August 28, 2013 | by Nicole White
Just as stem cells generate bone marrow and blood cells, while maintaining their constant production, leukemia has its own stem cells. These cancer-generating cells are tough to kill – and tend to be resistant to treatment.
A new City of Hope study, published in Blood, found that a combination treatment can effectively block the signaling molecules that protect the stem cells in acute myeloid leukemia (AML), while also making them more susceptible to chemotherapy. Researchers are now enrolling participants for a human clinical trial of the approach.
“Targeting one pathway is not enough,” said Ravi Bhatia, M.D., director of City of Hope’s Division of Hematopoietic Stem Cell and Leukemia Research. Although patients can go into remission despite the survival of some of their leukemia stem cells, they stand a heightened chance of relapse.
“We think this approach in which we use these drugs in combination with existing therapy is going to be very important in increasing the number of patients who go into remission and stay in remission,” Bhatia said.
The study examined two types of signaling molecules: a family of kinases connected to the SRC gene, plus the receptor tyrosine kinase c-Kit. The study found that both types of signaling molecules play a role in stem cell survival in AML, and contribute to the survival and proliferation of the leukemia stem cells.
A drug known as dasatinib can inhibit these signaling molecules, but when used alone to reduce the growth of stem cells, its effect was moderate, Bhatia said.
However, combined with chemotherapy, dasatinib could be a potent weapon in the arsenal against this type of leukemia, the study found.
City of Hope researchers studying the tumor microenvironment found that a gene known as P-53 plays a crucial role in regulating the response to chemotherapy. The gene detects the stability of DNA in a cell and, when the DNA is damaged, signals that the cell should die. In AML, this gene seems to be inactive; desatinib appears seems to be able to turn on the gene. The gene is then able to signal cells to die when they are damaged by chemotherapy drugs.
“This enhances the effect of chemotherapy on leukemia stem cells,” Bhatia said. “It works in the test tube, and in animal models. Based on these, we’re going to pursue this in patients by giving them desatinib in combination with chemotherapy. The idea is that this drug will sensitize them to the chemotherapy, and we’re going to get better killing off of the leukemia stem cells as a result of the combination.”
Increased understanding of the dynamics within the microenvironments around tumors and stem cell therapies will play an important role in future leukemia treatments.
“Patients should know that there are a number of studies already showing promise in the lab, and that early clinical trials are in the pipeline,” he said. “Leukemia and lymphoma can be challenging diseases, but there are exciting new options being tested.”