7/30/2019 Recent Research Highlights Cancer Stem Cells as Moving Targets

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Recent Research Highlights Cancer Stem Cells asMoving Targets

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

Patricia Fitzpatrick Dimond, Ph.D.

According to the cancer stem cell (CSC) hypothesis, a few self-renewing stem-like cells fuel cancer. The persistence ofthese tough-to-kill cells could explain why tumors recur after successful therapy. On August 19, however, scientists atMITs Broad Institute, Tufts University, and Harvard Medical School reported that removing cancer stem cells will justprompt 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., andPiyush B. Gupta, Ph.D. Their experimental and mathematical studies, published in Cell, showed that any subpopulation oftumor 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. Thescientists said that in breast cancer, stem-cell like cells arise de novo from nonstem-cell-like cells. The research teampointed 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 andinvestors are hoping that combining anti-stem cell agents with standard treatments will more effectively kill tumors andmake sure they dont return.

Killing Enough Cells

For the research published in Cell, Dr. Landers group sorted the different cell types from each other and then grew theirrelatively pure populations for six days. Each of the three populations quickly returned to the same equilibrium, andpopulations 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 celltypes 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 ofone 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 theLander 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 underliestumor development in many cases, but its not the complete story. Studying EMT provides insight into markers that areassociated with tumor-initiating cells, but our assays dont rely on in vitro cell culture.

What we are doing is very different, emphasizing in vivo studies with patient-derived tumors and targeting the pathwayscritical 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 andnotch3 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 firms IND filing forOMP-18R5 in April.

OMP-18R5 is part of OncoMeds 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 licenseOncoMeds biologics at any point up to the end of Phase I studies.

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Insight & Intelligence : Sep 13, 2011

7/30/2019 Recent Research Highlights Cancer Stem Cells as Moving Targets

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Besides the August 19 Cellpaper, another salvo in the cancer stem cell war was lobbed on the basis of fuzzy math in2007 by Scott Kern, M.D., of Johns Hopkins Medical School, and Darryl Shibata, at the Norris Comprehensive CancerCenter at the University of Southern California Keck School of Medicine. They re-evaluated data from published studiesand related claims within awarded U.S. patents. The investigators suggested that the mathematical support for theconcept of therapeutically useful stem cells was, at that time, weak and may even invalidate the foundations of thesepublications and patent claims.

Mathematical arguments should be used more consistently, they said, because they can serve as a guide for interpretingstudies into cancer stem cells of solid tumors. The authors concluded that they personally suspected tumorigenicbehavior 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. Kerntold GEN. For example, he said, We understand the concept of stem cells in cancer, and it makes a lot of sense,particularly in leukemias, its clear that there is a cell population thats 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 thispoint, 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 thatwhile it is attractive to think of one cell type in a tumor as the major culprit in tumor survival, the emerging picture of tumorgrowth, survival, and metastasis is much more complicated. Dr. Kern noted that what was really being measured is aconcept 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 atumor 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 moleculescombined with conventional chemotherapies that kill other cancer cells may provide an effective way to get at intractablecancers.

Patricia F. Dimond, Ph.D. (drpdimond@comcast.net ), is a principal at BioInsight Consulting.

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