Epigenetic therapies in haematological malignancies: searching for true targets.
Epigenetic alterations complement genetic mutations as a molecular mechanism leading to cell transformation, and maintenance of the cancer phenotype. Of note, they are reversible by pharmacological manipulation of the enzymes responsible for chromatin modification: indeed, epigenetic drugs (histone deacetylase inhibitors and DNA demethylating agents) are currently on the market, inducing proliferative arrest and death of tumor cells. These drugs, however, have been effective only in a few tumor types: the lack of consistent clinical results is mainly due to their use in a poorly targeted approach, since the epigenetic alterations present in cancer cells are mostly unknown. In a few cases (notably, leukemias expressing RAR and MLL fusion proteins), the molecular mechanisms underlying tumor-selective and tumor-specific epigenetic alterations have started to be deciphered. These studies are revealing a dazzling complexity in the mechanisms leading to alterations of the epigenome, and the need of combination therapies targeting different chromatin modifiers to reach an effective reversion of epigenetic alterations.
Altucci
Lucia
L
Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Vico L. De Crecchio 7, 80138 Napoli, Italy.
Minucci
Saverio
S
European Institute of Oncology, Via Adamello 16, 20100 Milan, Italy; Department of Biomolecular Sciences and Biotechnologies, University of Milan, Via Celoria 26, 20100 Milan, Italy. Electronic address: saverio.minucci@ifom-ieo-campus.it.
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019175:DNA Methylation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion