A University of Utah School of Medicine-led study has identified a previously unknown but crucial component in the process to make platelets, a discovery that could help spare multiple myeloma patients from a dangerous side effect of the primary drug (bortezomib) used to treat their cancer.
In a July 25, 2014, article in The Journal of Clinical Investigation online, the researchers show that when the proteasome, which is a protein complex that breaks down the proteins that regulate cellular processes, is pharmaceutically inhibited platelet production in human and mice cells was blocked. Platelets are cells that bind together and help induce clotting to stop bleeding. The researchers also show that Fasudil, a drug approved for use outside of the United States but not in this country, restored platelet counts in adult mice whose proteasome activity had been suppressed by administering bortezomib and by knocking out a particular gene.
Andrew S. Weyrich, Ph.D., professor of internal medicine, Attilio D. Renzetti Jr. Presidential Endowed Chair and a corresponding author on the study, says giving Fasudil to multiple myeloma patients could prevent their platelet counts from dropping dangerously low, a condition known as thrombocytopenia, that’s caused by bortezomib, the drug considered to be the standard of care for the blood cancer.
“A low platelet count is a big issue for people who receive bortezomib for this cancer,” Weyrich says. “When platelet levels drops too low, it can mean interrupting treatment to allow the platelet count to recover. Fasudil potentially could help keep platelet counts normal while multiple myeloma patients receive bortezomib.”
Dean Y. Li, M.D., Ph.D., professor of medicine and vice dean for medicine at the U of U School of Medicine, is also a corresponding author on the study. First author Dallas Shi is a student in the medical school’s M.D./Ph.D. program, which Li directs and is aimed at developing physician-scientists who possess superb clinical skills and receive rigorous scientific training.
The researchers found that when the proteasome was blocked by bortezomib, platelet production was prevented in both human and mouse megakaryocytes, the cells that make platelets and their predecessor proplatelets. Megakaryocytes isolated from mice lacking the gene that encodes the proteasome also failed to produce proplatelets.
Further study showed that the megakaryocytes’ inability to make platelets was caused by the hyperactivation of RhoA, a small protein that helps megakaryocytes maintain the proper shape to produce platelets. But when the researchers gave the mice Fasudil, which inhibits RhoA, platelet production returned to normal ranges.
Although it’s not approved in the United States, Fasudil is used in Japan and elsewhere to treat cerebral vasospasms, or constricted arteries that arise as a complication of brain aneurysms. It also is in U.S. clinical trials for treating high blood pressure, diabetic macular edema and other health issues. Currently, however, no clinical trials for treating low platelet counts are taking place with Fasudil.
“If the Food and Drug Administration did approve Fasudil for use by multiple myeloma patients, it could, in principle, be moved to the clinic relatively fast in the United States,” Weyrich says.
That still could mean several years before the drug would be available on the market. But if human clinical trials bear out the results of this study, the drug probably could be made available for use by multiple myeloma patients much faster than the normal timeframe.
Multiple myeloma is a blood cancer that develops in bone marrow and affects plasma cells, which produce antibodies to help protect against infection. The National Cancer Institute (NCI) estimates that in 2011, 83,367 people in the United States were living with multiple myeloma. The NCI also estimates that 24,050 new U.S. cases will be diagnosed in 2014 and that 11,090 people will die of the disease.
- Dallas S. Shi, Matthew C.P. Smith, Robert A. Campbell, Patrick W. Zimmerman, Zechariah B. Franks, Bjorn F. Kraemer, Kellie R. Machlus, Jing Ling, Patrick Kamba, Hansjφrg Schwertz, Jesse W. Rowley, Rodney R. Miles, Zhi-Jian Liu, Martha Sola-Visner, Joseph E. Italiano, Hilary Christensen, Walter H.A. Kahr, Dean Y. Li, Andrew S. Weyrich. Proteasome function is required for platelet production. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI75247
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