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The new calling work of oncology can be coexistence instead of demolition 31st August 2016, PÉTER TÁTRAI

In the past six decades’ medication’s approach towards tumours was with the intention of demolition. But in almost all cases, there are some tumour cells, which survive even the most drastic therapy, and for the second time they rebuild a tumour which is much more difficult to attack. The limitations of the traditional strategy raise the possibility of that cancer actually should not be defeated, but kept at bay.

The traditional cancer-healing strategies all build on the theory, that the best solution for the patient is the minimalized demolition of the tumour, and for this purpose, with the therapies one needs to “reach the wall”. The tumour removal surgeries are carried out in the spirit of surgery radiality, delicately balancing between the possible fullest removal of the tumour, and maintaining the functions of the surrounding soft tissues; and during the planning of the radiation and medical therapy they tend to set such a high therapy intensity, which is barely, but still endurable for the patient. All this is done in the hope of killing even the smallest trace of the tumour by the end of the therapy. But according to the experiences; this is almost an impossible mission; on the contrary, it seems like the aggressive treatment actually actively contributors to the recrudescing of the tumour.

A change of paradigm in oncology after sixty years?

After six decades of efforts – producing both significant results, but from the aspect of the final aim full of failures – part of the researchers and medical doctors are urging a change of paradigm in oncology. In their opinion, instead of striving for the full healing of cancer, tumour illness should be formed into a kind of chronic condition, with which one can live with for decades. The future of cancer healing might not be the final victory over tumours, but the “taming” of the tumour as an illness – to live with a tumour should be equal to living with well-maintained diabetics. According to the new strategy, in order for the tumours to be controllable in a long run, they should not be attacked so frontally as it had been done until now. In the past few years Robert Gatenby, the research professor of the Lee Moffitt Cancer Center of Florida has developed a significant theoretical frame for the foundation of the new way of the “more tender” treatment of tumours. As the representative of the school propagating the Eco evolution of tumours; Gatenby considers tumours to be ecosystems, in which there is an evolution process based on the Darwinist selection. Tumours, similarly to a real symbiosis are heterogenous: both the tumour cells, both the micro-environment they experience differ from place to place.

It is known, that the basis of tumours is genetical deformities, mutations, and during the evolution of the tumour; new and new mutations keep emerging. Therefore, the differences between the tumour cells – at least partly – can be explained by the differing mutational patterns of the individual sub-populations of the tumour. But the tumour cells can adapt to their environment and the challenges they face without acquiring new mutations: it is enough for them to re-regulate the expression level of their ready-coded protein in the genome.

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

Diversity, detoxication and competition – the three great weapons of tumour cells

Gatenby’s treatment model is based on three main theories, all of which are well-founded by convincing experimental data. At first, he starts off from the hypothesis, that the tumour cells already vary before the beginning of the treatment, regarding their responsiveness towards the therapy. Due to the above-mentioned heterogeneity of the tumour cells, some tumour cells will react better and some will react less to medical treatment. The second theory is that after the beginning of the treatment, the tumour cells do not necessarily need to acquire new mutations in order to become more resistant, but it is enough for them to activate the detoxicating metabolism-routes naturally existing in the cells. This is important, because by setting their already existing tools in; the cells are able to become therapy-resistant much faster, then if they had to wait for a “lucky” mutation. Due to its essence, the occurrence of mutations is a random process, and even though the mutations securing resistance secure a selective advantage to their carriers, the occurrence of the new mutations and the process of selection assume a series of cell divisions. Contrary to this, the “top flight” of the detoxicating metabolism does not even require cell division, inly the switching on of the appropriate genes. At last, Gatenby builds into his model the third theory, that the sub-populations of tumour cells – similarly to the members of a natural symbiosis – are competing with its other within the tumour for the living-space and nutrient. Taking these three basic theories as a basis, it is possible to deduct substantial conclusions regarding the inner dynamics of tumours. During chemotherapy, tumour cells resistant to the therapy obviously enjoy a selective advantage compared to their mates which are receptive towards the therapy, namely, the resistant cells are more able in the presence of the therapy; as an external selection pressure – their reproduction ability is better –, then the one of the sensitive ones. This has not been a very important surprise so far. But Gatenby calls the attention to the extremely significant fact, that in the absence of chemotherapy, the ability relations are exactly the reverse: the resistant cells are less reproductive then the ones which are receptive.

The root-cause of this is to be found in the mechanism of resistance.

