Drugs that target cancer stem cells (yellow) could help prevent tumor relapse. Credit: Peter Znamenskiy

Cancer Stem Cells and How to Get Rid of Them

If you have not yet heard of cancer stem cells (CSCs), often considered to be the real culprits in cancer, it is about time you do. CSCs are stem cells found in tumors. Drugs that target them are showing promise in clinical trials. More on that later; first, let’s introduce the concept of stem cells:

All normal tissues in our bodies develop from a small number of very special cells known as stem cells. Stem cells can divide a seemingly unlimited number of times. The process of producing two daughter cells from one stem cell is asymmetric: the two daughter cells are different. One of them is destined to remain precisely like the ‘mother’; that is, a stem cell capable of endless division when needed. The other daughter cell is destined to divide only a limited number of times and, while at it, produce differentiated progeny, that is, specialized cells that will go on to form mature cells of a relevant tissue or organ, be it the blood or the liver.

Normal (healthy) stem cells are usually dormant, unless there is a need to regenerate the tissue for which they are ‘responsible.’ For example, cells lining intestines are continuously renewed: older cells slough off and die regularly, but stem cells take care of producing a new lining. Similarly, blood and skin cells need to be replaced/renewed quite often; this is achieved by maintaining a small number of stem cells. In short, normal stem cells only show their ‘stemness’ when they receive the ‘divide’ signal demanding the addition of new cells in a tissue.

It turns out, many cancers have kept this hierarchy, sort of, but in a distorted fashion. Similar to normal stem cells, CSCs are capable of infinite division, but this process is no longer controlled. CSCs do not need to receive the divide signal from any tissue, they just keep going and producing numerous cancer cells, resulting in tumor growth.

Although they drive tumor growth, the real reason why CSCs are important in developing new cancer treatments is that they are apparently impervious to many cancer treatments, such as chemotherapy and targeted therapy.

The underlying theory (supported by evidence) is that the majority of cells in a tumor may respond to chemotherapy (or targeted therapy) by dying, but CSCs have protection mechanisms. This is likely related to the well-known ability of tumors to return some time after treatments that initially work. It could be that a few cancer stem cells unaffected by treatment eventually resume their incessant division and produce new tumors. If so, it would make sense to also hit the CSCs with a drug that selectively wipes them out, preventing the tumor from coming back after treatments are over.

In order to do so, one has to know the vulnerabilities of CSCs. A study recently published in Nature found such a ‘soft spot’ in CSCs that gives rise to chronic myeloid leukemia (CML), a disease seen as very high numbers of specialized myeloid cells in the blood. The authors found that certain antidiabetic drugs (glitazones) get rid of CSCs in CML.

CML develops in bone marrow cells known as myeloid stem cells. A chromosomal abnormality known as BCR-ABL in these cells drives excessive production of mature myeloid cells. Normal, mature, BCR-ABL-carrying myeloid cells can be eliminated successfully by the targeted drug Gleevec (imatinib). However, BCR-ABL-carrying, abnormal myeloid stem cells do not respond to Gleevec. They stick around in small numbers even after prolonged treatment, eventually start producing huge numbers of leukemic cells that are much more aggressive than before treatment, and are difficult or impossible to eliminate.

The Nature study revealed a weakness in CML stem cells: they cannot survive in the presence of a glitazone. Pioglitazone was given to three CML patients who had already undergone a course of Gleevec treatment, but still had BCR-ABL-carrying leukemic stem cells left. After prolonged treatment with this antidiabetic drug, BCR-ABL-carrying stem cells could no longer be detected in any of the three patients. The importance of this study for CML patients is difficult to overestimate.

Selective targeting of stem cells in solid tumors (eg, lung cancer, melanoma, prostate cancer) may prove more difficult, but there are new positive developments. Experiments with isolated CSCs are now revealing their potentially targetable vulnerabilities. Certain cellular pathways are critical for the survival of CSCs, of which the most clinically explored are the Notch, Hedgehog, and Wnt pathways. Numerous inhibitors of activity of these cellular pathways are in clinical trials.

For example, a drug now known as Rova-T preferentially targets CSCs in small cell lung cancer by interfering with the Notch pathway. A recent report from the Rova-T trial showed very promising preliminary results of the drug’s efficacy in this almost always fatal malignancy. Tarextumab (OMP-59R5) is another antibody drug that targets a different protein in the same Notch pathway. It is used to treat pancreatic cancer, and is now being combined with chemotherapy in a mid-phase trial. Tarextumab has also received a nod from the U.S. Food and Drug Administration (FDA): an orphan drug designation for lung and pancreatic cancer.

One more CSC-targeting drug is also worth a mention: BBI608; on its own, it has shown promising activity in gastrointestinal cancers. It is now in more than a dozen trials that combine it with chemotherapy in the hope of killing both regular cancer cells and CSCs. BBI608 was first identified in laboratory experiments aimed at finding chemical compounds that selectively kill CSCs; it appears to work by inhibiting the activity of a gene regulator protein called STAT3.

Most scientists think that CSCs are responsible for maintaining the growth of numerous cancer types, their spread to distant organs (metastasis), and resistance to anticancer drugs—especially chemotherapy. Even if only some of this holds true, it certainly makes CSCs a worthy target in cancer treatment.

Image Credit: Drugs that target cancer stem cells (yellow) could help prevent tumor relapse. Credit: Peter Znamenskiy