Communicative reprogramming non-curative hepatocellular carcinoma with low-dose metronomic chemotherapy, COX-2 inhibitor and PPAR-gamma agonist: a phase II trial

Walter, Ingrid; Vogelhuber, Martin; Wiedmann, K. H.; Endlicher, Esther; Klebl, Frank; Andreesen, Reinhard; Herr, Wolfgang; Ghibelli, Lina; Hackl, Christina; Wiest, Reiner; Reichle, Albrecht

doi:10.1007/s12032-017-1040-0

Cited by 26 publications

(38 citation statements)

References 43 publications

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“…In conclusion, in therapeutic perspectives it is not only the extent of apoptosis induced on cancer cells that determines the therapeutic outcome of anticancer therapies, but also the cell response and the type of cell death must be taken into account, considering that the final therapeutic effects depend on the dynamics existing between induced apoptosis and tissue repopulation, in addition to the well-known systemic effects. Consequently, the response of cancer to cytotoxic drugs depends on complex reprogramming mechanisms controlled by tumor microenvironment, recently described in clinical and translational studies as anakoinosis, the communicative reprogramming anticancer therapy Anakoinosis ( Hart et al, 2015 ), recently emerging as an innovative approach achieving important results even on metastatic cancers ( Thomas et al, 2015 ; Hart et al, 2016 ; Ugocsai et al, 2016 ; Walter et al, 2017 ). Indeed, the findings that low dose anticancer agents may promote and control signaling pathways, provide evidence of a pro-anakoinosis effect of DNA damaging anticancer drugs, even including pro-differentiation effects implying cell reprogramming.…”

Section: Discussionmentioning

confidence: 99%

Lowering Etoposide Doses Shifts Cell Demise From Caspase-Dependent to Differentiation and Caspase-3-Independent Apoptosis via DNA Damage Response, Inducing AML Culture Extinction

et al. 2018

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Cytotoxic chemotherapy, still the most widely adopted anticancer treatment, aims at eliminating cancer cells inducing apoptosis with DNA damaging agents, exploiting the differential replication rate of cancer vs. normal cells; efficiency is evaluated in terms of extent of induced apoptosis, which depends on the individual cell sensitivity to a given drug, and on the dose. In this in vitro study, we report that the concentration of etoposide, a topoisomerase II poison widely used in clinics, determines both the kinetics of cell death, and the type of apoptosis induced. We observed that on a set of myeloid leukemia cell lines, etoposide at high (50 uM) dose promoted a rapid caspase-3-mediated apoptosis, whereas at low (0.5 uM) dose, it induced morphological and functional granulocytic differentiation and caspase-2-dependent, but caspase-3-independent, cell death, displaying features consistent with apoptosis. Both differentiation and caspase-2- (but not 3)-mediated apoptosis were contrasted by caffeine, a well-known inhibitor of the cellular DNA damage response (DDR), which maintained cell viability and cycling, indicating that the effects of low etoposide dose are not the immediate consequence of damage, but the result of a signaling pathway. DDR may be thus the mediator responsible for translating a mere dosage-effect into different signal transduction pathways, highlighting a strategic action in regulating timing and mode of cell death according to the severity of induced damage. The evidence of different molecular pathways induced by high vs. low drug doses may possibly contribute to explain the different effects of cytotoxic vs. metronomic therapy, the latter achieving durable clinical responses by treating cancer patients with stable, low doses of otherwise canonical cytotoxic drugs; intriguingly caspase-3, a major promoter of wounded tissue regeneration, is also a key factor of post-therapy cancer repopulation. All this suggests that cancer control in response to cytotoxic drugs arises from complex reprogramming mechanisms in tumor tissue, recently described as anakoinosis.

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Section: Discussionmentioning

confidence: 99%

Lowering Etoposide Doses Shifts Cell Demise From Caspase-Dependent to Differentiation and Caspase-3-Independent Apoptosis via DNA Damage Response, Inducing AML Culture Extinction

et al. 2018

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“…The question for the appropriate dose of each drug in an anakoinosis inducing schedule can be answered only pragmatically, based on clinical results and scheduled dose reductions, but currently, not yet pharmacokinetically (Hart et al, 2015 ; Bocci and Kerbel, 2016 ; Ciccolini et al, 2017 ; Walter et al, 2017 ).…”

Section: Specific Methodological Aspects Of Anakoinosis Inducing Thermentioning

confidence: 99%

“…Starting point for the current review are a series of systematically developed clinical trials on refractory metastatic tumor diseases including at least one nuclear receptor agonist and metronomic low-dose chemotherapy or epigenetically active drugs as pro-anakoinotic therapy approaches (Hart et al, 2015 , 2016 ; Walter et al, 2017 ).…”

