Targeting Chromatin-Mediated Transcriptional Control of Gene Expression in Non-Small Cell Lung Cancer Therapy: Preclinical Rationale and Clinical Results.
Targeting chromatin-mediated transcriptional control of gene expression is nowadays considered a promising new strategy, transcending conventional anticancer therapy. As a result, molecules acting as DNA demethylating agents or histone deacetylase inhibitors (HDACi) have entered the clinical arena in the last decade. Given the evidence suggesting that epigenetic regulation is significantly involved in lung cancer development and progression, the potential of epigenetically active compounds to modulate gene expression and reprogram cancer cells to a less aggressive phenotype is, at present, a promising strategy. Accordingly, a large number of compounds that interact with the epigenetic machinery of gene expression regulation are now being developed and tested as potential antitumor agents, either alone or in combination with standard therapy. The preclinical rationale and clinical data concerning the pharmacological modulation of chromatin organization in non-small cell lung cancer (NSCLC) is described in this review. Although preclinical data suggest that a pharmacological treatment targeting the epigenetic machinery has relevant activity over the neoplastic phenotype of NSCLC cells, clinical results are disappointing, leading only to short periods of disease stabilization in NSCLC patients. This evidence calls for a significant rethinking of strategies for an effective epigenetic therapy of NSCLC. The synergistic effect of concurrent epigenetic therapies, use at low doses, the priming of current treatments with previous epigenetic drugs, and the selection of clinical trial populations based on epigenetic biomarkers/signatures appear to be the cornerstones of a mature therapeutic strategy aiming to establish new regimens for reprogramming malignant cells and improving the clinical history of affected patients.
Laboratory of Cellular and Molecular Engineering "S. Cavalcanti", Department of Electrical, Electronic and Information Engineering "G. Marconi" (DEI), University of Bologna, via Venezia 52, 47521, Cesena, FC, Italy. alice.pasini@unibo.it.
Alice
A
Pasini
Department of Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, FC, Italy.
Angelo
A
Delmonte
Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, FC, Italy.
Anna
A
Tesei
Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, FC, Italy.
Daniele
D
Calistri
Laboratory of Cellular and Molecular Engineering "S. Cavalcanti", Department of Electrical, Electronic and Information Engineering "G. Marconi" (DEI), University of Bologna, via Venezia 52, 47521, Cesena, FC, Italy.|Health Sciences and Technologies, Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Cesena, FC, Italy.
Emanuele
E
Giordano
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D002843:Chromatin / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*
D000970:Antineoplastic Agents; D002843:Chromatin