Killing Cancer
CSC Primer
Regular stem cells are prized for their ability to make copies of themselves (self-renew) without actually becoming a specific cell type. Rather, they maintain the potential to become a specialized cell type—say, a heart or liver cell—in response to a certain mix of chemical signals. CSCs share the same characteristics:
- Cancer stem cells can self-renew: CSCs can continue to divide and produce identical copies of themselves.
- Cancer stem cells can differentiate: CSCs can become specialized and develop into multiple cell types that make up tumors.
Cancer stem cells have been identified in most human tumors.
Where do CSCs come from? Most tissue types within our bodies have a collection of regular stem cells that remain in a self-renewing, non-specialized state—they are not carrying out the function of any specific tissue. Tissue damage activates those stem cells to develop into replacement cells for that specific tissue. Now, if a mutation occurs in one or more genes involved with cell division, those regular stem cells could morph into cancer stem cells. The opposite may be true too, because some fully developed cancer cells acquire mutations which could cause them to revert back to a stem-like state. Since all kinds of stem cells have a relatively long lifespan, the odds of mutation accumulation increases, which supports the idea of CSCs driving cancer.
CSCs are different enough from actual tumor cells that many treatments which target and kill tumor cells don’t adequately destroy cancer stem cells. Even if the tumor recedes, the CSCs remain a possible source of reemergence, pointing to the need for therapies that exterminate cancer at its source.
The image above shows the difference between using CSC specific therapy versus conventional cancer therapy. By eliminating the yellow cancer stem cell from a tumor, the cancer is cut off from its source of proliferation, leading to tumor regression.
Monoclonal Antibodies
Stemcentrx (South San Francisco, CA) is developing Rova-T, an antibody-drug conjugate that targets both tumor cells and cancer stem cells. Antibody-drug conjugates use the ability of an antibody to recognize a single protein target to deliver a toxic drug directly to cells which have the target on their surface. Rova-T targets the protein DLL3, found on the surface of both CSCs and tumor cells. When tested in mice that received tumor grafts from small cell lung cancer patients, Rova-T eliminated both tumor cells and CSCs, suggesting the drug may be successful in treating the initial cancer and preventing recurrence in humans. Rova-T is currently in Phase II clinical testing.
OncoMed Pharmaceuticals (Redwood City, CA) is targeting CSCs with their lead candidate, a monoclonal antibody named demcizumab, currently in Phase II clinical testing for pancreatic cancer and non-small cell lung cancer. Demcizumab aims for tumor cells and CSCs with the surface protein DLL4, which activates white blood cells to destroy those cancer cells. DLL3 and DLL4 are part of the same family of proteins, and both play a role in activating a signaling pathway inside of cancer cells that promotes their development.
Small Molecule Inhibitors
Boston Biomedical (Cambridge, MA) is tackling the CSC signaling pathways that drive CSC development with the small molecule drug napabucasin. Currently in Phase III clinical studies for gastric/esophageal adenocarcinoma, colorectal, and non-small cell lung cancer, napabucasin inhibits a protein called STAT3. STAT3 turns on genes that promote cell growth and development. Normally, STAT3 activation is very tightly regulated, occurring only in response to specific cues from the cell’s environment. In cancer stem cells, STAT3 is active all the time, so inhibiting STAT3 may prevent the transformation of CSCs into tumor cells.
Another cell-signaling pathway thought to be involved in CSC development and activation is the Focal Adhesion Kinase (FAK) pathway. (FAK) pathway. When FAK is overactive, cells lose their ability to respond to signals that activate cell death. Verastem (Cambridge, MA) has a small molecule FAK inhibitor, VS6063, in Phase II clinical studies for non-small cell lung cancer.
Fusion Proteins
Stemline Therapeutics (New York, NY) created a fusion protein that targets the IL3 receptor, which is present on both tumor cells and CSCs. A fusion protein is a single protein that combines characteristics of two different proteins to fight disease.
Stemline’s product, SL-401, combines the IL3 protein with the diphtheria toxin protein. IL3 normally functions to activate white blood cells as part of the immune response. In SL-401, this function is not relevant; it is simply being used to attach the diphtheria toxin to cancer cells and CSCs that have the IL3 receptor on their surface. These cancer cells then “take up” or internalize SL-401. Once inside, the diphtheria toxin is released, killing the cell. SL-401 is in Phase II clinical testing for blastic plasmacytoid dendritic cell neoplasm, and in Phase I/II for acute myeloid leukemia.
Targeting cancer at its stem cell source offers new hope for longer term, progression-free cancer survival. Time will tell, but hopefully one of the many CSC-targeting therapeutics — monoclonal antibodies, small molecule inhibitors, and fusion proteins — in development will one day soon be clinical reality.