Section: Master Modulators the Backbone Of Anakoinosis Inducing Thermentioning

confidence: 99%

“…The worldwide alarming incidence of advanced liver cell carcinoma represents a great challenge for tumor therapy. An anakoinosis inducing therapy approach, including pioglitazone, COX-2 inhibitor and metronomic low-dose chemotherapy, has shown a comparably favorable influence on overall survival in advanced liver cell carcinoma, in comparison to more sophisticated systems therapies, including sorafenib, lenvatinib or anti-PD-1 antibodies (Walter et al, 2017 ). At that, an anakoinosis inducing therapy is cost-effective, and shows a lower toxicity rate.…”

Section: Master Modulators the Backbone Of Anakoinosis Inducing Thermentioning

confidence: 99%

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Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis

et al. 2018

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Classic tumor therapy, consisting of cytotoxic agents and/or targeted therapy, has not overcome therapeutic limitations like poor risk genetic parameters, genetic heterogeneity at different metastatic sites or the problem of undruggable targets. Here we summarize data and trials principally following a completely different treatment concept tackling systems biologic processes: the principle of communicative reprogramming of tumor tissues, i.e., anakoinosis (ancient greek for communication), aims at establishing novel communicative behavior of tumor tissue, the hosting organ and organism via re-modeling gene expression, thus recovering differentiation, and apoptosis competence leading to cancer control – in contrast to an immediate, “poisoning” with maximal tolerable doses of targeted or cytotoxic therapies. Therefore, we introduce the term “Master modulators” for drugs or drug combinations promoting evolutionary processes or regulating homeostatic pathways. These “master modulators” comprise a broad diversity of drugs, characterized by the capacity for reprogramming tumor tissues, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs etc., or for example differentiation inducing therapies. Data on 97 anakoinosis inducing schedules indicate a favorable toxicity profile: The combined administration of master modulators, frequently (with poor or no monoactivity) may even induce continuous complete remission in refractory metastatic neoplasia, irrespectively of the tumor type. That means recessive components of the tumor, successively developing during tumor ontogenesis, are accessible by regulatory active drug combinations in a therapeutically meaningful way. Drug selection is now dependent on situative systems characteristics, to less extent histology dependent. To sum up, anakoinosis represents a new substantive therapy principle besides novel targeted therapies.

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“…Particularly, these clinical trials in patients with diabetes type II highlight the striking anti-inflammatory component of PPARα. The initial hypothesis that efficacious anti-inflammatory therapy may also control advanced cancer could be confirmed by introducing pioglitazone in treatment of refractory metastatic cancer [ 4 , 5 ]. From pre-clinical data, the appropriate PPARα agonist for cancer treatment has to be defined, yet [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue

Heudobler

Rechenmacher

Lüke

et al. 2018

IJMS

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In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called ‘master modulators’ of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogramming of tumor tissues, i.e., anakoinosis, meaning ‘communication’ in ancient Greek. The concerted activity of master modulators may multifaceted diversify palliative care or even induce continuous complete remission in refractory metastatic tumor disease and hematologic neoplasia by establishing novel communicative behavior of tumor tissue, the hosting organ, and organism. Re-modulation of gene expression, for example, the up-regulation of tumor suppressor genes, may recover differentiation, apoptosis competence, and leads to cancer control—in contrast to an immediate, ‘poisoning’ with maximal tolerable doses of targeted/cytotoxic therapies. The key for uncovering the therapeutic potential of Peroxisome proliferator-activated receptor γ (PPARγ) agonists is selecting the appropriate combination of master modulators for inducing anakoinosis: Now, anakoinosis is trend setting by establishing a novel therapeutic pillar while overcoming classic obstacles of targeted therapies, such as therapy resistance and (molecular-)genetic tumor heterogeneity.

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Communicative reprogramming non-curative hepatocellular carcinoma with low-dose metronomic chemotherapy, COX-2 inhibitor and PPAR-gamma agonist: a phase II trial

Cited by 26 publications

References 43 publications

Lowering Etoposide Doses Shifts Cell Demise From Caspase-Dependent to Differentiation and Caspase-3-Independent Apoptosis via DNA Damage Response, Inducing AML Culture Extinction

Lowering Etoposide Doses Shifts Cell Demise From Caspase-Dependent to Differentiation and Caspase-3-Independent Apoptosis via DNA Damage Response, Inducing AML Culture Extinction

Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis

Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue

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