Development of 8-chloro-adenosine therapy

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Nucleoside analogues have a played pivotal role in the treatment of hematological malignancies. While the first analogue was used more than 50 years ago, during the last five years, four new congeners were FDA approved for therapy. A common feature among these clinically used analogues is that they are all DNA directed; analogues that are exclusively affecting RNA have not been brought to the clinic. 8- chloroadenosine (8-CI-Ado) is a novel and unique nucleoside analogue that is first in its class to be tested in the clinic. First, in contrast to other clinically used analogues, this agent has a nbose sugar. Second, 8-CI- Ado is phosphorylated by adenosine kinase which is present in high specific activity in cancer cells as opposed to deoxycytidine kinase which activates currently used analogues. Third, the triphosphate of 8-CI- Ado, 8-CI-ATP is incorporated into RNA without any effect on DNA synthesis. Fourth, 8-CI-ATP is also incorporated into poly(A) tail of transcripts resulting in inhibition of polyadenylafion and mRNA synthesis. As a consequence of the actions on mRNA synthesis, there is a depletion of short-lived transcnpts. Fifth, biochemical studies and molecular modeling data have suggested that 8-CI-ADP is a substrate and 8-CI- ATP is an inhibitor for mitochondrial ATP synthase, the apical enzyme of the oxidative phosphorylation pathway which results in a depletion of cellular bioenergy. Collectively these features make this analogue a first in its class. Based on this background, we hypothesize that 8-Cl-Ado will elicit novel pharmacodynamic responses to non-growing or indolent malignant cells. The uniqueness of 8-CI-Ado was recognized by peers in this field as we obtained two RAID awards from NCI, an IND from the FDA, and GMP material to conduct our phase I clinical investigation in patients with CLL. To achieve our overall goal and to test our hypothesis, we plan to pursue the following three aims. First, using well-defined biomarkers, evaluate pharmacokinetics and pharmacodynamics of 8-CI-Ado during phase l/ll clinical trial in patients with CLL. Second, formulate in vitro rationales for clinical translation of mechanism-based combinations of 8-Cl-Ado with small molecule inhibitors. Third, determine metabolism, actions, and cytotoxic endpoints in lymphoma cell lines that will be translated to a clinical trial in lymphoma. RELEVANCE (See instmctions): This Project will test a new agent 8-chloro-adenosine, in chronic lymphocytic leukemia (CLL) and lymphoma. This is a first in its kind of agent to move to clinic. Additionally, different strategies will be investigated regarding best combination approaches for this agent. Hence these investigations are aimed at improving the cure rate of CLL and lymphoma.