Versatile pumps – stubborn tumour cells

The most common trick among tumour cells, with which they avoid the effect of the chemotherapy substances, is that they place a large amount of so called. multidrug resistance-pump on their surface. The multidrug resistance-pumps are such proteins, which – impregnated into the cell-membranes - vigilantly guard over the strange molecules which try to penetrate from outside, and if they discover any of such, they throw it out before it could penetrate into the inner part of the cell. The name of the pumps indicate that they are able to identify and remove numerous, chemically not related cell-foreign compounds, and thorough this, they make the cell to become resistant towards uncountable possible medicines. Naturally, this protection is not for granted: the cell pays in hard energy-currency for the job of the pumps. It has been proven, that the tumour cells might use up to one third of their entire energy production for the operation of the pumps. This giant cost pays back though – it provides selective advantage in the efficiency competition –, if the pumps have something to protect against. But during “times of peace”, namely at the lack of chemotherapy, cells not being in the possession of pumps can use all the energy their competitors use for feeding their pumps for their own growth and reproductivity. And since both the resistant and the sensitive sub-populations are competing for the same limited resources, in the absence of therapy; the resistant cells wasting their energies in wain; come of worst from the battle.

The disadvantages of intensive chemotherapy

So, the model forecasts that in the absence of medicine; the tumour cells receptive to therapy as a result of the competition roll back and keep at bay the sub-populations resistant to the therapy. But the intensive chemotherapy which almost exceeds the maximally endurable dose radically changes the balance of forces, and turns the status quo prior to the therapy completely upside down. Under such circumstances, when the cells sensitive to the therapy die in masses, the resistant populations which had been kept under control until then start to expanding explosively.

Ecology knows this phenomenon very well, under the name competitive release, as is well aware of its sometimes-catastrophic consequences. What happens if a newly introduced weed-killer only demolishes some of the plant species being in natural competition with each other? The rest of them, as a result of competitive release; overflow the entire living-space, and we cannot protect ourselves from them with the same weed-killer again. A very similar process happens inside our bowels during a significant antibiotics cure: the medicine decimates the mostly innocent, but sensitive bowel bacterial, and opens the way for the much more unpleasant disease agents, which have been naturally regulated by the competition. And if the latter one’s cause illness as they proliferate, we will have to remove some entirely different antibiotics against them from our shelf – until there is a choice to pick from. Gatenby makes his conclusion: the drastic, dose intensive chemotherapy, unless it is able to defeat the resistant cells too, is not only doomed, but it literally cuts the wood beneath itself. By providing a selective advantage to the resistant cells, and demolishes their natural competitors, it elevates the “special forces” of the therapy resistant cells, which re-develop the tumour sometimes just months after the ending of the therapy, but at most within a few years. And we shall not forget: this recurrence tumour is no longer sensitive to the previously applied treatment. The blotter of sins of intensive chemotherapy is actually much longer then this: we are well aware of its other unwanted side effects, as a result of which it does not keep under control, but enhances the development of the tumour. The bone marrow – due to its rapid cell division is one of the main sufferer of the side effects of the chemotherapy substances, and since this tissue is responsible for the reinforcement of the soldiers of the immune system, the white blood cells; its damage leads to the set-back of the immune-protection. Yet, the immune-system plays a very important role in limiting the growth of tumours, therefore the eroding of the immune competency is no good news for the body battling with cancer. We also have to recall, that tumours are not only made up of tumour cells, but they are organized around a so-called stroma – a kind of frame – which consists of connective tissues and veins; and immune cells also penetrate into their frame. Chemotherapy substances do not spare the non-malicious components either: they distract the structure of the veins, as a result of this they lose their normal permeability, and they also eliminate the white blood cells battling against the tumour on the spot. The abnormally structured veins provide bad blood supply, and the lack of oxygen ignites such mechanisms in the tumour cells; which enhance their exit from the tissues structure, namely the metastasis. Upon all this, the bad veins cannot secure that the medicine reaches the tumour cell effectively, so while the healthy part of the body is suffering from the side effects, the inner part of the tumour enjoys some kind of protection.

The drastic, dose intensive chemotherapy, unless it is able to defeat the resistant cells too, is not only doomed, but it literally cuts the wood beneath itself.

Tumour therapy with a gentle approach

What would the alternative be then? Gatenby – reaching to the tradition latent in tumour-healing for actually decades now – recommends the gentler form of chemotherapy. Such and adaptive therapy, which only uses high doses, until its stops the exponential growth of the tumour; and afterward, continuously following the size of the tumour, it modifies the doses in a way, that the sensitive balance between the cell populations sensitive to the therapy and those which are resistant to it should not be disarrayed. So instead if intending to completely eradicate the tumour, it is his expressive intention to reserve the tumour cells therapy responsive fraction, which it plays out as an “insider enemy” against the potentially dangerous, resistant cell substance. The applied lower dose intensity also does not endanger the intactness of the stoma, therefore the stable veins of the tumour and the immune cells penetrating into the tumour can be turned to the advantage of the therapy.

