• Preventing Cancer Recurrence

    Disrupting Stem Cells Could Halt Cancer Spread

    As terrible as a cancer diagnosis can be, even more devastating are the words, “Your cancer has relapsed.”

    Oncologists know all too well that many cancers surge back despite initial success from surgeries, radiation treatments and chemotherapy. Relapses occur even among patients who have lived for several years in complete remission.

    The question facing the research community has been, “Why?”

    Recent research into the inner workings of cancer cells might hold the answer. Some scientists contend that cancer stem cells find ways to avoid or survive initial treatment, then begin churning out new cancer cells to replace those destroyed by treatment.

    Researchers at Cincinnati Children’s are working on ways to target and kill cancer stem cells — or at least disrupt their function. If successful, this work may lead to longer remissions for more children and adults with cancer. For some, the new approach might even cure their cancer.

    What is a Cancer Stem Cell?

    The cancer stem cell theory asserts that the maintenance of cancer is driven by a small subset of cancer cells that possess stem cell-like properties. There are various kinds of cancer stem cells, but they are the only cells that can initiate tumor growth.

    Exactly how these cells cause cancer relapse is not fully understood. The stem cells may go dormant, avoiding drugs that attack fast-dividing “daughter” cells. They may lack key receptors that make them virtually invisible to chemotherapy agents. Or they may hide in microenvironments that treatments simply cannot reach.

    One way or another, once treatment begins destroying the most common cancer cells, the cancer stem cells survive treatment to re-activate and churn out more cancer cells. In many cases, the new generations are highly resistant to follow-up treatment.

    New Weapon Against All

    Much of the early work on cancer stem cells has occurred in leukemia.

    “Most chemotherapy agents kill cancer cells while they are dividing. Dormant stem cells are not well-targeted,” says Jose Cancelas, MD, PhD. “But even dormant cells have needs. So to kill them, we need to find and block those needs.”

    Cancelas directs research at the Hoxworth Blood Center, which is affiliated with the University of Cincinnati Medical Center, and he leads the cancer stem cell program at Cincinnati Children’s. An expert in blood cancers, Cancelas studies the microenvironments where cancer stem cells live. He focuses on signaling proteins called Rac-GTPases, which play a role in regulating how cancer cells migrate.

    Blocking the function of Rac-GTPases could prevent cancers from metastasizing. However, previous versions of blocking compounds have proven too toxic to serve as effective treatments.

    Now Cancelas and colleagues may have uncovered a new approach. In a paper published online in June 2012 in the journal Blood, Cancelas’ team, in collaboration with researchers in the laboratory of Yi Zheng, PhD, reported on a new molecular pathway. The Vav3 pathway plays an important role in cell proliferation in acute lymphoblastic leukemia (ALL), but has a minimal role in non-cancerous cells.

    In addition to identifying this important pathway, the research team identified a small-molecule agent that can block it. They are testing the agent in “humanized” mice, which are bred to exhibit human forms of cancer by a colleague at Cincinnati Children’s, James Mulloy, PhD.

    “So far, the therapy has been effective in mouse models. But there is still a long way to go before it can be ready for human clinical trials,” Cancelas says.

    If a drug can be developed to control the Vav3 pathway, Cancelas predicts it would be used in combination with existing chemotherapies, rather than as a first-line treatment. And preventing relapse in people with ALL may be just the beginning.

    “Cancer stem cell target therapies, if proven to be successful against one type of cancer, could revolutionize how we do therapy for many kinds of cancer," "Cancer stem cell target therapies, if proven to be successful against one type of cancer, it could revolutionize how we do therapy for many kinds of cancer." Cancelas says.

    Exploring RNA Therapeutics

    In a related effort to prevent cancer recurrence, Lee Grimes, PhD, and colleagues at Cincinnati Children’s are studying how to use microRNA therapy as a weapon against cancer – especially against rare and powerful forms of acute myeloid leukemia (AML) that strike during infancy.

