Optimisation of Cancer Drug Treatments Using Cell Population Dynamics - Mathematical Methods and Models in Biomedicine - page 292

Apart from toxicity issues, at this intermediate level (the tissue), will also be
considered in models presently under construction [ 42 ] the possible evolution of
cells towards drug resistance, which is the other main problem encountered in cancer
therapeutics. To prevent or overcome the emergence of resistant cell subpopulations,
it is usually better to make use of several anticancer drugs acting on different
targets, to avoid as much as possible strategies used by cancer cells, which, due
to their genomic instability, easily adapt by mutations to single-drug therapies. This
has been the case for instance with imatinib, a drug that has completely changed
the prognosis of CML, but has nevertheless, after being considered as a miracle
drug, also to be confronted to the issue of resistance in CML cells [ 126 ]. Future
optimisation problems in cancer therapeutics will have to take into account as a
constraint, given the possibility to induce drug resistance, to limit it, as much as
possible, not necessarily by a complete eradication of tumour cells, but, as sketched
in [ 58 , 61 ], more realistically by its containment, and this will likely more easily
done by using combinations of therapies than by using monotherapies.

9 Discussion and Conclusion

We have presented in this chapter firstly a brief review of models of cancer that have
been used or may be used to tackle the general problem of therapeutic optimisation
in oncology. As sketched elsewhere [ 37 , 38 ], theoretic drug delivery optimisation
is the last step of therapeutic optimisation, which must rely firstly on an accurate
representation of the behaviour of targets (wanted and unwanted) without treatment
and on the changes the means of action of the physician—drugs—exert on them.
The point of view we have adopted here may indeed be considered as comple-
mentary to the one of molecular biologists, pharmacologists and systems theoreti-
cians [ 77 , 78 ] who seek to control the cell division cycle at the single cell level
by targeted drugs that are hoped-for blockers of intracellular pathways essential
in cancer proliferation. Either by targeting a “hub” in the network by a single
drug (e.g., imatinib in CML targeting BCR-Abl chimeric tyrosine kinase [ 126 ])
or by combining drugs that can hit complementary pathways, they search for
“druggable” proteins that can be hit to arrest the cell cycle. A typical and recent
example may be found in [ 122 ]. However, this approach, obviously valuable to
provide new weapons in the war against cancer, by its nature cannot take into
account the constraints linked to toxicity or drug resistance issues, which must be
considered at the cell population level in a whole-body drug delivery optimisation
perspective. This molecular biology approach should also be completed by whole-
body pharmacokinetic-pharmacodynamic molecular modelling to represent the fate
of drugs in the organism, as sketched above and in [ 37 , 38 ]. In other words, these
approaches may be thought of as understanding the target and the weapon, whereas,
to stay in this metaphor, optimisation of drug control is training to shoot in all
conditions to safely reach the target.