{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T02:45:31Z","timestamp":1771987531686,"version":"3.50.1"},"reference-count":178,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>A series of seven clinical trials on relapsed or refractory (r\/r) metastatic neoplasias followed the question: Are networks of ligand-receptor cross-talks that support tumor-specific cancer hallmarks, druggable with tumor tissue editing approaches therapeutically exploiting tumor plasticity? Differential recombinations of pioglitazone, a dual peroxisome-proliferator activated receptor<jats:bold>\u03b1\/\u03b3<\/jats:bold> (PPAR\u03b1\/\u03b3) agonist, with transcriptional modulators, i.e., all-trans retinoic acid, interferon-\u03b1, or dexamethasone plus metronomic low-dose chemotherapy (MCT) or epigenetic modeling with azacitidine plus\/minus cyclooxygenase-2 inhibition initiated tumor-specific reprogramming of cancer hallmarks, as exemplified by inflammation control in r\/r melanoma, renal clear cell carcinoma (RCCC), Hodgkin\u2019s lymphoma (HL) and multisystem Langerhans cell histiocytosis (mLCH) or differentiation induction in non-promyelocytic acute myeloid leukemia (non-PML AML). Pioglitazone, integrated in differentially designed editing schedules, facilitated induction of tumor cell death as indicated by complete remission (CR) in r\/r non-PML AML, continuous CR in r\/r RCCC, mLCH, and in HL by addition of everolimus, or long-term disease control in melanoma by efficaciously controlling metastasis, post-therapy cancer repopulation and acquired cell-resistance and genetic\/molecular-genetic tumor cell heterogeneity (M-CRAC). PPAR\u03b1\/\u03b3 agonists provided tumor-type agnostic biomodulatory efficacy across different histologic neoplasias. Tissue editing techniques disclose that wide-ranging functions of PPAR\u03b1\/\u03b3 agonists may be on-topic focused for differentially unlocking tumor phenotypes. Low-dose MCT facilitates targeted reprogramming of cancer hallmarks with transcriptional modulators, induction of tumor cell death, M-CRAC control and editing of non-oncogene addiction. Thus, pioglitazone, integrated in tumor tissue editing protocols, is an important biomodulatory drug for addressing urgent therapeutic problems, such as M-CRAC in relapsed or refractory tumor disease.<\/jats:p>","DOI":"10.3389\/fonc.2023.1289222","type":"journal-article","created":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T04:34:10Z","timestamp":1704947650000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Peroxisome proliferator-activated receptor\u03b1\/\u03b3 agonist pioglitazone for rescuing relapsed or refractory neoplasias by unlocking phenotypic plasticity"],"prefix":"10.3389","volume":"13","author":[{"given":"Dennis 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