    Grimes directs the Cancer Pathology Program at Cincinnati Children’s and co-leads the program in Hematologic Malignancies with Mulloy. Much of Grimes’ translational work is funded by the National Institutes of Health and the Leukemia and Lymphoma Society of America.

    In the past 15 years, microRNAs (miRNAs) have emerged as important regulators of gene expression. Abnormal levels of miRNA have been linked to several forms of cancer, as well as other diseases. Such findings have triggered a global race to develop compounds that can control miRNA expression.

    Grimes is working on a potential RNA therapy that could help infants born with mutations involving the 11q23 chromosome. Unlike adult-onset leukemia, AML strikes children with these gene mutations during infancy. Their cancers are so strong that the patients are much less likely to survive, even with stem cell transplants and other advanced therapy.

    Grimes and colleagues identified a signaling pathway that regulates oncoproteins related to infant-onset AML. They also learned that the pathway can be blocked by a specific gene, Gfi1, which encodes a protein that represses the expression of other genes. Years of work have since con-firmed the pathway and the repressor function in fruit flies, mice and humans.

    In humans, the Gfi1 repressor itself cannot yet be affected by drug therapy. However, the researchers have identified microRNA inhibitors that can mimic Gfi1 repressor function. “We have found that antagonists of these microRNA, as a surrogate for the transcriptional repressor, can actually cure the leukemia in the mouse model,” Grimes says.

    The next step is to test the RNA therapy in “humanized” mice to determine its potential for clinical use. The team also is studying whether this microRNA inhibitor also can be used against adult leukemias.

    Promising cancer treatments take time, money

    Yi Zheng, PhD, director, Division of Experimental Hematology and Cancer Biology, leads an institution-wide hunt for small-molecule inhibitors that can disrupt the function of cancer stem cells. The team has already found several potential candidates.

    In 2004, the Zheng lab discovered a first-generation small inhibitor against Rac-GTPases that was later shown to work against leukemia stem cells in mouse models. In 2008, Zheng presented early findings at the American Society of Hematology that a lead drug candidate dubbed “CASIN” – a Cdc42 small-molecule inhibitor – plays a role in mobilizing normal blood stem cells from bone marrow into the bloodstream. Since then, Zheng and colleagues have reported that CASIN also helps push leukemia-initiating cells into the bloodstream, where they become much more vulnerable to chemotherapy. Cincinnati Children’s is working to further develop this potential treatment, which could make stem cell transplants much more effective.

    Meanwhile, in June 2012, Zheng and colleagues reported in Chemistry & Biology that in laboratory tests, a lead drug candidate dubbed “Rhosin” stopped breast cancer cells from spreading. The inhibitor targets RhoA, one component of a family of cell signaling proteins known as Rho-GTPases. These proteins help regulate cell movement and growth throughout the body. Rhosin is one of several projects using innovation funds from Cincinnati Children’s to move promising therapies closer to human clinical trials.

    Now, Zheng and colleagues are studying another lead compound, dubbed Y16, that appears to work in conjunction with Rhosin to further disrupt cancer cell signaling. New findings related to this research were published in the journal Proceedings of the National Academy of Sciences (PNAS) in February.

    Despite the promise these treatments show, the challenge remains to find the funding to move these discoveries beyond the lab.

    “Institutional support has become very important to move lead candidates toward commercialization. We are fortunate that Cincinnati Children’s has the vision to provide such support,” Zheng says. “Going from the lab to clinical trials requires enormous resources.”

    Zheng cautions that it will take several years for any of these drugs to reach market. He also predicts that none will be the single magic bullet that can wipe out cancer.

    “This is a very dynamic and complicated process. Not all cancer stems cells are the same. Some are more potent than others, some are more sensitive to drugs than others, and by the time you find a promising treatment, the cancer mutates,” Zheng says. “Now our goal is combination therapy. Instead of one magic bullet, we will need lots of different magic bullets.

  • Dr. Lee Grimes.

    Dr. Lee Grimes.