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Title: Mammalian target of rapamycin inhibitor RAD001 (everolimus) in early breast cancer
Author: Macaskill, Elizabeth Jane
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2010
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The mammalian target of rapamycin (mTOR) plays a key role in tumour cell cycle control, proliferation and survival, and has been implicated in resistance to endocrine therapy in breast cancer. RAD001 (everolimus) is a novel macrolide that inhibits mTOR and its downstream substrates in vitro. This study explores the use of RAD001 at a dose of 5mg daily in women with early breast cancer. 31 postmenopausal women were given RAD001 for 14 days prior to primary surgical intervention for early breast cancer. RAD001 was well tolerated in most patients, 5 did not complete treatment due to drug adverse effects. Tumour samples before (pre) and after (post) 14 days treatment were assessed for changes in proliferation and markers of the mTOR pathway. Significant reductions in proliferation (Ki67) and oestrogen receptor (ER) expression were seen, and the downstream effects of the mTOR pathway inhibited (p-S6 (ser235/236 and ser 240/244) and nuclear expression of p-Akt). Gene expression profiling from these tumour samples has confirmed these findings, demonstrating reduction in expression of proliferative genes and oestrogen dependence genes with RAD001 treatment. The mTOR protein exists in two distinct complexes, raptor and rictor, and it has previously been thought that mTOR inhibitors such as RAD001 only have effects upon raptor. The implication of this if correct would be upregulation of Akt (Protein Kinase B), which has been shown to be present in more aggressive and resistant tumour types. The cell line study described herein has demonstrated no upregulation in p-Akt expression with RAD001 treatment, and in one cell line inhibition of p-Akt was sustained with prolonged cell treatment. To further assess the role of Akt in resistance to endocrine treatment, tumour samples with known endocrine resistance or sensitivity were assessed for p-Akt expression before and after treatment. The results suggest an increase in nuclear expression of p- Akt in endocrine resistant tumours. The mTOR inhibitor RAD001 is therefore effective at reducing proliferation of early breast cancer, inhibiting mTOR in both raptor and rictor complexes, and may be of particular use in highly proliferative or resistant tumours that overexpress p-Akt.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available