The future of epigenetic therapy in solid tumours--lessons from the past.
TLDR
It is hypothesized that in using low-dose epigenetic-modulating agents, tumour cells can be reprogrammed, which overrides any immediate cytotoxic and off-target effect observed at high dose, and could give these agents a prominent place in cancer management.Abstract:
The promise of targeting epigenetic abnormalities for cancer therapy has not been realized for solid tumours, although increasing evidence is demonstrating its worth in haematological malignancies. In fact, true clinical efficacy in haematopoietic-related neoplasms has only become evident at low doses of epigenetic-targeting drugs (namely, inhibitors of histone deacetylase and DNA methyltransferases). Describing data from preclinical studies and early clinical trial results, we hypothesize that in using low-dose epigenetic-modulating agents, tumour cells can be reprogrammed, which overrides any immediate cytotoxic and off-target effect observed at high dose. We suggest that such optimization of drug dosing and scheduling of currently available agents could give these agents a prominent place in cancer management--when used alone or in combination with other therapies. If so, optimal use of these known agents might also pave the way for the introduction of other agents that target the epigenome.read more
Citations
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Liquid Biopsies: Genotyping Circulating Tumor DNA
Luis A. Diaz,Alberto Bardelli +1 more
TL;DR: The ability to detect and quantify tumor mutations has proven effective in tracking tumor dynamics in real time as well as serving as a liquid biopsy that can be used for a variety of clinical and investigational applications not previously possible.
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Gene Body Methylation Can Alter Gene Expression and Is a Therapeutic Target in Cancer
Xiaojing Yang,Han Han,Daniel D. De Carvalho,Daniel D. De Carvalho,Fides D. Lay,Peter A. Jones,Gangning Liang +6 more
TL;DR: It is shown that 5-aza-2'-deoxycytidine treatment not only reactivates genes but decreases the overexpression of genes, many of which are involved in metabolic processes regulated by c-MYC.
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Targeting the cancer epigenome for therapy
TL;DR: As epigenetic drugs target the epigenome as a whole, these true 'genomic medicines' lessen the need for precision approaches to individualized therapies.
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Epigenetic Determinants of Cancer
Stephen B. Baylin,Peter A. Jones +1 more
TL;DR: Epigenetic therapies are one standard of care for a preleukemic disorder and form of lymphoma and the application of epigenetic therapies in the treatment of solid tumors is also emerging as a viable therapeutic route.
Journal ArticleDOI
Cancer Epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance
TL;DR: The possible role of epigenetic abnormalities as well as genetic alterations in such dynamics and in the creation of cellular heterogeneity in cancers of all types are discussed.
References
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Journal ArticleDOI
DNA Methylation Screening Identifies Driver Epigenetic Events of Cancer Cell Survival
Daniel D. De Carvalho,Shikhar Sharma,Jueng Soo You,Sheng-Fang Su,Phillippa C. Taberlay,Theresa K. Kelly,Xiaojing Yang,Gangning Liang,Peter A. Jones +8 more
TL;DR: Experimental and bioinformatic approaches showed experimentally that these genes must be silenced by DNA methylation for cancer cell survival, suggesting these are key epigenetic events associated with tumorigenesis.
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Molecular coupling of DNA methylation and histone methylation
TL;DR: The domain structure of the DNA methyltransferase DNMT1, its accessory protein UHRF1 and their associated proteins are considered, and a mechanism by which DNA methylation and histone methylation may be coordinately maintained through mitotic cell division is proposed.
Journal ArticleDOI
EZH2 mutational status predicts poor survival in myelofibrosis
Paola Guglielmelli,Flavia Biamonte,Joannah Score,Joannah Score,Claire Hidalgo-Curtis,Claire Hidalgo-Curtis,Francisco Cervantes,Margherita Maffioli,Tiziana Fanelli,Thomas Ernst,Nils Winkelman,Amy V. Jones,Amy V. Jones,Katerina Zoi,Andreas Reiter,Andrew S Duncombe,Laura Villani,Alberto Bosi,Giovanni Barosi,Nicholas C.P. Cross,Nicholas C.P. Cross,Alessandro M. Vannucchi +21 more
TL;DR: EZH2 mutations are independently associated with shorter survival in patients with PMF and in multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZh2 mutation status.
Journal ArticleDOI
A DNA hypermethylation module for the stem/progenitor cell signature of cancer
Hariharan Easwaran,Sarah E. Johnstone,Leander Van Neste,Joyce E. Ohm,Tim Mosbruger,Qiuju Wang,Martin J. Aryee,Patrick Joyce,Nita Ahuja,Daniel J. Weisenberger,Eric A. Collisson,Jingchun Zhu,Srinivasan Yegnasubramanian,William Matsui,Stephen B. Baylin +14 more
TL;DR: Evidence is provided that DNA hypermethylation preferentially targets the subset of PcG genes that are developmental regulators, and this may contribute to the stem-like state of cancer.
Journal ArticleDOI
Resistance to BRAF inhibition in melanomas.
David B. Solit,Neal Rosen +1 more
TL;DR: PLX4032, an inhibitor of activated BRAF, has shown clinical efficacy in treating patients with melanomas carrying an activating mutation in BRAf, but resistance to the drug develops in some patients.
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