Identifying Novel In Vivo Epigenetic Dependencies in Glioblastoma
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Case Western Reserve University School of Graduate Studies / OhioLINK
2016
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=case1464856610 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-case14648566102021-08-03T06:36:51Z Identifying Novel In Vivo Epigenetic Dependencies in Glioblastoma Miller, Tyler Eugene Biology Biomedical Research Neurology Pathology Genetics Medicine Molecular Biology Cellular Biology Cancer Brain Cancer Glioblastoma RNA interference RNAi shRNA screening in vivo screening epigenetics enhancers transcriptional regulation transcription pausing transcription pause-release JMJD6 histone demethylase Brain cancer is a devastating disease and a dreaded diagnosis for patients. Cancer within the brain, more than any other organ in the body, more than skin or colon or breast, is a difficult diagnosis to treat and live with because the brain is not just a part of the person, it is the person. Memories, personality, emotions, intelligence, speech and movement all originate in the brain. Therefore, when cancer, or the treatments used to fight the cancer, affect the brain by disrupting or damaging an area of the brain that controls these functions, it not only changes the body of the person, but changes the person. It is a particularly cruel disease. Glioblastoma is the most common and aggressive form of malignant brain cancer, which we currently have no way to effectively treat. The majority of patients die within 16 months of receiving a diagnosis, many times following aggressive surgery, radiation and chemotherapy, and then a sequelae of declining physical and cognitive function. Effective therapies are urgently needed for these patients. Many studies have identified potential therapeutic targets through in vitro screens or genomic sequencing, but this has not led to effective clinical therapies. Here we present a novel method of identifying potential drug targets in glioblastoma using advanced RNA interference screening in an in vivo orthotopic microenvironment. Using this system, we discover that screening within a functional microenvironment reveals novel targets that have been missed by traditional in silico or in vitro screening. We also demonstrate that our targets identified in vivo are more clinically relevant than targets we were able to identify in vitro using the same system. We focused our screening on epigenetic modifier genes, as many of these enzymes are sensitive to microenvironmental conditions and are potentially druggable. Within epigenetic modifier genes, we revealed that factors involved in transcription pause-release and elongation are critical dependencies for GBM cells in vivo, but not in vitro. We then identified the transcription pause-release factor JMJD6 as a lead candidate and demonstrate that inhibition of JMJD6 in GBM cells prolongs survival in preclinical studies. We also reveal that JMJD6 expression, and transcription elongation factors as a whole, can predict patient prognosis. Our work provides a rationale for targeting the transcription elongation machinery as a therapeutic strategy in glioblastoma. More broadly, it demonstrates the power of in vivo phenotypic screening to identify therapeutically relevant targets in cancer. 2016-09-13 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1464856610 http://rave.ohiolink.edu/etdc/view?acc_num=case1464856610 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biology Biomedical Research Neurology Pathology Genetics Medicine Molecular Biology Cellular Biology Cancer Brain Cancer Glioblastoma RNA interference RNAi shRNA screening in vivo screening epigenetics enhancers transcriptional regulation transcription pausing transcription pause-release JMJD6 histone demethylase |
| spellingShingle |
Biology Biomedical Research Neurology Pathology Genetics Medicine Molecular Biology Cellular Biology Cancer Brain Cancer Glioblastoma RNA interference RNAi shRNA screening in vivo screening epigenetics enhancers transcriptional regulation transcription pausing transcription pause-release JMJD6 histone demethylase Miller, Tyler Eugene Identifying Novel In Vivo Epigenetic Dependencies in Glioblastoma |
| author |
Miller, Tyler Eugene |
| author_facet |
Miller, Tyler Eugene |
| author_sort |
Miller, Tyler Eugene |
| title |
Identifying Novel In Vivo Epigenetic Dependencies in Glioblastoma |
| title_short |
Identifying Novel In Vivo Epigenetic Dependencies in Glioblastoma |
| title_full |
Identifying Novel In Vivo Epigenetic Dependencies in Glioblastoma |
| title_fullStr |
Identifying Novel In Vivo Epigenetic Dependencies in Glioblastoma |
| title_full_unstemmed |
Identifying Novel In Vivo Epigenetic Dependencies in Glioblastoma |
| title_sort |
identifying novel in vivo epigenetic dependencies in glioblastoma |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2016 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1464856610 |
| work_keys_str_mv |
AT millertylereugene identifyingnovelinvivoepigeneticdependenciesinglioblastoma |
| _version_ |
1719440051793821696 |