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Evaluation of novel anti-metastatic therapy
[Thesis]. Manchester, UK: The University of Manchester; 2011.
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Abstract
The occurrence of metastasis from the primary tumour to distant organs is the primary cause of cancer mortality and therefore a highly attractive therapeutic target to improve cancer survival rates. Targeted anti-metastatic therapies hold the potential for lower cancer mortality rates, lower rates of reoccurrence and better quality of life for cancer patients. Src is a non receptor tyrosine kinase, and the first recognized oncogene, which is known to play a role in metastasis. Increased activity of SFKs has been found in many human tumours, correlating with invasiveness and poor prognosis, and in experimental tumour cell lines, contributing to enhanced cell migration and invasion, adhesion independent growth, survival and proliferation. Despite a body of evidence in pre-clinical trials demonstrating that inhibition of Src reduces the occurrence of cellular events associated with metastasis in vitro, and reduces tumour metastasis to distant organs in in vivo models, efficacy has not translated to phase II clinical trials. One such recent failure has been a phase II trial with the Src inhibitor AZD0530 in recurrent advanced or metastatic soft tissue sarcoma. Here we investigate the anti-metastatic effects of Src inhibition in the HT1080 fibrosarcoma cell in vitro in order to elucidate further the effects of SFK inhibition in sarcoma cells laying the ground work for future in vivo work investigating potential compensatory mechanism overcoming SFK inhibition in sarcoma cells. We found that SFK inhibition of HT1080 cells with AZD0530 inhibited cell migration and spreading but had no effect on cell polarization. AZD0530 treatment caused active paxillin (Tyr31-p) to relocalize from focal adhesions to the cytoplasm but had no effect on staining of active FAK (Tyr861-p). Paradoxically AZD0530 treatment led to increased phosphorylation of Src at the negative regulatory site Tyr 530. Results seen here provide evidence to warrant further elucidation of the effects of Src inhibition in HT1080 cells in order to elucidate potential combination therapies and biomarkers of tumour sensitivity to Src inhibition.