Targeted therapies in rare cancers
thesisposted on 27.02.2017, 23:14 by Kerr, Lauren Tessa
Cancer is a deliberating disease that affects 1/3 of the population and kills approximately 40,000 Australians every year. Current treatments for cancer are often severe and incur a number of adverse effects. New treatments with fewer side effects are urgently required, especially for rare cancers because identifying improved treatments has added difficulty due to challenges in recruiting sufficient patients for clinical trials, lack of knowledge of the rare cancer types by surgeons and physicians, reduced funding for research, as well as limited collaborative support. In this thesis we explore the use of targeted therapies and the development of novel tools to identify anti-cancer targets for two rare cancers: myxoid liposarcoma (MLS) and glioma. We examined an array of targeted therapies, some of which had been developed for other cancers, screening therapies against MLS patient-derived cell lines for impact on cell proliferation and survival. We identified a number of agents that were highly efficacious against MLS cell lines in vitro both alone and in combination with other treatments, and as single agents against MLS xenografts in mice. We demonstrated the importance of key cellular pathways in MLS cell lines. In particular, MLS cell lines were highly sensitive to inhibition of the VEGFC/D-VEGFR-3 signalling axis, inferring potential oncogenic addiction to this pathway. Further, we demonstrated that eIF4E and FUS-CHOP are both important proteins for the survival of MLS cell lines, which may be up-regulating the expression of proteins that contribute to oncogenesis. We developed novel tools to examine the role of ErbB4 in glioma and used these tools to examine 44 brain samples (glioma and non-neoplastic samples). Specifically we developed, optimised and analytically validated an RT-qPCR that quantified the levels of ErbB4 splice variants in cancer cell lines and patient tissue. We then used this assay to profile the expression of brain samples. These studies revealed that ErbB4 expression is significantly lower in glioma compared to normal brain, which suggests that ErbB4 may be a tumour suppressor protein in glioma. Splice variant expression was different in glioma samples compared to normal brain, with increased expression of the more oncogenic spice variant in tumour samples, especially in some patients; this suggests ErbB4 may still be contributing to disease progression in a subset of glioma patients. We identified a novel truncated ErbB4 splice variant, JM-e, which is o the extracellular proportion of ErbB4. JM-e expression was detected in cancer cell lines and universally in glioma and matched normal brain samples. There was significantly higher expression of JM-e in some glioma samples compared to matched normal brain. The studies presented in this thesis have further enhanced our knowledge of ErbB4 and its role in glioma, and identified novel targeted therapies that were highly efficacious in the treatment of MLS.