When Gleevec is not enough: Jackson Laboratory researchers demonstrate value of "helper" compound in treating some leukemias
| Date: November 7, 2006 |
Bar Harbor, Maine -- The aberrant Philadelphia chromosome is not a problem local to Philadelphia, but that's where researchers discovered the genetic mutation that's the root cause of some leukemias, including chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). Led by Associate Staff Scientist Shaoguang Li, M.D., Ph.D., researchers at The Jackson Laboratory, in collaboration with scientists at Bristol-Myers Squibb Oncology, are discovering startling new information about the mechanisms of Philadelphia-positive (Ph+) leukemias that will affect how they are treated clinically.
The Philadelphia Chromosome is actually a faulty mixture of two chromosomes, 9 and 22, which typically work perfectly well independent of each other. But in rare circumstances they physically exchange genetic material in a specific way, and the combined Philadelphia chromosome merges two harmless genes into something destructive. The resulting protein, called BCR-ABL, unleashes a cascade of events that ultimately leads to unregulated cell proliferation in blood cells, leading to Ph+ leukemia.
Bone marrow transplants can cure these leukemia patients, but the procedure could be risky, and sufficiently compatible donors often cannot be found. Therefore the drug imatinib mesylate (sold by the pharmaceutical company Novartis as Gleevec), which disables the destructive function of the BCR-ABL protein, represented a huge step forward in treatment, especially for CML in chronic phase. Imatinib doesn't cure CML, but it inhibits the deadly cascade launched by BCR-ABL, and most patients can use it to better manage the disease with minimal side effects.
While imatinib helps many human patients, Li is using mice with the equivalent of the Ph+ leukemias to investigate why some do not respond to it. Also, imatinib has little positive effect for Ph+ leukemia patients that have progressed to blast crisis, the phase during which the cancer cells undergo additional changes that lead to their out-of-control reproduction. Progression to blast crisis currently necessitates a bone marrow transplant for survival.
"Sometimes the BCR-ABL protein itself has a mutation, which makes it less susceptible to imatinib," said Li. "But in some patients who do not respond to imatinib, there's no imatinib-resistant mutations detected and the disease still progresses. No one understood how that happens when the known disease cascade is inhibited."
In research published in online in the Proceedings of the National Academy of Sciences, Li's team discovered is that imatinib does not inactivate all BCR-ABL signaling pathways in the cascade. Part of the cascade, proteins called SRC kinases, are still activated by BCR-ABL in imatinib-treated mouse leukemic cells. When Li treated the mice with a compound, dasatinib, that inhibits the SRC proteins as well as BCR-ABL, he found that not only was it more effective for CML, but it also led to complete B-ALL remission.
While these results are encouraging, a small population of leukemic cells (fewer than 1 percent) persisted through treatment with imatinib or dasatinib and led to a recurrence of the leukemia. These cells, leukemic stem cells, present an additional challenge.
"These results show that clinicians need to address SRC kinase activity as well as BCR-ABL to get the best outcomes with Ph+ leukemia," said Li, "but it's not a real cure. The keys to a cure for Ph+ leukemia are the leukemic stem cells, and we've now isolated them in the mouse for the first time. We will be working hard to figure out how to target and eradicate them."
The research was supported by grants from the Linda Tallen David Kane Cancer Education & Research Foundation, the Irving A. Hansen Foundation, the U.S. Department of Defense, the National Cancer Institute, and the Maine Cancer Foundation.
The Jackson Laboratory is an independent, nonprofit research institution based in Bar Harbor, Maine, with facilities in West Sacramento, Calif. Its research staff of more than 450 investigates the genetic basis of cancers, heart disease, osteoporosis, Alzheimer's disease, glaucoma, diabetes, and many other human diseases and disorders, as well as normal mammalian development and bioinformatics. The Laboratory is also the world's source for nearly 3,000 strains of genetically defined mice, home of the Mouse Genome Database and many other publicly available information resources, and an international hub for scientific courses, conferences, training and education.
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