Year: 2016
Type: dissertation
Abstract: Cancer arises mostly due to the stepwise acquisition of untamed growth\ncapabilities by various means, ranging from genetic, epigenetic to\nenvironmental factors. With the advancement made in molecular biology and\nassociated fields, the complex biological circuits leading to these pathological\nconditions have now started to be deciphered in-depth. In the present thesis I\nhave shown that mouse exome sequencing may be used to guide targeted\ntherapy in animal models (Paper I). In this study, we for the first time made\nmakeshift genomes of two very popular mouse strains namely BALB/c and\nDBA/2J.\nIn a subsequent paper, we could translate the concept of genetics and mouse\nmodeling for guiding patient enrollment into future clinical trials (Paper II).\nThereafter, we used RNA sequencing to decipher similarities shared between\ncell line-derived xenografts (CDXs) and patient-derived xenografts (PDXs)\ndeveloped in Paper II. Despite similar mutational profiles, CDXs and PDXs\nwere very different irrespective of their genotype. Here, we unravel hypoxia and\nspecifically hsa-miR-210 as a key player orchestrating the differences (paper\nIII). To our dismay, abrogating the regulation dictated by miR-210 using a miR\ndecoy; makes this cells become less sensitive to MEK inhibition in vivo,\nsuggesting a possible role of hsa-miRNA-210 in conferring resistance to MEK\ninhibitors.\nMyc proto-oncogene is deregulated in vast majority of cancers types but\nunfortunately remains to be inhibited by pharmacological means to date.\nRecently, Bromodomain and extra-terminal (BET) protein inhibitors (like JQ1)\nhave been shown as an indirect means to inhibit Myc. We set out to test the new\nand orally bio-available BET inhibitor (RVX2135) in a transgenic mouse model\nλ-MYC Mouse), where pathogenicity of the disease may\nbe solely attributed to the over-expression of MYC. To our surprise, the data\nsuggested an effect of BET inhibition independent of Myc inhibition using\neither the prototype JQ1 or the novel compound in our systems (Paper IV).\nMoreover, we not only show a possible mechanistic insight of BETi but also\nunravel a synergistic combination of BET and HDAC inhibitors. In a follow up\npaper, we show lethal synergistic combinations of BET inhibitors and inhibitors\nof the replication stress kinase ATR in lymphomas (Paper V).\nTaken together, this thesis unravels the use of various genetic and epigenetic\ntargets as suitable candidates for therapeutical intervention either as standalone\nand/or in combination; deciphered using different methods as an effective\nstrategy for combating various cancer types both in vitro and in vivo.
Author: Joydeep Bhadury
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2368419298