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Inhibition of enzyme could lead to improved chemotherapy and stem cell transplant results

Blocking the action of one enzyme could mean improved results for thousands of cancer patients who undergo bone marrow or cord blood transplants after chemotherapy, an Indiana University research team has reported.

Moreover, the enzyme — dipeptidylpeptidase 4, or DPP4 — can be blocked by sitagliptin, marketed by Merck and Co. as Januvia, a drug already on the market and approved for use in treating Type 2 diabetes.

“By blocking the activity of this enzyme, we believe there is potential to improve the activity of a variety of important compounds that could lead to improved outcomes for these procedures,” said Hal E. Broxmeyer, Ph.D., Distinguished Professor and professor of microbiology and immunology at the IU School of Medicine.

The research was published online this week by the journal Nature Medicine.

For many cancer patients, suppression of bone marrow activity is an unwelcome side effect of undergoing chemotherapy treatment. Other patients may undergo chemotherapy treatments meant to destroy the blood-producing stem cells in the bone marrow to eliminate the source of the cancerous cells. Those patients receive replacement stem cells either from bone marrow transplants or transplants using blood from umbilical cords.

The transplant procedures depend on the stem cells’ “homing” ability to find their way to the bone marrow compartments to restore the patients’ ability to produce vital blood and immune system cells. Already risky procedures, the cord blood transplants are also complicated by the relatively few number of stem cells available from the small amount of cord blood that can be used, especially when the recipients are adults.

In earlier work, Dr. Broxmeyer and his colleagues found that the DPP4 enzyme truncated an important compound — stromal cell-derived factor-1, or SDF-1 — that plays a role in helping the transplanted stem cells engraft into the patients’ bone marrow. In its truncated form, SDF-1 is much less effective. In the earlier work, the IU researchers determined that preventing DPP4 from truncating SDF-1 resulted in more efficient stem cell engraftment.

In the Nature Medicine paper, the researchers reported that in laboratory and animal model experiments, DPP4 also acted to truncate other compounds that are important when the transplanted stem cells reconstitute the bone marrow and begin the process of producing blood and immune system cells, called hematopoiesis.

The results suggest that blocking DPP4 could help patients’ bone marrow bounce back from chemotherapy treatment and stem cell transplants.

Additional research is needed to optimize sitagliptin for this use, and to conduct clinical trials to determine its effectiveness in patients, Dr. Broxmeyer said.

In addition to the hematopoietic proteins affected, important proteins in other cell and organ systems in the body also have truncation sites that could be targeted by DPP4, suggesting more research is needed to determine whether the enzyme may play a role in other cell systems and diseases, Dr. Broxmeyer said.

In addition to Dr. Broxmeyer, the first author, other scientists involved in the research were Heather A. O’Leary, Ph.D.; Charlie Mantel, Ph.D.; Brahmananda R. Chitteti, Ph.D.; Scott Cooper, Ph.D.; Steven Messina-Graham; Giao Hangoc, Ph.D.; Sherif Farag, M.D., Ph.D.; Sara L. Rohrabaugh; Xuan Ou, Ph.D.; Jennifer Speth; Louis M. Pelus, Ph.D.; Edward F. Srour, Ph.D., all of the IU School of Medicine; Jonathan Hoggatt, Ph.D., Massachusetts General Hospital; and Timothy B. Campbell, M.D., Ph.D., University of California, San Francisco. The work by Hoggatt and Campbell was performed while they were graduate students at the IU School of Medicine.

The research was supported by grants from the National Institutes of Health (R01 HL056416, R01 HL067284 and R01 HL112669, T32 DK07519, T32 HL07910, RR25 GM079657, a Center of Excellence in Hematology grant P01 DK090948, and HL69669 and HL96305).