A Novel Systems-Therapeutic Target: Integrating Acquired Genetic Aberrations Within Tissue Systems

Advanced cancers are characterized by remarkable resilience. Beyond driver mutations, tumor survival depends on the coordinated activity of vast networks of genes that are not themselves oncogenic but become essential for sustaining malignant growth — a phenomenon known as non-oncogene addiction (NOA). These NOA-driven circuitries integrate oncogenic signals across both tumor cells and the surrounding heterogeneous stroma, conferring viability and resistance to therapy.Understanding and dismantling NOA circuitries represents a promising but underexplored therapeutic strategy. Tumor tissue editing (TTE) has emerged as a framework for doing precisely this. TTE exploits receptor-triggered transcription factors — nuclear receptors and their ligands — to reprogram the transcriptional machinery that sustains NOA organizations in both cancer and stromal cells. Agents used in this context include PPARα/γ agonists (e.g., pioglitazone, rosiglitazone), all-trans retinoic acid (ATRA), dexamethasone, interferon-α, and hormone receptor agonists/antagonists.TTE gains further potency when receptor-triggered reprogramming is combined with agents that disrupt oncogenic transcriptional integration — referred to here as “jump starters.” These include:Metronomic low-dose chemotherapyHistone deacetylase (HDAC) inhibitorsTargeted therapies: mTOR inhibitors, MEK inhibitors, tyrosine kinase inhibitors, and immunomodulatory drugs (IMiDs, e.g., lenalidomide)Together, receptor-triggered transcription factors and jump starters work synergistically to reprogram or deconstruct the NOA circuitries that enable tumor persistence.Clinical and pre-clinical evidence supports this approach. TTE has demonstrated meaningful activity across relapsed/refractory (r/r) hematological malignancies, solid tumors, and sarcomas, with responses ranging from long-term disease stabilization to objective response and complete remission (CR) — including continuous CR in some cases. Critically, these responses appear genome-agnostic, suggesting that NOA circuitries are governed by oncogene-driven transcriptional networks rather than specific mutational profiles. This has been substantiated in clinical trials using differential TTE techniques.Looking ahead, the ability to diagnose NOAs, map NOA circuitries, and assess the editability of receptor-triggered transcription factors may become as clinically valuable as histological or molecular-genetic tumor classification is today — offering a new axis for personalized oncology.The aim of this Research Topic is to explore the systems-pharmacological potential of reprogramming or disrupting oncogenic data integration-driven NOA organizations as a novel therapeutic target.The main objectives are:To understand the role of non-oncogene addictions in tumor survival and stress responsesTo evaluate the therapeutic potential of reprogramming cancer hallmarks to overcome drug resistanceTo assess the differential activity of receptor-triggered transcription factors in combination with jump startersWe welcome original research, reviews, and clinical reports addressing, but not limited to, the following themes:Reprogramming hallmarks of cancer: induction of differentiation, control of tumor-associated inflammation, enhancement of immunosurveillance, metabolic reprogramming, and compromising tumor viabilityThe impact of receptor-triggered transcription factors on oncogenic integration: PPARα/γ agonists, ATRA, glucocorticoids, interferon-alpha, hormone receptors, bile acids, and related ligandsJump starters for receptor-triggered transcriptional modulation:Metronomic low-dose chemotherapyHDAC inhibitorsTargeted therapies (mTOR inhibitors, MEK inhibitors, IMiDs, tyrosine kinase inhibitors)In vitro studies, mouse models, and clinical trials using jump starters and receptor-triggered transcriptional modulation Topic editors: Albrecht Reichle, Dennis Christoph Harrer, Lina Ghibelli, Daniel Heudobler, Florian Lüke Source: https://www.frontiersin.org/research-topics/78745/a-novel-systems-therapeutic-target-integrating-acquired-genetic-aberrations-within-tissue-systems