Gatenby and his team finally had the chance to try this promising theory in practice in the near past. Their study, in which they prove with the support of an animal test model that the adaptive therapy can keep tumours at bay compared to the traditional high doses chemotherapy, was published in the February 2016 edition of the Science Translational Medicine. Following the achievement of the tumour control at the beginning – breaking the exponential growth – they experimented with two types of the reduced dose modification of the traditional therapy on mice injected with human breast cancer cells. In the first version, the regularity of the dosage was not modified, but the dosage was reduced depending on how the tumour responded to the therapy. In the second variation, in response to the shrinking of the tumour, not the dose used by each of the treatments was reduced, but the therapy occasions were made less frequent. The control group received the traditional, timewise pre-set, continuously high dose and unchanged frequency chemotherapy.

In the group treated with standard chemotherapy, the size of the tumour was reducing at a fast pace at the beginning, but at the end of the defined dosage period, in the lack of further therapy it started growing again almost instantly, and during the approximately two months’ observation period it was growing in an intensifying rate. Contrary to this, in the first adaptive therapy group, in which the treatment was maintained with low dosage fitted to the size of the tumour, the tumour did not only refuse to start growing again, but out of 7 cases, in 6 cases the size of the tumour reduced to be under the size which is set to be treated, which made it possible to completely seize the dosage. And what is even more important; these adaptive treated tumours remained steadily small, giving a hint, that as the result of the treatment they became self-controlling. The results of the second group, with skipping therapy occasions were less convincing.

In his comment attached to the article in the same edition of the journal, Giannoula Klement, the child oncologist of the Tufts University Clinique of Boston enthusiastically welcomes the new therapy approach, adding that: until we do not have respect for the eco-evolution laws of the growth of tumours; we will only be able to continue playing the cat and mouse game with cancer.

Living together with cancer – even for decades

Klement emphasises, that the stable living together with tumours is not only a theoretical option, but it is an existing, and for a long time known phenomena. In young and middle aged women dissected for other reasons; they found malicious breast-tumours in an amazingly high frequency, which did not produce any clinical effects during the lives of the patients. Likewise, while in more than 40% of men above 60 years, histologically proven malignant prostate lesions are present, the frequency of prostate cancer breaking through the clinical horizon is only 1%. All these indicate, that tumours often have a sort of self-controlling dynamism without external intervention, and it is possible, that an unthoughtfully applied early treatment disarrays this inner balance. This observation reflects in the strategy used in the case of the less aggressive cases of prostate cancer, called the watchful waiting strategy: in such cases the doctor closely follows the way the size of the tumour changes, and only interrupts if it noticeably starts to grow.

Epithelioma tumour cells
Source: Flickr/NIH Image Gallery/Markus Schober and Elaine Fuchs, The Rockefeller University

Support from a spiritful researcher

Local researchers also join the efforts of Gatenby in a broader sense: a Hungarian team of researchers strives to turn the vulnerability of the chemotherapy resistant tumour cells for the advantage of healing in a slightly different way. Gergely Szakács, the head of the “Lendület-group” of the Natural Sciences Research Center of the Hungarian Scientific Academy discovered molecules with a unique behaviour during his years he sent in the United States as a doctorands. He named these molecules MDR-selective compounds. In a paradox way, these compounds attack exactly those tumour cells, which – due to their above mentioned multi drug resisting- (MDR-) pumps – are completely resistant to most of the chemotherapy substances. Returning from the US, Szakács intensely continued the studying of the MDR-selective compounds, and got to the conclusion, that they actually utilize their cell-damaging effect as a result of the operation of the pumps – but he has not been able to fully clarify how this process is happening. However, the appliance of these compounds for therapy purposes could multiply the strength of the strategy of Gatenby: in their presence, the maintenance of the pumps for the tumour cells would not be disadvantageous indirectly, due to their high-energy demands, but also because of the direct damage as well, which the MDR-selective compounds cause to the pumping cells. „The excellence program of the EU, our results supported by the application of the ERC made it clear, that the cancer cells which are resistant to therapy can be selectively attacked by the compounds discovered and tested by us – summarizes Szakács. –In the Enzymology Institute of Natural Sciences Research Center of the Hungarian Scientific Academy we patented such medicine-to be molecules, which target the Achilles-heel of the most hardly demolish able cancer cells. In accordance with the theory of the adaptive therapy, our objective is the fine-tuning of the therapy protocol. The method works perfectly in the cell-culture dish; currently we are working on the adaptation of a special animal model, which enables examination of the spontaneously developing tumours’ evolution, biopsy and response to therapy.”

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