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UBC Theses and Dissertations

The role of integrin-linked kinase in glioblastoma multiforme and its potential for targeted therapy Edwards, Lincoln A.

Abstract

Integrin-linked kinase (ILK) is a serine/threonine kinase that has been shown to be involved or implicated in diverse disease processes ranging from Alzheimer's disease to cancer. The involvement of ILK in cancer has been associated with its uncontrolled activation within cells due to the loss of its regulator, the tumor suppressor gene PTEN. Cellular events are tightly regulated by the actions of PTEN which can inhibit ILK activity. The focus of my thesis is to evaluate the role of ILK in glioblastoma cell lines and in vivo models derived from these cell lines. Three key questions were addressed: (i) Does ILK play a role in cancer progression in PTEN null glioblastoma cell lines? (Chapter 3) (ii) Given that combination therapy will provide optimal therapeutic results, what rationally chosen agents could be used in combination with an ILK inhibitor? (Chapters 4) And (iii) Is ILK a possible therapeutic target for the treatment of glioblastoma multiforme? (Chapters 5). It was hypothesizd that ILK is constitutively active in glioblastoma multiforme due to the high frequency of PTEN loss within this cancer and that targeting ILK alone and in combination would result in either tumor growth delay or cell death. Results from Chapter 3 indicate that ILK activity is elevated with loss of PTEN and verify ILKs role as an intermediate between PTEN regulation and PKB/Akt activation in glioblastoma cancer cells. Targeting ILK with an antisense oligonucleotide in vivo resulted in a significant tumor growth delay or stable disease (≤7% increase compared to a 100% increase of the saline treated control). Chapter 4 reveals that targeting ILK in combination with one other therapeutic agent (i.e. U0126) not only resulted in better therapeutic activity but that a synergistic combination could be achieved. Chapter 5 examined the effect of ILK targeting on tumor growth and the tumor micro-environment, suggesting that ILK inhibition may have antiangiogenic, chemo and radiosensitizing effects. These studies demonstrated the potential of ILK targeting in glioblastoma cancer, an important finding, given that this target had not been previously explored in GBM progression. In addition, the results offer key insights into the anti-tumor effects of targeting ILK alone and in combination as well as its role in the cell signaling pathogenesis in GBMs. These results also lay the foundation for pre-clinical data supporting the further exploration of ILK targeting for clinical use.

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