REVIEW article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Genome agnostic, multi-level non-oncogene addiction-based systems pharmacology for rescuing metastatic relapsed/refractory neoplasias
Dennis Christoph Harrer 1
Florian Lüke 1
Tobias Pukrop 1
Lina Ghibelli 2
Albrecht Reichle 1
Daniel Heudobler 1
1. University Medical Center Regensburg, Regensburg, Germany
2. University of Rome Tor Vergata, Rome, Italy, Rome, Italy
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Abstract
Rescue therapies for relapsed/refractory (r/r) metastatic neoplasias present significant unmet needs. Tumor tissue editing regimen for 13 r/r tumor types, carcinomas, sarcomas and hematologic neoplasias, included in 15 phase I/II trials, nuclear/cytokine receptor agonists, pioglitazone, plus/minus dexamethasone or all-trans retinoic acid or interferon-α to counterbalance tumor tissue homeostasis and reprogramming of cancer hallmarks, stress response inhibitors, COX-2 inhibitor, everolimus, lenalidomide, or clarithromycin, and a stress response inducer, low-dose metronomic chemotherapy with treosulfan, trofosfamide, capecitabine, or azacitidine. CR in three, cCR in another five r/r neoplasias, as the best response occurred after transcriptional reprogramming of cancer hallmarks, inflammation control or differentiation induction. Receptor agonist combinations for cCR induction can be identical among quite different tumor types and diversified within the same tumor histology. Data reveal ubiquitous, differential transcriptional access to non-oncogene addiction (NOA) networks that cope with cancer hallmarks/stress responses and three levels of therapeutic NOA targeting. (1) Agonists of nuclear/cytokine receptor NOAs critically target tumor identity and viability, while (2) transcriptional reprogramming of NOA networks that contribute to tumor tissue addiction, thereby genome-agnostically counteracting oncogene addictions. (3) Targeting edited NOAs may improve long-term outcome with CR/cCR (everolimus, IMiD). Transcriptionally accessible NOA targets offer high specificity, modest toxicity profile, low cost of therapy and outpatient treatment, independent of comorbidities. Adaptive targeting of the transcriptomic landscapes of tumor cell compartments breaks tumor tissue addiction and overcomes M-CRAC, post-therapy metastasis, cancer cell recolonization, acquired resistance and genetic heterogeneity. Thus, editing approaches
Summary
Keywords
Acute myelocytic leukemia, All-trans retinoic acid, Anakoinosis, Angiosarcoma, Azacitidine, Cancer hallmarks, Dexamethasone, Hodgkin's lymphoma
Received
15 May 2025
Accepted
09 January 2026
Copyright
© 2026 Harrer, Lüke, Pukrop, Ghibelli, Reichle and Heudobler. 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) or licensor 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.
*Correspondence: Albrecht Reichle
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