| Summary: | 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. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate
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