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Integrin Linked Kinase as a therapeutic target for treating breast cancer : the value of using multiple endpoints to assess therapeutic effects of targeted drugs and drug combinations

University of British Columbia

Substantial preclinical evidence indicates that inhibition of Integrin Linked-Kinase (ILK) correlates with cytotoxic/cytostatic cellular effects, delayed tumour growth in animal models of cancer and inhibition of angiogenesis. It is increasingly evident that optimal therapeutic benefits obtained using ILK targeting strategies will only be achieved in combination settings. For this reason the therapeutic potential of the ILK small molecule inhibitor, QLT0267, alone or in combination with chemotherapies commonly used to treat breast cancer patients was investigated. The results suggested that the combination of QLT0267 and docetaxel (Dt) interacted synergistically when assessing metabolic activity as a therapeutic endpoint. Further endpoint analysis in cell lines with low Her2/neu levels revealed that the QLT0267/Dt combinations resulted in a 3- fold decrease in concentration of QLT0267 required to achieve 50% inhibition of P-AKT. For Her2/neu positive cell lines the QLT0267/Dt combination was antagonistic. In vivo studies using breast cancer cells (LCC6) implanted orthotopically demonstrated that treatment with QLT0267/Dt engendered improved therapeutic effects. Using luciferase positive LCC6 cells metastatic, orthotopic and ascites tumour models were characterized. The results suggested that the orthotopic LCC6 tumour model was most sensitive to docetaxel. Using the more docetaxel treatment refractory LCC6 model (disseminated disease) it was shown that QLT0267 could not sensitize the tumours to Dt treatment. These data suggest that clinical benefits of QLT0267/Dt in patients with breast cancer would most likely be observed used in the adjuvant or neoadjuvant setting. Finally, preliminary studies indicate that the effects of QLT0267 were influenced by Her2/neu expression. To understand how, six Her2/neu positive breast cancer cell lines were evaluated following treatment with QLT0267. These cell lines demonstrated suppression (32 to 87%) of total Her2/neu protein. Attenuation of ILK activity or expression was associated with decreases in YB-1 protein and transcript levels and decreased YB-1 promoter activity. YB-1 is a known transcriptional regulator of Her2/neu expression. ILK inhibition also engendered suppression in TWIST (a regulator of YB-1 expression) protein expression. Taken together, these data indicate that ILK regulates the expression of Her2/neu through TWIST and YB-1, lending support to the use of ILK inhibitors in the treatment of aggressive Her2/neu positive tumours.

Text

2010-07-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/27023

Pathology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/