Targeting Blood Cancers at the Source
Recent identification of cells with stem cell-like properties in solid tumors including breast, brain, lung, and prostate cancer has generated considerable excitement in the cancer research community. Scientists now believe that these cells - which can both self renew to maintain the population of stem cells and produce more differentiated progenitor cells which make up the bulk of a tumor - may play a role in the formation, recurrence, and metastasis of many solid cancer types and present a target that must be eradicated to potentially produce a cure.
This research in solid tumors is only now beginning to accelerate, but investigators studying cancers of the blood have known about the existence of cancer stem cells in these malignancies for over a decade, and tactics for destroying stem cells in hematologic cancers have begun to make their way into early human trials.
Cancer stem cells are thought to be at the root of therapeutic resistance for many hematologic cancers. For example, chronic myelogenous leukemia (CML) responds to treatment with the targeted drug imatinib, but patients inevitably relapse when they stop taking the drug, and many patients' cancers progress even during treatment.
Researchers speculate that resistance of CML stem cells to imatinib is due to their quiescence, a state of relative dormancy where the cells do not divide, protecting them from both traditional chemotherapy, which targets rapidly dividing cells, and therapies such as imatinib that target cell-signaling pathways.
"Slow cycling [of cancer stem cells] is probably one of the biggest challenges that we face in terms of targeting for therapy," says Dr. John Dick, director of the Program in Stem Cell Biology at the University of Toronto, whose laboratory first identified cancer stem cells in acute myeloid leukemia in 1994.
One approach to addressing this challenge has been to "wake up" the cancer stem cells - to force them to divide and enter the cell cycle. This idea is being tested by the United Kingdom's National Cancer Research Network, whose GIMI trial is based on the observation that granulocyte-colony stimulating factor applied intermittently to leukemia stem cells in vitro could stimulate them to proliferate, thus increasing their sensitivity to imatinib.
This approach is also being tested at Johns Hopkins University. "We're trying to bring the immature stem cells to maturity, to induce them to differentiate into mature cells," explains Dr. Carol Ann Huff, assistant professor of oncology at Johns Hopkins, whose group is working with granulocyte-macrophage colony stimulating factor in conjunction with cell cycle inhibitors in both myelodysplasia and leukemia.
But Dr. Huff's clinical trials group is also looking at another tactic - taking advantage of the differences between cancer stem cells and "normal" cancer cells, "to actually eradicate the quiescent cancer cells" rather than bring them into the cell cycle, she explains.
"One of the things we've learned in leukemia and multiple myeloma is that agents that are active against the differentiated cells have little effect on leukemia or myeloma stem cells and vice versa," she says. "We believe that's part of the reason why we haven't been able to eradicate the stem cells with the current drugs that we have." Dr. Huff and her colleagues are now testing combination therapies with drugs known to reduce the bulk of circulating tumor cells - such as imatinib in CML or cyclophosphamide in multiple myeloma - and drugs with particular affinity for cancer stem cells, such as rituximab in multiple myeloma, which targets a protein expressed on the surface of the stem cells but not the bulk of the cancer cells.
Additional research into the unique molecular properties of cancer stem cells is needed, explains Dr. Dick, to advance such targeted treatment regimens. "We need to understand their properties," he says. "We need to understand what the mechanisms are that make them resistant to therapy, and...we need to understand the self-renewal mechanisms in these cells, because in the end that's the one property I think everyone would accept that a cancer stem cell has - the ability to renew itself in perpetuity. That's what makes the cancer stem cell so potent and really so different from the other cells in the tumor."