In clinical trials, ibrutinib has often shown exceptional activity in people with chronic lymphocytic leukemia (CLL). The agent targets a molecule called Bruton's tyrosine kinase (BTK). It permanently incapacitates the molecule, and this stops the transmission of an important signal that promotes cell growth and proliferation.
But ibrutinib also inhibits other molecules in CLL cells. Like BTK, these molecules are proteins called kinases, and they might be important for CLL-cell survival, the researchers say.
"Ibrutinib's lack of selectivity might mean that BTK is not the critical target in CLL, and that future drugs developed for CLL should focus on other molecules," says principal investigator Amy Johnson, PhD, associate professor of medicine in the division of hematology, and an OSUCCC - James researcher.
However, the findings, published in the journal Blood, validated BTK inhibition.
"This study shows that BTK is an important therapeutic target in CLL," says first author Jennifer Woyach, MD, assistant professor in the division of hematology and an OSUCCC - James researcher. "Inactivating BTK alone delayed CLL development in a mouse model, confirming that BTK is a clinically important target in CLL. This suggests that development of selective BTK inhibitors - in addition to multi-kinase inhibitors like ibrutinib - is reasonable in CLL."
To investigate the role of BTK in CLL, Johnson, Woyach and their colleagues used CLL cells from patients and two CLL mouse models, one of which spontaneously develops a malignancy very similar to human CLL. The researchers blocked BTK activity two ways: genetically and pharmacologically, using ibrutinib.
Key findings included:
"Overall," Johnson says, "our findings validate BTK as a target for CLL therapy and strongly suggest that selective kinase-inhibitors might work in CLL like the drug imatinib does in chronic myeloid leukemia."
Funding from the Leukemia and Lymphoma Society, D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, Harry Mangurian Foundation, the NIH/National Cancer Institute (grants CA140158, CA133250-05, CA177292, CA095426) and the Italian Association for Cancer Research (grant AIRC IG_12939) supported this research.
Other researchers involved in this study were Amy S. Ruppert, Matthew R. Stefanovski, Virginia M. Goettl, Kelly A. Smucker, Lisa L. Smith, Jason A. Dubovsky, William H. Towns, Jessica MacMurray, Melanie E. Davis, Bonnie K. Harrington and John C. Byrd, The Ohio State University; Engin Bojnik, Stefania Gobessi and Dimitar G. Efremov, International Centre for Genetic Engineering & Biotechnology, CNR Campus, Rome; Luca Laurenti, Catholic University Hospital, Rome; and Betty Y. Chang and Joseph J. Buggy, Pharmacyclics.
The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 228-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S.News & World Report.
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