Now researchers at the Abramson Cancer Center of the University of Pennsylvania have found a way around this problem. By disabling a BCR-ABL1-associated enzyme called Lyn kinase, they have induced cell death in drug-resistant CML cells taken from CML patients. Normal blood cells do not appear to be harmed by this approach because they are not so dependent on the Lyn kinase as CML cells. The Lyn kinase is therefore a good candidate for a targeted therapy.
"We know that patients treated with Gleevec can develop mutations in the BCR-ABL1 protein," explains Alan M. Gewirtz, MD, Professor of Medicine in Penn's Division of Hematology/Oncology. "Once the BCR-ABL1 gene mutates, Gleevec can no longer combine with the BCR-ABL1 protein, so it remains active, and the cancerous blood cells survive and grow." Gewirtz and colleagues' research appears in the November issue of Nature Medicine.
"Lyn kinase is a member of a family of proteins that we know plays a role in cell survival, growth, and development," explains Gewirtz. "CML cells, especially those that arise in Gleevec-resistant patients, are very dependent on its function." To disable it, the researchers used short interfering RNA (siRNA) to "silence" the gene that codes for the Lyn kinase protein.
An siRNA is a short, double-stranded piece of RNA with a unique chemical sequence, or tag, that allows it to combine specifically with a particular messenger RNA (mRNA) that shares the same tag. After the siRNA is introduced into a cell it attaches to the mRNA whose tag it shares, and this targets the mRNA for destruction using a natural disposal system present in all cells. Without an mRNA to direct the production of Lyn kinase protein, the Lyn gene is effectively shut down, or "silenced." With Lyn out of the picture, the cancer cell dies.
"We hope that this therapy will be able to enter the clinic rapidly, perhaps even within the next couple of years," say Gewirtz. "The basic methodologies are in place but an siRNA molecule still needs FDA approval."
Andrezej Ptasznik, Yuji Nakata, Ann Kolata, and Stephen G. Emerson from Penn were all co-authors on the paper. This research was funded in part by grants from the Doris Duke Charitable Foundation, the National Institutes of Health, and the Leukemia and Lymphoma Society.
This release can also be found at: www.uphs.upenn.edu/news
The Abramson Cancer Center of the University of Pennsylvania was established in 1973 as a center of excellence in cancer research, patient care, education and outreach. Today, the Abramson Cancer Center ranks as one of the nation's best in cancer care, according to U.S. News & World Report, and is one of the top five in National Cancer Institute (NCI) funding. It is one of only 39 NCI-designated comprehensive cancer centers in the United States. Home to one of the largest clinical and research programs in the world, the Abramson Cancer Center of the University of Pennsylvania has 275 active cancer researchers and 250 Penn physicians involved in cancer prevention, diagnosis and treatment.
PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation's first integrated academic health system).
Penn's School of Medicine is ranked #3 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three owned hospitals [Hospital of the University of Pennsylvania, which is consistently ranked one of the nation's few "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
Journal
Nature Medicine