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Chemo and Radioresistance in Brain-Related Tumors

Perry, James David
http://rave.ohiolink.edu/etdc/view?acc_num=osu1397567849

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Glioblastoma and brain metastasis from breast cancer are two notoriously aggressive and difficult to treat neoplasms of the brain. Glioblastoma (GBM) is the most common adult brain tumor, affecting nearly 9,000 patients per year. Brain metastasis from breast cancer occurs in approximately 5% of patients overall, and in 10-16% of patients with metastatic disease. Median survival time for Glioblastoma patients is 15 months, while outcomes for breast cancer brain metastasis patients are also poor, with median survivals ranging from 3.4-25.3 months. In this work, we will introduce Galectin-1 as a novel regulator of the PI3K signaling pathway. Galectin-1 expression alters radioresistance in glioma cell lines, activates PI3K signaling in vitro and in cell culture, interacts with the PI3K enzyme, and prevents pharmacological inhibition of this enzyme. This data demonstrate that Galectin-1 directly modulates PI3K signaling leading to patient relevant outcomes and leads us to believe that Galectin-1 can serve as an alternative activator of the PI3K pathway. aVß3 integrins have been identified to play a direct role in tumor cell growth as well as invasion and metastasis. Here, we show that Galectin-1 may play a role in protecting glioma cells from the effects of cilengitide. Cilengitide induced detachment and apoptosis while reducing proliferation in slightly greater rates in Galectin-1 knockdown cells in an isogenic U87 cell model. This new information posits Galectin-1 as a molecule of interest as a possible predictive marker for cilengitide treatment efficacy. The ability of cilengitide to enhance the effects of radiation was examined preclinically in breast cancer cell lines. We demonstrated that cilengitide induced cellular detachment, reduced proliferation, and induced apoptosis in our cell line panel. Combined treatment with cilengitide and radiation served to further reduce proliferation compared to either treatment alone, although clonogenic assays did not show formal radiosensitization. Following ß3 integrin knockdown, radiosensitization in combination with cilengitide was observed in a previously non-responsive cell line (MDA-MB-231). These data suggest that the combination of radiation therapy and cilengitide may prove to be effective.
Arnab Chakravarti, MD (Advisor)
Tim Lautenschlaeger, MD (Committee Member)
Balveen Kaur, PhD (Committee Member)
Timothy Cripe , MD, PhD (Committee Member)
Chang-Hyuk Kwon, PhD (Committee Member)
136 p.
Biomedical Research; Molecular Biology
Glioblastoma; Galectin-1; Radiation, Cilengitide; Treatment Resistance; Breast Cancer Brain Metastasis

Recommended Citations

Citations

  • Perry, J. D. (2014). Chemo and Radioresistance in Brain-Related Tumors [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397567849

    APA Style (7th edition)

  • Perry, James. Chemo and Radioresistance in Brain-Related Tumors. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1397567849.

    MLA Style (8th edition)

  • Perry, James. "Chemo and Radioresistance in Brain-Related Tumors." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397567849

    Chicago Manual of Style (17th edition)

osu1397567849
356
© 2014, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.