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
More filters
Journal ArticleDOI
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.
Journal ArticleDOI
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.
Journal ArticleDOI
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.
Journal ArticleDOI
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
More filters
Journal ArticleDOI
Phase II Multi-Institutional Trial of the Histone Deacetylase Inhibitor Romidepsin As Monotherapy for Patients With Cutaneous T-Cell Lymphoma
Richard Piekarz,Robin Frye,Maria L. Turner,John Wright,Steven L. Allen,Mark Kirschbaum,Jasmine Zain,H. Miles Prince,John P. Leonard,Larisa J. Geskin,Craig B. Reeder,David Joske,William D. Figg,Erin R. Gardner,Seth M. Steinberg,Elaine S. Jaffe,Maryalice Stetler-Stevenson,Stephen Lade,A. Tito Fojo,Susan E. Bates +19 more
TL;DR: The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.
Journal ArticleDOI
Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia
Hagop M. Kantarjian,Yasuhiro Oki,Guillermo Garcia-Manero,Xuelin Huang,Susan O'Brien,Jorge E. Cortes,Stefan Faderl,Carlos E. Bueso-Ramos,Farhad Ravandi,Zeev Estrov,Alessandra Ferrajoli,William G. Wierda,Jianqin Shan,Jan Davis,Francis J. Giles,Hussain I. Saba,Jean Pierre J. Issa +16 more
TL;DR: It is concluded that a low-dose, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.
Journal ArticleDOI
Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer
Rosalyn A. Juergens,John Wrangle,Frank P. Vendetti,Sara C. Murphy,Ming Zhao,Barbara Coleman,Rosa Sebree,Kristen Rodgers,Craig M. Hooker,Noreli Franco,Beverly Lee,Salina Tsai,Igor Espinoza Delgado,Michelle A. Rudek,Steven A. Belinsky,James G. Herman,Stephen B. Baylin,Malcolm V. Brock,Charles M. Rudin +18 more
TL;DR: It is demonstrated that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.
Journal ArticleDOI
SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis
Alejandro Vaquero,Michael Scher,Dong-Hoon Lee,Ann Sutton,Hwei-Ling Cheng,Frederick W. Alt,Lourdes Serrano,Rolf Sternglanz,Danny Reinberg +8 more
TL;DR: The mammalian cytoplasmic protein SirT2 is a member of the Sir2 family of NAD+-dependent protein deacetylases involved in caloric restriction-dependent life span extension and has a strong preference for histone H4K16Ac in their de acetylation activity in vitro and in vivo.
Journal ArticleDOI
Epigenetic reprogramming and induced pluripotency
TL;DR: iPS cells provide a unique platform to dissect the molecular mechanisms that underlie epigenetic reprogramming, and can teach us about principles of normal development and disease, and might ultimately facilitate the treatment of patients by custom-tailored cell therapy.
Related Papers (5)
A decade of exploring the cancer epigenome — biological and translational implications
Stephen B. Baylin,Peter A. Jones +1 more