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Title: Activation of MAPK signalling results in resistance to therapies for ovarian cancer
Author: McGivern, Niamh
ISNI:       0000 0004 5990 651X
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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Ovarian cancer is the fifth most common cancer affecting women in the UK, and is the most lethal of all gynaecological cancers. Treatment primarily consists of debulking surgery followed by a platinum and taxane based chemotherapy, and despite initial high levels of response, the majority of women will relapse with platinum resistant disease, resulting in a poor prognosis. Few targeted therapies have entered the clinic for the treatment of ovarian cancer, however there is strong preclinical data to suggest there is a therapeutic window to target SRC tyrosine kinase in this disease. The SAPPROC trial was a phase 11 trial investigating the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel in platinum resistant ovarian cancer, however, this study showed no benefit to survival from this combination. The work presented in this thesis has investigated potential mechanisms of resistance to SRC inhibitors in ovarian cancer, and by using two complementary screening approaches, highlighted a role for activated MEK signalling in driving this resistance. Further work demonstrated that a SRC and MEK are parallel pathways, and inhibition of one leads to activation of the other. This has important therapeutic implications, and a combination of SRC and MEK inhibitors was shown to synergistically inhibit the growth of ovarian cancer cells, and so this combination may be logical in the clinic. Importantly, the SAPPROC trial was performed in platinum resistant ovarian cancer patients, and it has previously been reported that platinum resistant cells exhibit activated MAPK signalling. A novel platinum resistant ovarian cancer cell line was generated in vitro, and demonstrated activated MAPK, as well as resistance to SRC inhibition. This suggests that SAPPROC may have failed to show any benefit of SRC inhibition in platinum resistant patients has their tumours already exhibit activated MEK, and therefore did not respond to SRC inhibition. This highlights the need to further understand mechanisms of drug resistance, the the importance of this in the design of clinical trials.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available