| Summary: | Thesis (MSc)--Stellenbosch University, 2015. === ENGLISH ABSTRACT: Breast Cancer remains one of the world’s leading causes of cancer related deaths
amongst women. Its treatment has evolved from invasive, highly toxic therapies to
treatments that possess a higher specificity and a lower toxicity. Despite
improvements in overall survival, many patients do not benefit from these agents
because of acquired and/or inherent tumour resistance, which could hinder treatment
efficacy. Novel treatment strategies are, therefore, warranted to address these
challenges and to significantly improve patient responses. Inhibiting components of
the HER-2 signalling pathway can significantly sensitise breast cancer cells to low
doses of ionising radiation.
The objective of this study was to inhibit key molecular targets of the human
epidermal growth factor receptor 2 (HER-2) signalling pathway and expose breast
cancer cell lines to doses of radiation, so as to establish potential therapeutic targets
that may be amenable to combined modality therapy, and formulate a cocktail of
inhibitors to evaluate its radiosensitising capability.
This study found that pre-treatment of two breast cancer cell lines (MDA-MB-231 and
MCF-7) with a HER-2 inhibitor (TAK-165) had little or no effect on radiosensitivity.
However, a radiation enhancement was observed when these cells were pre-treated
either with BEZ235, a dual inhibitor of phosphoinositide 3-kinase (PI3K) and
mammalian target for rapamycin (mTOR), or a cocktail of TAK-165 and BEZ235.
These findings suggest that concurrent inhibition of HER-2, PI3K and mTOR during
radiotherapy might improve treatment response of breast cancer patients. === AFRIKAANSE OPSOMMING: Borskanker bly steeds een van die leidende oorsake van sterftes aan kanker in
vrouens. Behandeling het vanaf ‘n ingrypende, hoogs toksiese terapie verander na ‘n
regimen wat hoogs spesifiek met ‘n laer toksisiteit is. Nogtans trek baie pasiënte
geen voordeel uit hierdie nuwe benadering nie, omdat inherente en/of verworwe
tumorweerstand daarteen suksesvolle uitkomste verhoed.
Nuwe behandelingstrategieë is dus nodig om hierdie uitdagings te bekamp en om
resultate in pasiënte aansienlik te verbeter.
Inhibisie van komponente van die HER-2-seinoordragkaskade kan borskankerselle
gevoelig maak vir lae dosisse van geïoniseerde bestraling.
Die doelwit van hierdie studie was om sleutelteikens in die HER-2-
seinoordragkaskade te inhibeer en om borskankerselle daarna aan bestralings
dosisse bloot te stel. Sodoende word potensiële terapeutiese teikens wat vatbaar is
vir gekombineerde modaliteitsterapie geïdentifiseer, waarna ‘n kombinasie van
inhibitore geformuleer en geëvalueer kan word ten opsigte van hulle kapasiteit om
gevoeligheid vir bestraling te verhoog.
Die studie bevind dat voorbehandeling met ‘n HER-2-inhibitor (TAK-165) van
borskankersellyne (MDA-MB-231 en MCF-7) min of geen invloed gehad het op
stralingsensitiwiteit nie. ‘n Stralingsversterking is egter geïdentifiseer toe die selle
vooraf behandel is met óf BEZ-235, ‘n tweevoudige inhibitor van fosforinositied 3-kinase (PI3K) en soogdierteiken vir rapamisien (mTOR), óf ‘n mengsel van TAK-165
en BEZ-235.
Hierdie bevindinge suggereer dat gelyktydige inhibisie van die HER-2-
seinoordragkaskade, PI3K en mTOR gedurende stralingsterapie moontlik die
uitkoms in borskankerpasiënte kan verbeter.
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