Molecular Pathways: The Complexity of the Epigenome in Cancer and Recent Clinical Advances

Abstract

Human cancer is causally linked to genomic and epigenomic deregulations. Epigenetic abnormalities occurring within signaling pathways regulating proliferation, migration, growth, differentiation, transcription, and death signals may be critical in the progression of malignancies. Consequently, identification of epigenetic marks and their bioimplications in tumors represents a crucial step toward defining new therapeutic strategies both in cancer treatment and prevention. Alterations of writers, readers, and erasers in cancer may affect, for example, the methylation and acetylation state of huge areas of chromatin, suggesting that epi-based treatments may require "distinct" therapeutic strategies compared with "canonical" targeted treatments. Whereas anticancer treatments targeting histone deacetylase and DNA methylation have entered the clinic, additional chromatin modification enzymes have not yet been pharmacologically targeted for clinical use in patients. Thus, a greater insight into alterations occurring on chromatin modifiers and their impact in tumorigenesis represents a crucial advancement in exploiting epigenetic targeting in cancer prevention and treatment. Here, the interplay of the best known epi-mutations and how their targeting might be optimized are addressed. Clin Cancer Res; 18(20); 5526-34. Ó2012 AACR.

c-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer

“…Although HDACi have often been described as preferentially tumor selective, the underlying mechanism(s) of their action remain unclear (8,46). To establish markers of HDACi response, it is crucial to investigate their effect ex vivo and in vivo on patients in order to validate data from in vitro experimentation.…”

“…First, MYC is one of the most frequently altered genes in cancer and is strongly modulated by HDACi. Second, clinical trials using HDACi are ongoing against all major cancer types including AMLs (6,8,52). Third, to date, only one gene, HR23B, has been proposed as potentially predictive for HDACi response in cancer patients, although only in cutaneous T-cell lymphoma (CTCL; refs.…”

“…Epigenetic transcriptional repression of tumor suppressor genes, cell cycle and DNA repair, and activation of invasion-and metastasis-regulating genes has been demonstrated in a wide variety of tumors. Recently, the effects of DNA methyltransferase inhibitors (DNMTi) and/or histone deacetylase inhibitors (HDACi) in advanced cancers have been investigated in clinical trials (6)(7)(8); at least 15 HDACi are currently under clinical investigation either alone or in combination with other therapeutic modalities for the treatment of hematological and solid malignancies (9).…”

Genetic mutations in epigenetic modifiers as therapeutic targets in acute myeloid leukemia

“…Treatment with epidrugs may inhibit enzymes such as DNMTs or HDACs, reactivating the transcription of silenced genes and restoring normal cellular growth and differentiation [122]. Recently, the effects of DNMTi, such as 5-AZA and decitabine, and/or HDAC inhibitors, such as SAHA, romidepsin and more recently LBH589, in AML have been investigated in clinical trials [123]. These epidrugs are currently under clinical investigation either alone or in combination with other therapeutic modalities for the treatment of hematological malignancies [122].…”

Novel Antiproliferative Chimeric Compounds with Marked Histone Deacetylase Inhibitory Activity

“…2−4 In the present report, we applied this paradigm to develop novel multifunctional ligands able to interfere with different molecular pathways involved in neoplastic diseases, specifically targeting some control mechanisms of epigenetics 5,6 and cell cycle progression.…”