Investigating mechanisms of anti-cancer drug resistance in breast cancer cells and extracellular vesicles
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LOWRY, MICHELLE, Investigating mechanisms of anti-cancer drug resistance in breast cancer cells and extracellular vesicles, Trinity College Dublin.School of Pharmacy & Pharma. Sciences, 2019Download Item:
Abstract:
Breast cancer is the most common female cancer diagnosed worldwide. In 2018 alone, there were over 2 million new breast cancer cases diagnosed. In Ireland, breast cancer is the most commonly diagnosed cancer in women. In Ireland, breast cancer accounts for approximately 3,141 cases each year. Of which, a subtype of breast cancer called HER2overexpressing/HER2+ breast cancer accounts for 15-25% of breast cancers. This subtype of breast cancer has a genetic mutation that causes the cancer cells to produce larger amounts of the protein called HER2. HER2 promotes the growth of cancer cells and patients with this type of breast cancer often have high levels of metastasis, or spread of the cancer to other organs. Unfortunately, like with many cancer therapies, some patients do not respond to anti-HER2 therapies, i.e. patients are or become resistant to therapy. Some patient’s tumours will immediately not respond to therapy (innate resistance), whereas, other patient tumour’s will initially respond well to the therapies but overtime the cancer cells can find ways to overcome the effects of the therapy i.e. the tumours become resistant to therapy (adaptive resistance). Innate and adaptive resistance to anticancer therapies are the main reasons that anti-cancer drugs fail in the clinic. It is imperative that we investigate the mechanisms of drug resistance, find ways to overcome this resistance and find ways to predict and/or find predictive biomarkers.
The focus of this PhD is on a drug that stops HER2 working, it is called Neratinib. Neratinib prevents HER2 functioning and in doing so it can prevent cancer cell growth. Neratinib was approved by the Food and Drug Administration (FDA) in July 2017. Neratinib is showing promise in the clinic but, like most therapies, the issue of resistance prevails. We have developed HER2+ breast cancer cell lines that are resistant to neratinib i.e. neratinib does not kill them. When we compared cells that die from neratinib with cells that do not die after neratinib treatment, we found that the resistant cell lines produce very large amounts of a protein called PROTEIN X. The cells that are sensitive to neratinib or the cells that die after neratinib treatment, do not produce large amounts of PROTEIN X. We believe that PROTEIN X acts like a defence system for breast cancer cells.
This discoveries made in this PhD may be imperative to overcoming neratinib resistance in the future, for predicting response to therapy (so that patients can be stratified into those who are likely versus unlikely to respond to HER-targeting), and so improving the survival rates of patients treated with neratinib and other HER2-targeted therapies. We also believe that PROTEIN X has potential as a predictive biomarker for HER2 therapies such as lapatinib and trastuzumab, but most notably for neratinib. PROTEIN X may be an important marker for future therapeutic decisions in clinics.
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Author: LOWRY, MICHELLE
Advisor:
O'Driscoll, LorraineQualification name:
Doctor of Philosophy (Ph.D.)Publisher:
Trinity College Dublin. School of Pharmacy & Pharma. Sciences. Discipline of PharmacyType of material:
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Breast cancer, Cancer drug resistanceMetadata
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