Drugs that target the unique properties of cancer stem cells can be very effective in preventing the development and spread of cancer. There may be drugs on the market even now that can have an effect if used in the right way.
Text & photo: Nicklas Hägen
STEM CELLS are cells that have not matured into specific types of cell themselves, for example into blood cells or skin cells, but underlie the development of these cells. A fraction of the cells in the body are stem cells and they play a central role in foetal development, in the growth of children and young people and in how new cells are created when old ones have come to the end of their useful existence or are damaged.
Since the start of the new millennium it has become increasingly clear that so-called cancer stem cells exist. These are cells that drive the development of cancer cells and are a key factor in the formation of tumours. It is assumed that these cancer stem cells are responsible for the metastasis of cancer and for the recurrence of cancer, even when the tumours have been eliminated.
“The hypothesis is that the cancer stem cells have mutated from tissue stem cells or other, more specialised stem cells,” says Daniel Abankwa, a docent at Åbo Akademi University and group leader at the Turku Centre for Biotechnology.
“Where cancer cells with stem cell characteristics specifically come from or how they are created through mutation and so on are academic questions that are open to debate. But all the evidence I have seen points to the existence of special cancer stem cells that are resistant to the drugs we use to treat normal cancer cells.”
Abankwa is researching Ras, a protein in the ‘shell’ of a cell that is active when cells divide and mature into a specific type of cell. Ras is part of the signalling network existing between a cell and its environment and it is instrumental in setting the cell ‘machinery’ in motion when it is time for it to be activated.
Ras occurs in three forms – H-, K- and N-Ras. All three have been shown to mutate and be overactive in cancer, but K-Ras exhibits the highest mutation frequency and appears to be the form of Ras that influences or actually promotes the stem-cell-like properties of certain cancer cells.
“In many cases where the cancer involves mutations in K-Ras, the prognosis is very bleak, often tantamount to a death sentence,” says Abankwa.
“Now we are starting to amass data indicating that what makes cancer stem cell drugs effective is that they attack K-Ras and not H-Ras. This helps us to search for drugs that have the right effect.”
Properties from chemical compounds
Abankwa will receive funding from the Academy of Finland until autumn 2018 for his project “The development of drugs to treat breast cancer by targeting K-Ras”. By screening chemical compounds, his research group has already found certain classes of compounds that appear specifically to subdue the protein’s activity in stem cells.
“We looked at 400 compounds in our second screening and found 14 that reacted specifically with K-Ras. We validated half a dozen of them and two were as potent as or more powerful than the best potential drug for cancer stem cells that we were previously aware of. Our research got off to a flying start,” adds Abankwa.
“A drug that inhibits K-Ras may be the ‘holy grail’ for cancer research. K-Ras is central to cancer stem cells and cancer stem cells are central to the tumour as such. What is being done to combat K-Ras can be a real game-changer.”
At the same time as examining different molecules that will hopefully be more effective than the drugs already on the market, there is also a reason for looking afresh at old drugs. Phenothiazines are a group of old antipsychotic drugs that were used – and are still used today to a certain extent – to treat schizophrenia.
“In our studies they specifically moderate K-Ras and not H-Ras and reduce the stem cell properties of stem cells in cell cultures, while other studies have shown that certain phenothiazines effectively counter metastasis and tumour growth.”
These drugs were being used to treat cancer back at the end of the 1980s, but without any great success. This might be because they were not tested on the right patients.
“With the aid of gene profiling, it would be possible to select patients who would probably respond to the drug. I hope to find a clinician who would be willing to test these on people, because the drug is already approved for use on humans and it could save lives.”