scispace - formally typeset
Search or ask a question
Journal ArticleDOI

The future of epigenetic therapy in solid tumours--lessons from the past.

01 May 2013-Nature Reviews Clinical Oncology (Nature Publishing Group)-Vol. 10, Iss: 5, pp 256-266
TL;DR: 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.

Content maybe subject to copyright    Report

Citations
More filters
Journal ArticleDOI
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.
Abstract: Genotyping tumor tissue in search of somatic genetic alterations for actionable information has become routine practice in clinical oncology. Although these sequence alterations are highly informative, sampling tumor tissue has significant inherent limitations; tumor tissue is a single snapshot in time, is subject to selection bias resulting from tumor heterogeneity, and can be difficult to obtain. Cell-free fragments of DNA are shed into the bloodstream by cells undergoing apoptosis or necrosis, and the load of circulating cell-free DNA (cfDNA) correlates with tumor staging and prognosis. Moreover, recent advances in the sensitivity and accuracy of DNA analysis have allowed for genotyping of cfDNA for somatic genomic alterations found in tumors. 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.

1,756 citations

Journal ArticleDOI
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.

882 citations


Cites background from "The future of epigenetic therapy in..."

  • ...…clinical trials have been initiated to investigate the possibility of extending their utilization to solid tumors, such as ovarian and lung cancers, either alone or in combination with other drugs (Azad et al., 2013; Juergens et al., 2011; Li et al., 2014; Matei et al., 2012;Wrangle et al., 2013)....

    [...]

  • ...Over the past few years, various DNAmethyltransferase inhibitors have been developed with the goal of reactivating aberrantly silenced genes, andmany of themhave shown encouraging results in both preclinical and clinical settings, highlighting the potential of epigenetic therapy (Azad et al., 2013; Balch and Nephew, 2013; Yamazaki and Issa, 2013)....

    [...]

  • ...More recently, clinical trials have been initiated to investigate the possibility of extending their utilization to solid tumors, such as ovarian and lung cancers, either alone or in combination with other drugs (Azad et al., 2013; Juergens et al., 2011; Li et al., 2014; Matei et al., 2012;Wrangle et al., 2013)....

    [...]

  • ...…inhibitors have been developed with the goal of reactivating aberrantly silenced genes, andmany of themhave shown encouraging results in both preclinical and clinical settings, highlighting the potential of epigenetic therapy (Azad et al., 2013; Balch and Nephew, 2013; Yamazaki and Issa, 2013)....

    [...]

Journal ArticleDOI
TL;DR: As epigenetic drugs target the epigenome as a whole, these true 'genomic medicines' lessen the need for precision approaches to individualized therapies.
Abstract: Next-generation sequencing has revealed that more than 50% of human cancers harbour mutations in enzymes that are involved in chromatin organization. Tumour cells not only are activated by genetic and epigenetic alterations, but also routinely use epigenetic processes to ensure their escape from chemotherapy and host immune surveillance. Hence, a growing emphasis of recent drug discovery efforts has been on targeting the epigenome, including DNA methylation and histone modifications, with several new drugs being tested and some already approved by the US Food and Drug Administration (FDA). The future will see the increasing success of combining epigenetic drugs with other therapies. As epigenetic drugs target the epigenome as a whole, these true 'genomic medicines' lessen the need for precision approaches to individualized therapies.

837 citations

Journal ArticleDOI
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.
Abstract: SUMMARYEpigenetic changes are present in all human cancers and are now known to cooperate with genetic alterations to drive the cancer phenotype. These changes involve DNA methylation, histone modifiers and readers, chromatin remodelers, microRNAs, and other components of chromatin. Cancer genetics and epigenetics are inextricably linked in generating the malignant phenotype; epigenetic changes can cause mutations in genes, and, conversely, mutations are frequently observed in genes that modify the epigenome. Epigenetic therapies, in which the goal is to reverse these changes, are now one standard of care for a preleukemic disorder and form of lymphoma. The application of epigenetic therapies in the treatment of solid tumors is also emerging as a viable therapeutic route.

771 citations


Cites background from "The future of epigenetic therapy in..."

  • ...…new possibilities in the area of epigenetic therapy—that is, where epigenetic changes are targeted for therapeutic reversal, as discussed further in Section 9 (Egger et al. 2004; Spannhoff et al. 2009; Kelly et al. 2010; Bernt et al. 2011; Daigle et al. 2011; Dawson et al. 2012; Azad et al. 2013)....

    [...]

  • ...In cancer, the epigenome is widely altered and drugs that can broadly “reprogram” such cells and blunt many tumor pathways may be the most valuable (Jones and Baylin 2007; Baylin and Jones 2011; Dawson et al. 2012; Azad et al. 2013; Ahuja et al. 2014)....

    [...]

  • ...HDACis, used alone, however, have had little success, especially in solid tumors (Azad et al. 2013; Ahuja et al. 2014)....

    [...]

  • ...…approach called “epigenetic therapy” has been developed in which drugs that can modify chromatin or DNA methylation patterns are used alone or in combination to affect therapeutic outcomes (Egger et al. 2004; Kelly et al. 2010; Dawson and Kouzarides 2012; Azad et al. 2013; Ahuja et al. 2014)....

    [...]

  • ...…action of these compounds for blocking the catalytic site of DNMTs is quite well understood and they have been used for some time to reactivate silenced genes in tissue culture or xenograft models (Santi et al. 1984; Ghoshal et al. 2005; Kelly et al. 2010; Tsai and Baylin 2011; Azad et al. 2013)....

    [...]

Journal ArticleDOI
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.

752 citations


Cites background from "The future of epigenetic therapy in..."

  • ...…such resistance with epigenetic therapies, such as use of small molecules that can reverse DNA methylation and histone deacetylation, have been the subjects of recent reviews, as have implications for targeting other chromatin regulatory proteins (Azad et al., 2013; Baylin and Jones, 2011)....

    [...]

References
More filters
Journal ArticleDOI
04 Mar 2011-Cell
TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

51,099 citations

Journal ArticleDOI
07 Jan 2000-Cell
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.

28,811 citations

Journal ArticleDOI
TL;DR: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.
Abstract: Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castrationresistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drugrelated adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)

10,674 citations

Journal ArticleDOI
23 Feb 2007-Cell
TL;DR: The surface of nucleosomes is studded with a multiplicity of modifications that can dictate the higher-order chromatin structure in which DNA is packaged and can orchestrate the ordered recruitment of enzyme complexes to manipulate DNA.

10,046 citations

Journal ArticleDOI
04 Oct 2012-Nature
TL;DR: The ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity.
Abstract: We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

9,355 citations