Box 1. More repurpose.


An Indiana University School of ­Medicine team has shown that the diabetes drug Januvia sitagliptin can enhance the recovery of hematopoietic stem and progenitor cells after chemotherapy or radiotherapy.2 The group is now working out the timing and dosing of the dipeptidyl peptidase-4 (DPP-4) inhibitor in the new indication.

A number of proteins involved in ­hematopoiesis have DPP-4 truncation sites, which are sites that are cleaved by the peptidase. Previous studies by the Indiana team showed that DPP-4 inhibition can block this truncation and improve a protein's activities. Thus, they wanted to see whether genetic or pharmacological disruptions of DPP-4 would enhance recovery of hematopoietic stem cells (HSCs) after radiation or ­chemotherapy.

Indeed, Dpp-4 knockout mice receiving chemotherapy or radiotherapy showed greater hematopoietic progenitor cell (HPC) recovery than wild-type mice receiving the same treatments. In wild-type mice receiving radiation or chemotherapy, pretreatment with Januvia increased HPC and HSC recovery in bone marrow compared with vehicle pretreatment.

Results were published in Nature Medicine.

Merck & Co. Inc. and Ono Pharmaceutical Co. Ltd. market Januvia to treat type 2 diabetes.

"Our immediate ongoing efforts are focused on identifying the best timing and dosing of sitagliptin and other DPP-4 inhibitors in mice to enhance recovery of neutrophils and platelets after radiation, chemotherapy or stem cell transplantation," said Hal Broxmeyer, lead author and professor of microbiology and immunology at the Indiana University School of Medicine.

His lab's overarching efforts are focused on DPP-4 truncation. "A number of biological molecules active on many different cells, tissues and organs have putative DPP-4 truncation sites," he said. "Our team wants to understand the potential implications of what the truncated molecules may do and what DPP-4 inhibition in these systems may mean. It is our belief that DPP-4 and its inhibition will have far-reaching implications to biology in general, not just for hematopoiesis."

The university has filed for patents covering the use of DPP-4 inhibitors to improve recovery of neutrophils and platelets after radiation, chemotherapy or stem cell transplantation. The findings are not licensed. -TB