Hematologic oncologist Ravi Bhatia, M.D., wants to nip leukemia in the bud. As director of City of Hopes nascent Department of Hematopoietic Stem Cell & Leukemia Research, Bhatia is battling leukemia by focusing on leukemic cells' very beginnings – when they are stem cells.
"We now recognize that several, if not all, leukemias arise from leukemia stem cells," Bhatia said. "This suggests that eradicating leukemia in a patient means we have to eliminate the leukemia stem cell population in the patient – and that simply targeting mature cells is not likely to be curative."
With this in mind, Bhatia and his colleagues in the new department are pursuing several projects to learn more about leukemia stem cells on several fronts. Their ultimate goal: to translate discoveries about the mechanisms of leukemia stem cell development and survival into targets for novel drugs and therapies.
Already, in the lab, he and fellow researchers are seeking out telltale markers of leukemia in hematopoietic stem cells, the progenitor cells that give rise to blood cells. And in the clinic, the scientists are gathering information from hundreds of patients to discover the still-mysterious factors that encourage leukemia to develop.
"Patients are very supportive of our investigations," Bhatia said.
Although medical scientists recognize several types of leukemia, the types have a common thread: a large number of abnormal blood cells. A hallmark of these abnormal, cancerous cells is that they divide rapidly – and rapid cell division is what makes cancerous cells vulnerable to chemotherapy.
But, as Bhatia noted, patients with leukemia not only have mature leukemia cells in their bodies, they also have leukemia cells that are still in their first, primitive stages: leukemia stem cells. These leukemia stem cells may successfully evade chemotherapy because they develop slowly or may even be dormant. In a sense, they can hibernate through treatment, only to awake, develop and multiply later.
To come up with ways to battle the leukemia stem cells, the scientists must understand what makes the cells tick. For one, do the cells have an innate ability to thrive without the support of stroma, the nurturing environment usually critical to normal stem cells? If so, that may give clues on the cells’ survival abilities. And for another, are certain signaling pathways critical to the cells’ maturation? If that is the case, interfering with the pathways may keep the cells in check.
Also, if scientists can figure out what separates leukemia stem cells from normal ones, they may be able to develop tests to detect leukemia stem cells in the body through bone marrow biopsy or even blood tests in some cases. Today, City of Hope scientists are eagerly pursuing a number of markers that hold potential as key clues of leukemia. Not only might they be used for diagnostics, but they also could provide targets for new therapeutics, as well, Bhatia noted.
Besides laying the foundation for potential new drugs in the next decade, the scientists also are pursuing improved treatments in the next few years. For instance, researchers are designing a clinical trial to evaluate whether providing existing, available growth factors to leukemia patients will wake up potentially dormant leukemia stem cells and make the leukemia stem cells more vulnerable to chemotherapy’s cancer-killing effects.
Bhatia and his partners also search for the very origins of leukemia development. With his wife and collaborator, Smita Bhatia, M.D., M.P.H., chair of the Division of Population Sciences, Bhatia is studying the early events leading to stem cell transformation and mechanisms of susceptibility – that is, the genetic and environmental factors that lie at the core of leukemia’s development. Intriguingly, they are drawing on patients with a different hematologic cancer to look for answers.
Because as many as 10 percent of patients with Hodgkin’s or non-Hodgkin’s lymphoma who are treated through autologous hematopoietic (blood) cell transplantation (HCT) eventually develop leukemia, the research team believes this population provides a vast window into the mechanisms of leukemia.
The researchers already have recruited about 300 City of Hope patients with Hodgkin’s or non-Hodgkin’s lymphoma treated through autologous HCT, and they plan to recruit another 200 over the next two years. Scientists extensively test patients before and after treatment and monitor them for five years. Besides studying cells and looking at patients' exposure to chemotherapy, they also ask patients about factors such as family history and ethnicity. Researchers will compare those who develop leukemia to those who do not.
DNA analysis should help. Examining single nucleotide polymorphisms, or SNPs, “we’ll be looking for gene duplications and gene deletions," Ravi Bhatia said. “We hope to understand how agents damage DNA, how mutations develop and how they are passed along."
The National Cancer Institute funds the project through the Lymphoma SPORE. The project also includes collaborators from the Fred Hutchinson Cancer Research Center in Washington in addition to 10 City of Hope researchers.
"These are just a few of the directions we’re headed," Ravi Bhatia said. “We have great hope that we can build a program of excellence in basic and translational hematopoietic stem cell and leukemia biology and provide the infrastructure to translate novel therapeutic approaches from the laboratory to the clinic."