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

THERAPY/ PROGNOSTIC

Transcription Inhibition to Target CLL

Update:

CLL is characterized by a 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-directed do not work well for this disease.

We focused on developing chemotherapy that is not directed to DNA. We were able to determine metabolism and mechanism of action of a new agent, 8-chloro-adenosine, in CLL cells. We used cell samples freshly obtained from peripheral blood of patients with CLL. We compared this drug in CLL lymphocytes and in normal lymphocytes. Our data demonstrated that the drug works in a DNA independent way in CLL cells, and in laboratory experiments, the drug was effective in killing CLL cells. We have published two papers from this work during the first 18 months.

Because multiple myeloma is also a B-cell neoplasm and the plasma cells are not actively dividing, we hypothesized that 8-Cl-Ado would work in this disease also. Our data demonstrated that multiple myeloma cell lines treated with 8-Clo-Ado results in a decrease in Met transcript and protein levels. We further established that Met tyrosine kinase is a survival factor for these cells and once there is a decrease in the protein, cells undergo cell death. This was recently published in Cancer Research.

Using separate funding sources, we conducted Investigational New Drug (IND) directed toxicology studies and have now received IND approval from the FDA to move 8-Cl-Adenosine in the clinic for patients with CLL.