Anakoinosis has been recently introduced as a global reprogramming of the communication
of tumor systems, which enables conceptualizing new treatment strategies to rescue
refractory tumors (Hart et al., 2015). This paradigm-shifting concept aims at revealing
anticancer treatments that could perturb the communications between cellular components
within tumors and in turn counteract sustained tumor growth. It is opposed to conventional
chemotherapy or targeted therapies that mainly kill cancer cells, or micro-environment
therapies such as anti-angiogenics (Jain et al., 2006) (i.e., anti-VEGF) or immune-modulators
(Sharma and Allison, 2015) (i.e., immune checkpoint inhibitors) that focus on one
given compartment of the tumor microenvironment. Instead, this new approach advocates
for combinations of agents that may not exert any activity when given as single agents
but which, when combined, can lead to treatment response by impacting the tumor on
multiple levels in a concerted systems biological manner. Of note, agonistically active
drugs are among the broad variety of regulatory active drugs that can be used for
anakoinosis.
Using the metaphor of cancer as a war can help visualize this approach (Oronsky et
al., 2014). “Operation overkill,” “hit hard, hit fast, and hit often” remind us about
the maximum tolerated dose chemotherapy concept, and suggest that cancer is an enemy
that we can defeat. However, when it comes to cancer, victory can only be achieved
through total eradication. Unfortunately, in the majority of cases, in particular
for metastatic and/or advanced diseases, this is not readily achievable. Moreover,
this paradigm can lead to counterproductive effects leading to selection of aggressive
cancer clones. Alternatively, one can imagine a guerilla strategy with repeated, coordinated
ambushes, sabotages and raids that can make the invaders gradually retreat and disappear.
This would be anakoinosis.
Some clinical examples of such strategies to treat refractory cancers have been reported
over the years. The combination used by Reichle et al. (Thomas et al., 2015) to treat
chemo-refractory acute myeloid leukemia with a combination of pioglitazone, low dose
5-azacytidine and all-trans retinoic acid, or the treatment reported by Pasquier et
al. to treat angiosarcoma with daily propranolol, weekly low dose vinblastine and
oral methotrexate (Pasquier et al., 2016) are illustrative examples of how this approach
can be used with some success. Interestingly, these protocols can also be regarded
as metronomics, which has been recently defined the combination of drug repurposing
and metronomic chemotherapy (André et al., 2013).
Metronomic chemotherapy was initially defined as the frequent administration of chemotherapeutic
drugs at doses significantly below the Maximum Tolerated Dose with no prolonged drug-free
breaks (Kerbel and Kamen, 2004) and more recently, as the minimum biologically effective
dose of a chemotherapeutic agent given as a continuous dosing regimen with no prolonged
drug-free breaks that leads to anti-tumor activity (Klement and Kamen, 2011). Initially
described as an antiangiogenic therapy, metronomic chemotherapy is now recognized
as an intrinsic multi-targeted therapy (Pasquier et al., 2010) that can not only impact
on several cellular components of the immune system (André et al., 2014) but also
directly impact and cancer cells or cancer stem cells (André et al., 2017). Additionally,
metronomic chemotherapy is frequently associated with drug repositioning, which consists
in using already-approved medications that were not originally developed as anticancer
drugs but whose antitumor properties have been unveiled (Bertolini et al., 2015).
While the definitions of metronomic is more PK grounded and anakoinosis PD grounded,
they overlap greatly as anakoinosis relies on reprogramming based drug repositioning
and metronomic administration of chemotherapy (vs. MTD chemotherapy) and metronomics
is now regarded as a multi-targeted anticancer therapy. Whether metronomic act through
forced/reprogramming behavior of cancer cells is an open debate and the term “reprogramming”
needs to be better defined.
Anyhow, looking at metronomics as an anakoinosis modulator can give us interesting
new insights about how this therapeutic strategy works, how can resistance occur,
how future protocols should be designed, and how preclinical work could explore the
full biologic impact of this approach. For instance, the acknowledgement of the multi-targeted
nature of metronomics may at least in part explain the relative failure to identify
reliable biomarkers when using metronomic approaches in the clinic that have mainly
focused on angiogenic biomarkers. Elsewhere, the complex combinations of anti-cancer
agents with metronomic etoposide, cyclophosphamide, thalidomide, fenofibrates, celecoxib,
bevacizumab and intrathecal aracytine and etoposide have been showed to induce long-term
remission or tumor control in refractory medulloblastoma or atypical rhabdoid terratoid
tumors in children (Peyrl et al., 2012), while none of the agent used can lead to
such effects when used as monotherapy. Interestingly, a similar combination without
thalidomide also led to tumor control in a primary refractory atypical rhabdoid terratoid
tumor (Berland et al., 2017), illustrating that at the individual level, not all drugs
are necessary to ensure clinical activity. However, the global combination of agents
would likely ensure activity in a majority of patients through simultaneous targeting
of important interacting molecular pathways and hubs resulting in a “biologic system”
targeting effect.
In fact, the concept of anakoinosis is similar in some ways to the chaotic perspective
of cancer (Coffey, 1998). Researchers and clinicians have focused on breaking down
tumors into individual (cells) and sub-individual elements (chromosomes, genes, mutations)
with ever-increasing details. However, one of the major resulting consequence is that
extrapolation from individual components behavior to the behavior of the whole system
is not reliable, mostly because non-linear interactions between the components render
the system chaotic (Weiss et al., 1994; Janecka, 2007). Moreover, at the outer edge
of chaos, communications between cancer cells and the system is altered, and cancer
cells grow at the expense of the larger system (Janecka, 2007)
Actually, the best strategies to control a chaotic system rely on the introduction
of small perturbations administered with good timing (Coffey, 1998). Therefore, by
relying on the frequent administration of agents at relatively low dose, metronomics
introduces small perturbations in the chaotic system and may therefore represent a
promising new approach to cancer treatment. Similarly, as proposed by Janecka (Janecka,
2007), treating a chaotic complex cancer system shall not rely on cellular killing
but on cellular “retraining”.
The recent introduction of the concept of anakoinosis unveils a new rationale to treat
cancer as well as a new frame to potentially understand the complex pharmaco-dynamics
of metronomics related to its intertwined biological effects.
Most studies have focused on metronomic chemotherapy as an anti-angiogenic strategy,
as a pro-immune strategy or more rarely as an anticancer cells strategy (André et
al., 2017; Orlandi et al., 2018). Metronomic chemotherapy has almost never been considered
to impact/reprogram a whole tumor system at several levels. Considering, metronomic
as an anakoinosis modulator introduces a paradigm shift which could pave the way for
better understanding and using it.
Author contributions
All authors contributed the concept of this opinion article, wrote, edited the drafts,
and final version of the manuscript.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.