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      Metronomics: Intrinsic Anakoinosis Modulator?

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          Abstract

          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.

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          Metronomic chemotherapy: new rationale for new directions.

          Tumor angiogenesis is recognized as a major therapeutic target in the fight against cancer. The key involvement of angiogenesis in tumor growth and metastasis has started to redefine chemotherapy and new protocols have emerged. Metronomic chemotherapy, which is intended to prevent tumor angiogenesis, is based on more frequent and low-dose drug administrations compared with conventional chemotherapy. The potential of metronomic chemotherapy was revealed in animal models a decade ago and the efficacy of this approach has been confirmed in the clinic. In the past 5 years, multiple clinical trials have investigated the safety and efficacy of metronomic chemotherapy in a variety of human cancers. While the results have been variable, clinical studies have shown that these new treatment protocols represent an interesting alternative for either primary systemic therapy or maintenance therapy. We review the latest clinical trials of metronomic chemotherapy in adult and pediatric cancer patients. Accumulating evidence suggests that the efficacy of such treatment may not only rely on anti-angiogenic activity. Potential new mechanisms of action, such as restoration of anticancer immune response and induction of tumor dormancy are discussed. Finally, we highlight the research efforts that need to be made to facilitate the optimal development of metronomic chemotherapy.
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            Metronomics: towards personalized chemotherapy?

            Since its inception in 2000, metronomic chemotherapy has undergone major advances as an antiangiogenic therapy. The discovery of the pro-immune properties of chemotherapy and its direct effects on cancer cells has established the intrinsic multitargeted nature of this therapeutic approach. The past 10 years have seen a marked rise in clinical trials of metronomic chemotherapy, and it is increasingly combined in the clinic with conventional treatments, such as maximum-tolerated dose chemotherapy and radiotherapy, as well as with novel therapeutic strategies, such as drug repositioning, targeted agents and immunotherapy. We review the latest advances in understanding the complex mechanisms of action of metronomic chemotherapy, and the recently identified factors associated with disease resistance. We comprehensively discuss the latest clinical data obtained from studies performed in both adult and paediatric populations, and highlight ongoing clinical trials. In this Review, we foresee the future developments of metronomic chemotherapy and specifically its potential role in the era of personalized medicine.
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              Self-organization, complexity and chaos: the new biology for medicine.

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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                25 June 2018
                2018
                : 9
                : 689
                Affiliations
                [1] 1Service d'Hématologie et Oncologie Pédiatrique, Hôpital pour Enfants de La Timone, AP-HM , Marseille, France
                [2] 2Aix-Marseille Univ., Centre National de la Recherche Scientifique, INSERM, Institut Paoli Calmettes, CRCM , Marseille, France
                Author notes

                Edited by: Albrecht Reichle, Universitätsklinikum Regensburg, Germany

                Reviewed by: Patrizia Filetici, Consiglio Nazionale Delle Ricerche (CNR), Italy

                *Correspondence: André Nicolas nicolas.andre@ 123456ap-hm.fr

                This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2018.00689
                6026805
                7acf675e-93b3-42f7-966e-ebb87f52965e
                Copyright © 2018 Nicolas, Carré and Pasquier.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 April 2018
                : 07 June 2018
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 19, Pages: 3, Words: 1909
                Categories
                Pharmacology
                Opinion

                Pharmacology & Pharmaceutical medicine
                anakoinosis,metronomic chemotherapy,drug repositioning,biology of system,chaos

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