Abstract
Even when cancer has many different phenotypic traits, each tumor cell “sick” genome drives allthe malignant processes in its different evolutionary phases. In this way, cancer is mainly atargeted-genetic disease, perhaps the more complex one in nature, with the only teleonomic purposeof achieving its evolutive progression, a fate that invariably leads to patient death if not welltreated.
Today, much is what we know in Cancer Science about: oncogenes, tumor suppressor genes,growth factors, transcription factors, kinase pathways, adhesion molecules, dynamics of the tumormicroenvironment, etc. All of these elements may be “hacked” by the tumor to achieve selfsufficiencyin growth signals, dedifferentiation, chromatin remodeling, anti-growth signalinsensitivity, apoptosis evasion, limitless replicative potential, stemness heterogeneity,microenvironmental alterations, angiogenesis, immune evasion and metastases, among other
malignant capabilities.
All the above-mentioned may be potential therapeutic onco-targets and many kinds of “bullets”have been designed to tackle the different oncogenic processes. Unfortunately, the “malignant foe”of tumor drug resistance makes it not impossible, but very difficult, to continue much time with thefirst therapeutic best-option for the patient. It must be noticed that second therapy lines ofchemotherapy, applied mainly after a first tumor relapse, imply drugs that, in general and even usedin combination, are less effective than the first line ones.
Nevertheless, it must also be said that some malignant tumors have the possibility to be cured withthe administration of second line drugs, such as germinal cell tumors, choriocarcinoma, pediatrictumors, Ewing’s sarcoma, blood cancers, and some cases of breast and ovarian cancer. With the riseof new therapeutic approaches coming so quickly into the clinical setting, as new emerging smallmolecules, immune-checkpoint inhibitors (large molecules-type), novel designed vaccines, genetherapies, CAR-T cell treatments and immunotherapies, some patients may be cured even afterbecoming refractory after front- lines of Chemo. This therapeutic concept works well in someleukemias and lymphomas and is in the way to prove its worth in solid tumors.
It is known that cancer cells and tissues are very complex and heterogeneous. This heterogeneityimplies different gene mutations and cell kinetics with a great impact in clinics. Fast cell kinetics isrelated to better therapeutic responses as is the case in some testicular cancers, leukemias andlymphomas. There are also some “microanatomic” therapeutical targets not yet completelyunderstood but very promissory, like mitochondria and its peculiar metabolic pathways (implyingoncometabolites such as ketoglutarate); some glycolysis enzymes as potential targets, autophagyenhancement; aberrant Golgi apparatus glycosylation (important in the cell membrane
maintenance); exosomes and other extracellular vesicles, that transport mainly micro-RNAs;ribosome integrity; etc. The future will make us learn about how to properly and selectively arrivepharmacodynamically to them.
Checkpoint inhibitors immunotherapy is an exceptional novel treatment in a huge expansion phase,as is the development of small molecules that are directed to abnormal genes and their derivedproteins (proteomics). If we could block the main underlying mechanism of tumor progression, wecould say we are in good shape to cope with the disease outcome, as we could cure it or at leastmake it a chronic disease prolonging the stable disease status (SDS) of the patient.
After the DNA becomes “ill”, its altered translation message derives a great deal in protein kinases(PTKs) that phosphorylate other substrates that are also proteins, activating different cascades ofcell signaling pathways. Interactions protein-protein are of vital importance (e.g., KRAS-RAF),conducting many different processes that make the cell grow and proceed in its malignantprogression. This operative system can be compared to Tokyo’s subway, where there are so manystations with the possibility to take a train (protein) to make the right combination. But if one or twoof these trains that are central or neuralgic (drivers) suddenly stop, many others are affected. Thiscan be homologated to the blockade of a mutant driver gene in a cell signaling pathway that leads totumor cell growth.
Still blocking only one target is not enough, as there are probably many different malignant cellpopulations with other mutated drivers that finally lead to a pharmacodynamic resistance outcome.In Greek mythology, the Hydra of Lerma was an ancient aquatic monster in the form of apolycephalus serpent (whose number of heads ranges from three, five, seven or even moreaccording to the source). The Hydra had the virtue of regenerating two heads for each one that waslost or amputated. Hercules oversaw the phenomenon (one head of the hydra he cut, other twoheads appeared instead), teaching us in what sense tumorigenesis and tumor resistance may work.
Associated with the above-mentioned is the clonal expansion: as more tumor clones and subclonesdevelop, higher is the probability of tumor drug resistance due to tumor heterogeneity. This opensresearch to the fascinating area of tumor cell dynamics. Here, aspects as to why different clonesmay compete or cooperate between each other are still partially unmet scientific questions that needto be answered. For the moment, we can speak about the “mood of the clone” and probably thegrowth factor involved.
Inside the model that considers cancer as a disease of clonal evolution, an initially benign tumoraccumulates mutations that confer malignant phenotypes of increasing aggressiveness. Clonal celllineages may coexist and compete within a tumor, a phenomenon called clonal interference.Examples of this kind are tumor-associated mutations such as Myc gain-in-function, P53 pointmutations or loss-of-function, loss of ribosomal genes, aneuploidy and RAS gain-in-function, just tomention some of the known ones. On the other hand, two different clones that evolvedcomplementary traits may cooperate to render in higher tumor malignancy, even if each one byitself is not able to do so. In this sense the game theory, coming from computer science, mayperhaps be useful in the study of cell clone fate.
In brief, even when advances in current cancer therapeutics are enormous, as they are able to tacklemany different cellular targets and processes, future medicine must try to take advantage of growingknowledge about cell clone cooperation / competition in a tumor-specific way. In this sense, clonecompetition-based therapies are emerging as new potential avenues that can achieve the knock-outof the different underlying mechanisms of tumorigenesis and drug resistance. We are on this.
