Cancer stem cells in their sights

Stem cell research can help to develop new cancer therapies. A new research field at the German Cancer Research Center (DKFZ) in Heidelberg builds on this context. Professor Dr. Andreas Trumpp is Head of the Department for Stem Cells and Cancer and is Managing Director of the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)founded in 2008, which aims to combine basic stem cell research with applied research and development activities. Trumpp and his staff are now testing a new therapy concept in a clinical study with leukaemia patients that specifically targets cancer stem cells.

According to the cancer stem cell hypothesis, a tumour is mainly made up of growing cancer cells which can generally be destroyed quickly by means of chemotherapy drugs or radiation. By contrast, cancer stem cells from which the tumour originated are much more resilient. These form by mutating from normal stem cells or mature body cells and often account for less than one per cent of all the cancer cells. “The most potent of these cancer stem cells are in a kind of deep sleep,” says Andreas Trumpp. In this resting phase, they survive the cancer therapy, since radiation or chemotherapy only kill off those cells that actively divide. Months or even years later, single surviving cancer stem cells might become reactivated and cause tumour relapse and progression to form metastases.

Trumpp and his staff are working on how to wake up sleeping cancer stem cells, i.e. stimulating their cell division to sensitize them for chemotherapy-mediated killing. In the search for a suitable wake-up signal, the researchers made an important discovery. They were able to prove that dormant, blood forming stem cells in the bone marrow of mice respond to the immune signalling molecule interferon alpha with a strikingly increased division rate. This indicated that the same signal might also activate the sleeping, malignant blood stem cells of certain leukaemia patients.

This led to a collaboration with the group headed by Prof. Dr. Andreas Hochhaus from the University Hospital in Jena, who is examining the effectiveness of various therapies in patients affected by chronic myeloid leukaemia (CML). A class of highly efficacious drugs, so-called tyrosine kinase inhibitors (TKIs), is available for this type of cancer, which is caused by a specific mutation within blood-forming stem cells. These inhibitors block specifically the reproduction of these cancer cells without harming normal cells. While in the majority of patients the leukaemia virtually disappears, the TKIs have to be taken life long since after stopping of TKIs, the leukaemia reappears relatively quickly. This suggests that in contrast to normal leukaemic cells, leukaemia stem cells are resistant to TKIs. Interestingly, in some patients, who had been previously been treated with interferon alpha, which was the treatment of choice before the new TKIs were introduced in 2001, the leukaemia did not return after the TKIs were stopped. Results from Trumpp’s research group now suggest that interferon alpha may have activated the resting leukaemic stem cells in CML patients and therefore made them vulnerable for the subsequent TKI therapy.

The researchers now want to verify this suspicion in a clinical study with the German CML Study Group. This will involve patients who will receive a short pulse of highly-dosed interferon alpha followed by the standard therapy with the TKIs Imatinib or Dasatinib. Blood and bone marrow samples are taken in the course of the study to examine whether the additional interferon treatment has led to a quicker decline in the number of both, leukaemic cells in general and leukaemic stem cells in particular. Patients who achieve complete molecular remission and who then remain cancer-free after a number of years after stopping treatment with TKIs would be viewed as cured. This would be one of the first cancer therapies to be based on the specifically targeted activation and destruction of cancer stem cells.

We are examining whether interferon alpha could also affect other forms of cancer,” says Andreas Trumpp. In principle, each cell possesses receptors for this signalling substance, so, possibly any cancer stem cells could be activated by this strategy. On the other hand, CML might be a special form of cancer for which both the waking signal for the leukaemic stem cells as well as an effective, specifically targeted chemotherapy is available, notes Hochhaus. It may however be possible that – by using various tumour-specific drugs – the principle of “first awakening and then killing” could be applied to a whole series of cancer diseases in the future.