Metastatic melanoma cells -
© National Cancer Institute / Unsplash CC BY-SA
Conventional cancer treatments (such as chemotherapy) destroy sensitive cells ... resulting in faster proliferation of resistant cells, according to our partner The Conversation.
To counter this paradox, adaptive therapy aims to control cancer based on the “competitive” relationship between different tumor cells.
The analysis of this phenomenon was carried out by Benjamin Roche, research director at the Institute for Research for Development (IRD) and Frédéric Thomas, research director at the National Center for Scientific Research (CNRS).
Today, cancers are one of the leading causes of death in many countries, and their incidence and mortality continue to increase.
Many types of treatment exist, but their effectiveness remains limited, due to the frequent development of resistance.
In order to counter this phenomenon, the tendency has so far been to develop new drug molecules, in order to broaden the therapeutic potential against the various forms of resistance.
Nevertheless, new resistance often emerges, particularly in the context of the treatment of metastatic cancers.
For this reason, it seems relevant to focus on the causes of the emergence of these resistances, rather than trying to deal with the consequences.
Killing as many cells as possible may not be the best approach
Current conventional strategies aim to deliver the maximum tolerated treatment dose to the patient, with the goal of killing as many cancer cells as possible.
Unfortunately, heterogeneity within tumors is often significant, particularly in metastatic cancers.
In other words, not all tumor cells have exactly the same properties, they can change as the tumor grows.
Under the effect of the treatments, a selection occurs which will favor the cells capable of resisting it, according to a mechanism similar to that which occurs during the use of antibiotics used against bacteria or "-icides" of all kinds. (pesticides, rodenticides, fungicides,
etc.
): Treatments such as chemotherapy destroy sensitive cells, resulting in faster proliferation of cells resistant to treatment.
The latter will indeed benefit from more resources to develop, since they will have been freed from competition with sensitive cells.
In other words, conventional chemotherapy strategies often "select" resistant cancer clones.
New therapies based on controlling cancer rather than eradicating it could improve patient survival and quality of life © The Conversation
In order to develop treatment strategies that are both effective and sustainable, it therefore appears necessary to take into account the evolutionary dynamics of cancers.
One possible solution is to use “adaptive therapy”.
Controlling cancer rather than eradicating it
Adaptive therapy consists of controlling cancer based on the competitive relationship between sensitive and resistant cells.
In the absence of treatment, sensitive cells will proliferate better than resistant cells, since resistance often has a cost for cells: the ability to resist the poison of therapies generally relies on adaptations, the mere presence of which causes costs. energy for the cell.
Thus, in the absence of treatment, the growth of the tumor will be mainly ensured by the contribution of sensitive cells.
Conversely, the treatment will eliminate sensitive cells, but will leave a "free field" for resistant cells which can proliferate, depriving the oncologist of a therapeutic option.
Adaptive therapy proposes to alternate periods with and without treatment, in order to destroy enough cancer cells not to endanger the life of the person being treated, but to keep enough sensitive cells to slow down the proliferation of resistant cells.
It is therefore based on treatment cycles which are adapted according to the evolutionary dynamics of the cells: when the tumor has sufficiently reduced, the treatment is stopped or the dose reduced.
When the tumor grows too large, the treatment is reinstated or the dose increased.
This strategy does not make the tumor completely disappear, but only keeps it at a bearable size for as long as possible.
Adaptive therapy is therefore currently only considered for cancers that are considered incurable by conventional treatments, such as metastatic and castration-resistant prostate cancer (mCRPC).
70-year-old man with advanced prostate cancer with hypercalcemia and diffuse osteoblastic bone metastases. Abdominal x-ray showing osteoblastic changes in the bones of the spine, pelvis and femur © WH Liao, SH Lin & TT Wu / Wikimedia CC BY-SA 2.0
Promising results and avenues to explore
Preclinical trials in mice, as well as several clinical trials currently underway in humans, show very encouraging results for adaptive therapy.
This is particularly true for mCRPC, a cancer for which adaptive therapy appears to be able to significantly delay the onset of resistance, going from 16 months on average to more than 29 months (clinical trial still ongoing).
An advantage of adaptive therapy is that, since the treatment is administered cyclically, the dose of drugs used is dramatically reduced.
