Research News

A collaborative research and clinical team at Cleveland Clinic has identified eltrombopag, currently used for the treatment of Aplastic anemia and chronic immune thrombocytopenia, as a potential therapeutic specific for a certain type of leukemia. The discovery could lead to the development of new therapeutics for leukemia – which currently has no cure – by targeting diseased cells while preserving and expanding normal blood cells.  

In their recently published paper in the Journal of Clinical Investigation, the team of researchers, including Babal Jha, PhD, Center for Immunotherapy & Precision Immuno-Oncology, and Jaroslaw Maciejewski, MD, PhD, a hematologist in the Department of Translational Hematology & Oncology Research, found eltrombopag was a potent inhibitor of specific leukemia cells. The findings describe the mechanisms eltrombopag uses to cause loss of function mutation in a gene called TET2, inhibiting mutant blood cancer cells, while stimulating normal stem cell growth.

Investigations began during a collaboration between the labs of Drs. Jha and Maciejewski and resulted in the identification of eltrombopag as a powerful inhibitor of all three TET dioxygenases, which play a crucial role in the removal of methyl mark on cytosine in DNA.

“Fortunately, clinical trial data was already available,” says Dr. Maciejewski, “A previous study had attempted to repurpose eltrombopag to expand its use from cytopenias to leukemia. While the study was seen as unsuccessful, its data had never been analyzed based on the TET2 mutation status.” The team grouped patients by their tumor genetics and noted that while a few had TET2 mutations, most had normal TET2 genes.”

“TET activity is crucial for efficient transcription in the cell and hence the lineage, proliferation and survival,” says Dr. Jha. “While TET2 is frequently mutated, the other TET enzymes can cover enough targets to keep the cell alive, though dysfunctional.  Only when TET2 is inactivated during mutation do the cells become malignant.  Our goal is to exploit the therapeutic window whereby the drug can be dosed to inactivate mutant cells while sparring TET2 normal ones. Such a strategy would prevent malignant expansion while protecting normal blood cell production.”

Drug repurposing, also known as drug repositioning, is a process of identifying new therapeutic uses for old, existing and available drugs. It’s an effective strategy in discovering or developing drug molecules with new pharmacological and therapeutic uses. The process of repurposing drugs, compared with the development of new drugs, is a time-saving and cost-efficient method that results in higher success rates, drastically reducing the risk of drug development, particularly for rare diseases.