Advisor(s)
Anita Hjelmeland
Committee Member(s)
Christopher Willey
Gregory Friedman
James Markert
Lewis Shi
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Neurobiology
Date of Award
9-9-2024
Abstract
Central nervous system tumors, especially malignant brain tumors, account for the most years of potential life lost in adults and children with cancer. Malignant brain tumors are typically fatal cancers due to their highly aggressive nature, inability to obtain gross total resection, location in sensitive brain areas, and intra- and intertumoral heterogeneity, making therapeutic targeting difficult. High-grade glioma (HGG), malignant brain tumors of glial cell origin invariably recur due to intrinsic and adaptive resistance mechanisms against standard therapies. Therefore, novel treatments that overcome therapeutic resistance are desperately needed. One promising approach is oncolytic viruses (OVs), which achieve tumor regression by two separate oncolytic effects: 1) direct oncolysis of cancer cells through viral infection, replication, and lysis, and 2) stimulation of an antitumor immune response. Oncolytic herpes simplex virus-1 (oHSV) is the most studied OV in clinical trials of HGG and was recently proven safe, capable of turning immunologically “cold” tumors “hot,” and potentially efficacious in phase I and II trials. Herein, we demonstrate that acquired resistance to chemotherapy and radiation increases oHSV efficacy. Specifically, acquired resistance to the chemotherapy temozolomide (TMZ) leads to suppression of the antiviral type I interferon (IFN) pathway at the transcriptomic level in four of five patient-derived xenografts (PDXs). IFNβ secretion and IFN-stimulated gene expression were significantly decreased in a GBM cell line with acquired resistance to TMZ generated in vitro (U251T) in comparison to TMZ-sensitive, parental control cells (U251). These results were confirmed in GBM patient derived xenograft (PDX) cells with acquired resistance to TMZ generated in vivo (JX22T). oHSV infection was significantly increased in vitro in JX22T, JX39T, and U251T cells, and oncolysis was significantly increased in JX22T and U251T cells, independent of viral entry receptor CD111 expression. Finally, oHSV oncolysis was significantly increased in JX14 and X1153 PDXs with acquired resistance to radiation (JX14-RT, X1153-RT). Transcriptomic analyses of these PDXs suggested enhanced oHSV oncolysis is due to an IFN-independent pathway that has yet to be defined. This dissertation describes insights to acquired TMZ or radiation resistance, as well as determinants of oHSV efficacy, which may be leveraged for clinical gain.
ProQuest ID
Recommended Citation
Gary, Sam Edward, "Improving Direct Oncolytic Effect Of Oncolytic Hsv To Overcome Therapeutic Resistance Of Brain Tumors" (2024). All ETDs from UAB. 7580.
https://digitalcommons.library.uab.edu/etd-collection/7580