Thus, in the context of mCRPC, the patient receives on average only 47% of the dose used for conventional therapies.
In view of the side effects of anticancer treatments, this element is far from being negligible for the patient's quality of life.
If adaptive therapy represents to date the most successful avenue in terms of treatments based on principles of evolutionary ecology, other promising directions of research are under study.
The sciences of ecology and evolution show, for example, that it is possible to limit the size of a given population if the latter finds itself caught between two antagonistic constraints, causing resistance to the first to increase the size of the population. vulnerability to the second and vice versa.
Thus, certain species of rodents that live on the edge of deserts may choose to go to the desert side, where they are frequently victims of predation by nocturnal raptors, or prefer the more wooded parts in which there are fewer raptors, but where they may encounter more predatory snakes.
Their demography is then channeled by this double constraint.
The jerboa is a rodent that can inhabit different biotopes. Here, an Egyptian jerkin © Николай Усик / Wikimedia CC BY-SA 3.0
This strategy has already been successfully applied in the field of the fight against viruses: it is illustrated by the success of combination therapies, such as anti-HIV triple therapies.
It also works with cancer cells, because the latter are also subject to the constraints of evolution and are not able to resist everything.
Other lessons in ecological and evolutionary sciences
The evolutionary sciences, in particular the biology of extinctions, also shed decisive light on the strategic order of administration of the various treatments.
We know, for example, that the process of species extinction often takes place as follows: a first major event considerably reduces the size and diversity of a population until it approaches what in biology we call the “minimum viable”.
Then, it is often small events, which would not have had significant effects on the large initial population, which randomly end the extinction, by not causing the selection of resistant variants.
For example, it was not a single meteorite that killed all the dinosaurs at once, it was only the first trigger event.
The previously weakened populations then died out due to a cascade of small events that subsequently occurred: climate change, reduced access to food, competition, parasitism, etc.
One could imagine transposing these lessons to cancer, by developing a therapeutic strategy that takes advantage of them.
Initially, it would be a question of applying neoadjuvant chemotherapy (the aim of which is generally to reduce the size of a tumor before surgery or radiotherapy) which, like the meteorite previously mentioned, would reduce the size and diversity of the tumor.
In a second step, this therapy would be stopped (even if it seems to continue to be effective - which is not done at present).
Finally, a myriad of small, mildly aggressive treatments would be administered to what was left of the tumor.
These treatments would be continued for a while, even after the tumor appears to be gone.
Another interesting avenue is to “lure” cancer cells by using fake drugs that mimic real anti-cancer drugs.
Indeed, cancer cells that resist therapy are often those that have "efflux pumps".
Very expensive in energy, these systems allow them to reject anticancer therapies outside.
When real drugs are administered, having such a system is obviously beneficial, since cells that have it can resist treatment, while those that do not are killed.
On the other hand, if we administer a fake drug capable of making these systems work anyway, the resistant cells would spend all their energy in bringing out a poison that is not poison: they would then lose the benefit of having these pumps.
In such a case, the tumor would certainly continue to grow, but it would be mainly composed of cells without pumps.
Alternating real drugs and fake drugs would then allow stable maintenance of the tumor, as with adaptive therapy.
Our "Cancer" file
According to Andrew Read, professor at the Penn State Cancer Institute, we could summarize in three points the anti-cancer strategy that seems to be looming for humanity:
1) avoid the causes of cancer by adopting an adapted lifestyle, 2) if a cancer develops despite everything, try eradication when possible, 3) when eradication is not or no longer possible, forget this goal , and opt for therapies that can stabilize the cancer in a chronic disease with which it is possible to live in an acceptable way.
The sciences of ecology and evolution will be central to achieving this third objective.
Without forgetting also psychology, because this last therapeutic option requires that the patients concerned be ready to accept the idea of living with their tumor.
Without however that this one is not in theory responsible one day for their death.
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This analysis was written by Benjamin Roche, research director at the Institute for Research for Development (IRD) and Frédéric Thomas, research director at the National Center for Scientific Research (CNRS), with the participation of Sophia Belkhir, student in master 2 Biosciences at ENS de Lyon.
The original article was published on The Conversation website.
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