blood from CLL patients and healthy donors. Eventually, we will use this knowledge and test this compound in the clinic for patients with CLL. With that respect, we have finished all the toxicology and pharmacology studies with this agent and are currently doing IND-directed toxicology to seek an FDA approval to use this agent as investigational new drug in the clinic for patients with CLL. We already have an IRB approved phase I protocol to use this agent for CLL patients.