Sir Peter MacCallum Department of Oncology - Theses
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ItemAn investigation of type-1 interferon and the immune response against breast cancer metastasis( 2016)Breast cancer is a highly prevalent disease that, like many cancers, lacks effective therapies aimed at treating and preventing metastasis. Harnessing the host immune system to recognise and eliminate malignant cells has recently emerged as an effective therapeutic strategy in many cancers. However, response rates to these approved immunotherapies remain modest in the absence of a more detailed understanding of tumour immunity. The type I interferons are a family of cytokines that have long been understood to enhance the immune response to cancers, though their clinical application has led to underwhelming results in numerous types of cancer. This thesis provides new evidence that proposes the re-visitation of cancer immunotherapies that stimulate the type I interferon pathway. We show that host-derived type interferon is critical for the suppression of breast cancer metastasis through natural- killer cell activation. Induction of a type I IFN response by administering agents that mimic a viral infection (poly(I:C), a double-stranded RNA analog) proved to be powerful anti-metastatic agents in multiple pre-clinical models of triple-negative breast cancer (TNBC). This was linked to widespread immune activation which conferred NK cells with enhanced cytotoxic function to eliminate disseminated tumour cells. The efficacy of this novel immunotherapeutic approach was also found to rely upon the treatment setting in which it was used. Evidence is presented that demonstrates administration prior to primary tumour removal (neo-adjuvant therapy) as the only effective therapeutic regimen. We propose that such immunotherapies are most effective at eliminating circulating and early disseminated cells rather than established metastatic lesions. This provides some explanation to the inefficacy of previous interferon trials that were conducted in patients with late-stage metastatic disease. It also calls into question whether other immunotherapies could be used earlier in cancer treatment to maximise the chances of a clinical response. Finally, we uncover that expression of IRF9, a key transcription factor in the type-I interferon signaling pathway, accurately predicts TNBC patient prognosis. Loss of IRF9 in a patient’s primary tumour predicted significantly poorer overall survival due to metastatic spread. As we show that tumour cells are not directly responsible for the poly(I:C)-induced interferon response, we propose that patients with IRF9-negative TNBC could benefit from neo-adjuvant interferon-based immunotherapy.
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ItemInvestigating MYB in the context of mammary gland biology, transformation and as a therapeutic target in breast and colon cancer( 2014)Breast cancer is the second most common form of malignancy diagnosed in Australian women, imposing an enormous social and economic burden on society. If the cancer spreads to secondary locations, patient survival decreases dramatically. Therapeutic strategies for treatment of metastatic disease are desperately needed in breast cancer. Recently we have shown that when Myb is conditionally deleted from the mammary gland of MMTV-Neu and MMTV-PyMT mice, tumour formation is ablated. To provide further insight into the function of Myb in mammary gland development, cre-mediated conditional knock out of c-myb in the mouse mammary gland was examined. The conditional deletion of c-myb led to a reduction in branching and terminal end bud formation. These data indicate that if MYB could be inhibited for breast cancer therapy, there are potentially few side effects on the normal mammary gland. The ability to inhibit DNA binding transcription factors is a long sort after goal in oncology, as their importance in disease initiation and progression is well documented. To target MYB, we have developed a DNA vaccine. Preclinical studies have largely examined the MYB DNA vaccine in the context of colon cancer models using prophylactic vaccination. However, preliminary data indicate that it may also be effective in reducing the metastatic burden in preclinical breast cancer models. This thesis aims to further investigate the role of MYB during mammary gland development and provide insights into its involvement in tumourigenesis. Furthermore, the MYB DNA vaccine will be assessed for its effectiveness as a therapeutic treatment in clinically relevant surgical models of metastatic breast cancer, as well as further development as a therapeutic in the setting of colon cancer.