New key word for oncology: coexistence instead of eradication

Over the past 60 years the primary aim of doctors has always been to attempt to completely eliminate tumours. However, some tumour cells survive even the most drastic therapies. These can later build up to a second tumour, which may be even more difficult to combat. The limitations of traditional therapy suggest that instead of attempting to eradicate cancer completely, it should rather be kept at bay.

2016. szeptember 5.

All conventional anti-cancer treatments are built on the assumption that, for the benefit of the patient, tumour cells must be completely eradicated, i.e. treatments should cause the maximum possible damage without killing the patient. Tumour surgery is characterised by radicalism – maintaining a balance between fully removing the tumour and keeping the functionality of the surrounding tissues. Where radiotherapy and chemotherapy are concerned, the maximum possible therapeutic intensity which can be tolerated by the patient is set. All these efforts hope to ensure that no trace of the tumour remains in the body. However, experience has shown that this goal is practically impossible to achieve. What is more, this aggressive treatment protocol itself contributes to the recurrence of the tumour.

Paradigm shift in oncology after sixty years?

Some researchers and doctors urge that a paradigm shift is due in oncology following a six-decade-long trial and error period which of course has borne some fruitful results, but is still far from reaching the expected goals. In their view, instead of trying to fully cure cancer, a tumorous disease should be transformed into a chronic state, tolerable for decades. Thus, the final aim of cancer treatment should rather be the ‘taming’ of the tumour rather than completely eradicating it.

Cancer patients could live together with their illness, in a similar manner to people with properly controlled diabetes.

According to the new strategy, the long-term control of tumours cannot be achieved through a typical frontal assault presently being used. Professor Robert Gatenby, a researcher at Lee Moffitt Cancer Center, has devised a remarkable theoretical framework for the foundation of a new, ‘gentler’ cancer treatment approach. As a representative of the school advocating the eco-evolution of tumours, Professor Gatenby conceives of cancer as an ecosystem in which an evolutionary process based on Darwinian selection is to be witnessed. Just like real ecosystems, tumours are heterogeneous. Both tumour cells themselves and their microenvironment are different in various locations of the tumour.

Metastatic melanoma cells
Source: Flickr/NIH Image Gallery/Julio C. Valencia, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health

As is commonly known, tumours develop owing to genetic changes, i.e. cell mutations. In the course of tumour development, new mutations are produced from time to time. Thus, differences between tumour cells can partly be accounted for on the basis of the different mutational patterns of the subpopulations in the tumour. However, tumour cells are capable of changing without mutations as well: they can adapt to the challenges of their environment by re-regulating the expression of the proteins encoded in their genome.

Gentle tumour treatment

What should be the alternative? Based on a latently present cancer-treatment tradition, Gatenby proposes a much milder version of chemotherapy. This adaptive therapy applies high doses in the initial phase until the exponential growth of the tumour is stopped. Then the size of the tumour is repeatedly checked, and drug dosage is modified so that the fine balance between drug-resistant and non-resistant tumour cells should not be upset. Instead of eradicating the whole tumour, the therapy aims at keeping non-resistant tumour cells, which can thus play the role of inner enemy against the potentially dangerous drug-resistant cell types. Additionally, lower dose intensity does not harm the stroma either. Thus, stable blood vessels and immune cells entering the tumour can both be used to support the therapy.

The promising theory has recently been tested in practice by Gatenby and his team. Their study, published in the February 2016 issue of Science Translational Medicine, discusses the animal tests which have proven that adaptive therapy can control tumours for a considerably longer time than conventional high-dose chemotherapy. Having reached initial tumour control, i.e. when exponential growth was stopped, two versions of lower-dose therapy were tested on mice into which human mammary cancer cells were injected. In the first test, treatment frequency was stable, but doses were lowered based on the response of the tumour. In the second test, doses stayed the same, but the treatments were less frequent as the tumour shrank. The control group received conventional, high-dose chemotherapy for a limited time, with treatments at regular intervals.

Help from a Hungarian scholar

Hungarian scientists have also joined Gatenby’s initiative. They have devised a new method to exploit the vulnerability of therapy-resistant tumour cells. In the course of his PhD studies in the United States, Gergely Szakács, team leader in a Lendület (Momentum) Research Group at the MTA Research Centre for Natural Sciences, discovered molecules that behave in a special way. He calls them MDR-selective molecules (MDR standing for Multi-Drug Resistance). Paradoxically, using their MDR pumps, these molecules attack those tumour cells that are resistant to most drugs used in chemotherapy.

After having returned from the United States, Szakács pursued intensive studies on the behaviour of MDR-selective molecules. He discovered that these molecules can harm other cells with the help of the MDR-pumps, although the exact mechanism still needs to be clarified. However, including these molecules in the therapy could magnify the strength of Gatenby’s strategy in two ways. On the one hand, the maintenance of MDR-pumps would be detrimental to cancer cells in an indirect way, owing to their high energy needs. On the other hand, the MDR-selective molecules could do direct harm to the pumping cells themselves.

‘Our research, financed by the EU excellence program, ERC, has shown that drug-resistant tumour cells can be combated selectively by compounds discovered and examined by us’, reports Szakács. ‘In the Institute of Enzymology of the MTA Research Centre for Natural Sciences, we have obtained a patent for drug candidate molecules that attack the Achilles heel of those tumour cells which are the most difficult to kill. Along the lines of adaptive therapy, our aim is to fine tune the therapy protocol. The method works excellently in vitro. Currently, we are trying to adapt a special animal model, which would enable us to examine the evolution and the histology of spontaneously-developing tumours, as well as their reaction to therapy.’

The relevant publications of Gergely Szakács can be read here and here.