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SCREENING FOR EPIGENETIC INHIBITORS OF OSTEOSARCOMA METASTASIS

Bayles, Ian Matthew
http://orcid.org/0000-0003-1669-6412
http://rave.ohiolink.edu/etdc/view?acc_num=case1579859055599871

Abstract Details

2020, Doctor of Philosophy, Case Western Reserve University, Genetics.
Osteosarcoma is a the most common cancer of the bone, known for its notoriously complex and heterogeneous genotypes and high propensity to metastasize to the lung. When distal metastatic lesions present in patients, mortality rates increase significantly. Indeed, this is the case across all tumors with metastasis being responsible for 90% of all cancer deaths. For this reason, there is a dire need to identify new therapeutic options for patients with metastasis. Part of this issue originates in the fact that the majority of current therapies were designed to treat primary tumors, not distal metastasis. Additionally, the methods by which most therapeutic compounds are identified does not take into account the effects of the tumor microenvironment and how this setting might affect the tumor’s response to these compounds. Previous studies in our lab have identified that enhancer dysregulation is an essential process in osteosarcoma metastasis, driving cellular programs critical to invasion and colonization of the lungs. To this end, we developed an ex vivo metastasis screening system to identify compounds effective in the context of the metastatic microenvironment. In chapter 2, we describe the development of a targeted screen and identify that transcriptional CDK inhibitors, particularly CDK12 inhibitors, seem to be potent in reducing osteosarcoma metastasis in the lung. We go on to examine the effects of these inhibitors on the chromatin and transcriptome of osteosarcoma cells and identify the mechanisms through which they inhibit metastasis and kill the cells. These results provide evidence that CDK12 inhibitors could be a potential therapeutic option for treating osteosarcoma metastasis and further reinforces the notion that the metastatic microenvironment needs to be considered when evaluating anti-tumor compounds.
Peter Scacheri (Advisor)
Ahmad Khalil (Committee Chair)
Edward Greenfield (Committee Member)
Fulai Jin (Committee Member)
135 p.
Biomedical Research; Cellular Biology; Genetics; Medicine; Molecular Biology; Oncology
osteosarcoma; epigenetics; drug screening; cancer; drug discovery; assay development

Recommended Citations

Citations

  • Bayles, I. M. (2020). SCREENING FOR EPIGENETIC INHIBITORS OF OSTEOSARCOMA METASTASIS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1579859055599871

    APA Style (7th edition)

  • Bayles, Ian. SCREENING FOR EPIGENETIC INHIBITORS OF OSTEOSARCOMA METASTASIS . 2020. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1579859055599871.

    MLA Style (8th edition)

  • Bayles, Ian. "SCREENING FOR EPIGENETIC INHIBITORS OF OSTEOSARCOMA METASTASIS ." Doctoral dissertation, Case Western Reserve University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1579859055599871

    Chicago Manual of Style (17th edition)

case1579859055599871
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© 2019, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.