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Sep 13, 2011

Recent Research Highlights Cancer Stem Cells as Moving Targets

Drug developers hope that combining therapies will reduce cell population plasticity in cancers.

Recent Research Highlights Cancer Stem Cells as Moving Targets

Treating tumors boils down to how best to get rid of all the cells in a tumor [© KaYann - Fotolia.com]

  • According to the cancer stem cell (CSC) hypothesis, a few self-renewing stem-like cells fuel cancer. The persistence of these tough-to-kill cells could explain why tumors recur after “successful” therapy. On August 19, however, scientists at MIT’s Broad Institute, Tufts University, and Harvard Medical School reported that removing cancer stem cells will just prompt other cell types in the tumor to convert into CSCs to renew the population.

    Results could have significant implications for cancer cell therapy, claim lead researchers Eric S. Lander, Ph.D., and Piyush B. Gupta, Ph.D. Their experimental and mathematical studies, published in Cell, showed that any subpopulation of tumor cells returns eventually to equilibrium phenotypic proportions over time.

    More problematic for the idea of targeting CSCs to treat cancer is a second prediction arising from the research. The scientists said that in breast cancer, stem-cell like cells arise de novo from nonstem-cell-like cells. The research team pointed out that the notion that CSCs can only occur by self-renewal may be wrong.

    Despite this information, and plenty of conflicting opinions about the existence of true cancer stem cells, researchers and investors are hoping that combining anti-stem cell agents with standard treatments will more effectively kill tumors and make sure they don’t return.

  • Killing Enough Cells

    For the research published in Cell, Dr. Lander’s group sorted the different cell types from each other and then grew their relatively pure populations for six days. Each of the three populations quickly returned to the same equilibrium, and populations of nonstem cells generated new stem-like cells.

    The return to equilibrium process occurs so fast that it cannot occur as a result of different growth rates of the different cell types but must instead be due to cells changing their states. The authors showed that the process can be modeled and accurately predicted using a mathematical tool called a Markov model, in which cells change their states independently of one another. Although the process is completely decentralized, it quickly returns to the same equilibrium, the authors said. The model also predicted that nonstem cells can convert into stem-like cells, they added.

    GEN asked Paul J. Hastings, president and CEO of OncoMed, which is focused on CSCs, what the potential impact of the Lander paper might be on targeted cancer stem cell therapeutics.

    “We are very pessimistic about trying to compare targeting biological process like EMT (epithelial mesenchymal transition) to our approach to targeting cancer stem cells,” Hastings said. “EMT appears to be part of the process that underlies tumor development in many cases, but it’s not the complete story. Studying EMT provides insight into markers that are associated with tumor-initiating cells, but our assays don’t rely on in vitro cell culture.

    “What we are doing is very different, emphasizing in vivo studies with patient-derived tumors and targeting the pathways critical for tumor-initiating cells directly with monoclonal antibodies. We think that combining our approach with others, including chemotherapeutic agents and other small molecule therapies targeting key oncogenic pathways, will be useful.

    “There is no holy grail, and we are all going to find out how these things work when we put them into the clinic. Hopefully, they will either someday improve survival, cure patients, or increase the time to disease progression until relapse.”

    OncoMed reportedly has three clinical-stage CSC-targeting candidates: Phase I OMP-59R5, which inactivates notch2 and notch3 signaling; Phase I OMP-21M18, which blocks delta-like 4 ligand (DLL4), an activator of notch signaling; and OMP-18R5, an antibody that blocks selected receptors in the Wnt signaling pathway. FDA accepted the firm’s IND filing for OMP-18R5 in April.

    OMP-18R5 is part of OncoMed’s collaboration with Bayer HealthCare Pharmaceuticals inked in 2010. It is valued at $387.5 million per program and covers stem cell antibodies and protein therapeutics targeting the Wnt signaling pathway. The advancement of OMP-18R5 into the clinic triggers a $20 million milestone payment. Bayer has the option to license OncoMed’s biologics at any point up to the end of Phase I studies.

    Besides the August 19 Cell paper, another salvo in the cancer stem cell war was lobbed on the basis of “fuzzy math” in 2007 by Scott Kern, M.D., of Johns Hopkins Medical School, and Darryl Shibata, at the Norris Comprehensive Cancer Center at the University of Southern California Keck School of Medicine. They re-evaluated data from published studies and related claims within awarded U.S. patents. The investigators suggested that the mathematical support for the concept of therapeutically useful stem cells was, at that time, “weak and may even invalidate the foundations of these publications and patent claims.”

    Mathematical arguments should be used more consistently, they said, “because they can serve as a guide for interpreting studies into cancer stem cells of solid tumors.” The authors concluded that they personally suspected “tumorigenic behavior might be a varying probabilistic potential for all tumor cells rather than a quantal and deterministic feature of a minority of tumor cells. A definition of ‘solid tumor stem cells’ may evade us for some time.”

    As long as the definition of a stem cell remains vague, neither proof nor disproof are allowed in the discussion, Dr. Kern told GEN. For example, he said, “We understand the concept of stem cells in cancer, and it makes a lot of sense, particularly in leukemias, it’s clear that there is a cell population that’s going to maintain the cancer.

    “But what has happened over the last five years is that people have tried to extend this into solid cancers. And at this point, we draw the line; the evidence is weak once you move to solid tumors.”

    The August 19 paper, combining solid experimental evidence and some very unfuzzy math, supports the concept that while it is attractive to think of one cell type in a tumor as the major culprit in tumor survival, the emerging picture of tumor growth, survival, and metastasis is much more complicated. Dr. Kern noted that what was really being measured is a concept that cell biologists have been aware of for some time: the inherent plasticity of cell populations.

    Ultimately, though, discussions about cell type plasticity in tumors boils down to how best to get rid of all the cells in a tumor and finding therapeutics that can either kill them permanently or prolong the time to tumor progession. While CSCs may be moving targets, focusing on them with specific therapies such as anti-CSC antibodies or small molecules combined with conventional chemotherapies that kill other cancer cells may provide an effective way to get at intractable cancers.


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