With its March 28, 2014 title cover: “Solving Cancer/You Can`t Cure What You Don`t Understand”, Newskeek magazine posited the idea that our failure to cure cancer comes from our lack of grasping its full complexity. In an attempt to find the ever elusive panacea for cancer, contemporary science has put forth three main paradigms that I will describe briefly.
The xenobiont - “Cancer is an alien”. Over the last four decades, cancer has been considered principally a genetic disease and the research focus has been to characterize the nature and number of genes associated with oncogenesis. Today, it is clear that at the genetic level, each individual cancer has a unique make-up harboring idiosyncratic genetic alterations(1). Some of these genetic alterations are called “drivers” because they “drive” the oncogenic process and the cancer cells become “addicted” to them. Since Paget’s “magic bullet” concept, the main strategy in research has been the Nixonian “war on cancer”, which strove to define and target the idiosyncratic features of “the enemy.” The idea of cancer as being radically different has been recently pushed to extreme by Mark Vincent from the University of Western Ontario, who describes cancer a “protozoan-like organism”, “foreign to its host”, growing inside the human body(2). Like an alien unicellular life form, a xenobiont arises out of the reactivation in the genome of an “ancient de-repressed survival program”. The xenobiontic strategy has been used to design a plethora of genomic-driven molecular targeted therapy agents.
The symbiont - “Cancer is a parasite”. Robert Gatenby, at the Moffitt Cancer Center, proposed to “make peace” on cancer, and invented a novel anti-cancer approach called “adaptive therapy”(3). This anti-Nixonian strategy consists in the continuous administration of smaller than usual chemotherapy doses, in metronomic-like fashion, that would not completely eradicate the cancer cells, but it would prevent resistant clones from developing; thus, creating a parasite-host symbiotic state between the cancer cells and the normal organism. An example of the symbiotic approach is the use of maintenance treatment after achieving stable disease.
The oncobiont - “Cancer is an altered cellular program”. The current paradigm sees cancer as a chaotic disorganization of the cellular functions caused by random genetic mutations subject to Darwinian selection. The oncobiont paradigm considers the changes that occur inside the cancer cell as non-random transformations due to the switch to a modified cellular program that can be re-written or re-run differently, leading to a non-neoplastic state. Such “reprogramming” could bypass the genetic abnormalities present in cancer through rerouting the cancer cell phenotype to a benign phenotype(4,5). A succesful oncobiontic intervention is the use of all-trans retinoic acid (ATRA) in acute pro-myelocytic leukemia (APL).
The above three paradigms are informative and should be integrated in carefully orchestrated interventions, such as: a) targeting the idiosyncrasies of cancer; b) inducing a symbiosis between cancer and the normal organism and c) designing signals able to “modify” the cancer program. Applying these approaches in the appropriate clinical setting, hopefully, will improve the prognostic of cancer patients.