Epigenome as a therapeutic target for lymphoma

Details

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Version: After imprimatur
Serval ID
serval:BIB_B97FFCFAB133
Type
PhD thesis: a PhD thesis.
Collection
Publications
Institution
Title
Epigenome as a therapeutic target for lymphoma
Author(s)
Bernasconi Elena
Director(s)
Bertoni Francesco
Institution details
Université de Lausanne, Faculté de biologie et médecine
Address
Institute of Oncology Research
Via Vela 6
6500 Bellinzona
Publication state
Accepted
Issued date
2017
Genre
Thèse (PhD)
Language
english
Number of pages
95
Abstract
Lymphomas are neoplasms derived from lymphoid cells at various stages of development and they are among the ten most frequent types of human cancer. Their incidence has dramatically increased in the past several decades. Although lymphomas are among the most curable tumors, the mortality rate of lymphoma is still very high. Thus, the development of novel treatment strategies and the identification of biological and genetic relevant targets are urgent. Genes involved in chromatin remodeling are very frequently altered in lymphomas, indicating the importance of aberrant epigenetic mechanisms, and providing a rationale to evaluate drugs targeting pathway deregulated in lymphomas.
The aim of this work was to study the anti-lymphoma activity of novel epigenetic drugs, understanding their mechanism of action and identifying biologic and genetic features associated with responses. For this purpose, novel HDAC (ST7612AA1) and BET inhibitors (OTX015/MK-8628, BAY 1238097, BAY-7575 and BAY-5627) were studied in numerous lymphoma preclinical models.
ST7612AA1 is a potent pan-histone deacetylase inhibitor, that targets and consequently inhibits different class I and class II HDACs. Here, in vitro and in vivo significant antitumor activity in lymphomas was demonstrated, which was linked with an ability to induce transcriptional changes of several genes involved in key biologic processes.
OTX015/MK-8628 is a BET bromodomain inhibitor targeting BRD2-3-4 nuclear kinases and, here, it was tested as single agent and in combination with a series of conventional and targeted anti-lymphoma agents, in mature B-cell lymphomas. OTX015/MK-8628 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC and E2F1-regulated genes, cell cycle regulation, and chromatin structure. OTX015/MK-8628 presented in vitro synergism with several anti-cancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degree of sensitivity to OTX015/MK-8628 were identified, and it was found that OTX015/MK-8628 induced apoptosis only in a genetically defined subgroup of cells, derived from activated B-cell like DLBCL, bearing WT TP53, mutations in MYD88 and CD79B or CARD11.
Finally, a set of three novel BET bromodomain inhibitors (BAY-7575, BAY-5627 and remarkably BAY 1238097) showed a wide pre-clinical antitumor activity in lymphoma models. These inhibitors affected important biologic pathways, such as MYC, NFKB, TLR and JAK/STAT.
Through this work, new therapeutic strategies to target the epigenome of the lymphoma cells to possibly increase the curability of lymphoma patients could be developed.
Keywords
Epigenome, bromodomain, HDAC
Create date
30/03/2017 10:33
Last modification date
20/08/2019 15:27
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