Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue—Going Beyond Apoptosis Induction

Abstract

The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing apoptosis of cancer cells by blocking tumor-promoting signaling pathways or by eradicating cell compartments within the tumor. In contrast, a systems view of therapy primarily considers the communication protocols that exist at multiple levels within the tumor complex, and the role of key regulators of such systems. Such regulators may have far-reaching influence on tumor response to therapy and therefore patient survival. This implies that neoplasia may be considered as a cell non-autonomous disease. The multi-scale activity ranges from intra-tumor cell compartments, to the tumor, to the tumor-harboring organ to the organism. In contrast to molecularly targeted therapies, a systems approach that identifies the complex communications networks driving tumor growth offers the prospect of disrupting or "normalizing" such aberrant communicative behaviors and therefore attenuating tumor growth. Communicative reprogramming, a treatment strategy referred to as anakoinosis, requires novel therapeutic instruments, so-called master modifiers to deliver concerted tumor growth-attenuating action. The diversity of biological outcomes following pro-anakoinotic tumor therapy, such as differentiation, trans-differentiation, control of tumor-associated inflammation, etc. demonstrates that long-term tumor control may occur in multiple forms, inducing even continuous complete remission. Accordingly, pro-anakoinotic therapies dramatically extend the repertoire for achieving tumor control and may activate apoptosis pathways for controlling resistant metastatic tumor disease and hematologic neoplasia.

A Randomized Phase II Trial Comparing the Efficacy and Safety of Pioglitazone, Clarithromycin and Metronomic Low-Dose Chemotherapy with Single-Agent Nivolumab Therapy in Patients with Advanced Non-small Cell Lung Cancer Treated in Second or Further Line (ModuLung)

“…The clinical discrepancy between poor PFS in the biomodulation arm and a corresponding median OS equal to nivolumab second-line therapy may be discussed on the background of pre-clinical data showing multifold biomodulatory activities of the drug components administered in the experimental schedule ( Teresi et al, 2006 , 2006 ; Gottfried et al, 2011 ; Ge et al, 2012 ; Peng et al, 2015 ; van Nuffel et al, 2015 ; Heudobler et al, 2018b ; Chowdhury et al, 2018 ; Heudobler et al, 2019b ; Renner et al, 2019 ; Bahrambeigi et al, 2020 ; Batyrova et al, 2020 ; Fu et al, 2020 ). Summarizing the present clinical results and preclinical findings on the activity profile of single scheduled drugs, both datasets are hypothesis generating and suggest an impact of biomodulation on efficacy of the consecutive nivolumab therapy in third to fifth line.…”

“…Thus, the drug cocktail of the biomodulatory treatment arm may contribute to correcting aberrant homeostasis in cancer tissue, beyond the expected main effect, namely apoptosis induction, a procedure called anakoinosis ( Heudobler et al, 2019b ).…”

“…metabolic plasticity of tumor tissues ( Desbats et al, 2020 ). In contrast to classic targeted therapies and cytotoxic therapies, novel anakoinosis-inducing therapies may meet potential challenges arising with treatment-associated secondary changes in tumor tissue by establishing novel tissue homeostasis in a therapeutically meaningful way ( Heudobler et al, 2019b ). A time to second objective disease progression (PFS2) benefit in prospective trials or the induction of ‘biological memory’ clearly indicate the sustainable biomodulatory activity profile of drugs or drug combinations acting as pro-anakoinotic ‘master modifiers’ of tumor tissue ( Hart et al, 2015 ; Jackson et al, 2019 ; Bahlis et al, 2020 ).…”

“…A time to second objective disease progression (PFS2) benefit in prospective trials or the induction of ‘biological memory’ clearly indicate the sustainable biomodulatory activity profile of drugs or drug combinations acting as pro-anakoinotic ‘master modifiers’ of tumor tissue ( Hart et al, 2015 ; Jackson et al, 2019 ; Bahlis et al, 2020 ). ‘Master modifiers’ may prime tumor tissue in a clinically relevant way ( Hart et al, 2015 ; Heudobler et al, 2018a ; Heudobler et al, 2019b ). The major novel therapeutic aspect introduced by anakoinosis is considering tumor disease as a non-cell autonomous disease also in terms of therapeutic purposes ( Heudobler et al, 2019b ).…”

“…Our group has shown that a combination of therapies modulating tumor angiogenesis, inflammation and immune response can result in a significant survival benefit in patients with various advanced malignancies (reviewed in ( Hart et al, 2015 )). This approach, called biomodulation, aims to induce communicative reprogramming of dysregulated cellular and intercellular homeostasis (anakoinosis) ( Heudobler et al, 2019b ). In the trial reported here, biomodulation consisted of a combination of pioglitazone, clarithromycin and low-dose metronomic treosulfan.…”