Every year, approximately 240,000 women worldwide are diagnosed with ovarian cancer, and around 70% of them have a 5-year survival rate of only about 40%. The primary treatment is debulking surgery combined with chemotherapy, which aims to remove most of the primary tumour and any extensively spread tumour within the peritoneum.
Unfortunately, residual tumours often remain, and it is common for the disease to relapse and develop chemoresistance. While several new drugs have been introduced for patients with recurring chemoresistant ovarian cancer, none have demonstrated significant improvements in disease-free progression or survival rates. Therefore, there is an urgent need to discover novel compounds that, when combined with chemotherapy, can enhance the quality of life and survival of patients with recurrent ovarian cancer.
Our recent studies have shown that the mitochondrial-associated granulocyte-macrophage colony-stimulating factor signalling molecule (Magmas) is overexpressed in all high-grade serous ovarian tumours compared to benign and grade 1 tumours of the same type. Our research also indicates that a Magmas-specific small molecule inhibitor (BT#9) exhibits significantly greater cytotoxicity towards cancer cells, including chemoresistant ovarian cancer cell lines, than towards normal cells. Additionally, animal studies have confirmed that BT#9 does not affect normal organs, highlighting its potential as a cancer treatment with minimal side effects.
The specific aims of this project are as follows:
1. To identify the intracellular mechanisms of BT#9 by profiling proteomic changes resulting from RNAi-mediated knockdown of Magmas in patient-derived ovarian cancer cells.
2. To evaluate the proteomic response to BT#9 treatment in patient-derived ovarian cancer cell lines, including both drug-sensitive and drug-resistant lines, and to compare these responses with those observed following Magmas knockdown.
The common changes in protein expression observed in response to BT#9 treatment across both parental and drug-resistant cell lines, as well as in RNAi-mediated Magmas knockdown cell lines, are likely associated with drug resistance and the effects of BT#9. We will also evaluate the anti-tumour effectiveness of BT#9 using mouse models with patient-derived parental, RNAi-mediated Magmas knockdown, and drug-resistant ovarian cancer cell lines.
These studies aim to provide the foundation for the potential use of BT#9 in clinical settings to improve morbidity and mortality rates in ovarian cancer patients with recurrent disease.
Methods: The culture of cell lines and tumour cells isolated from ovarian cancer patients, western blotting, quantitative reverse transcription PCR (qRT-PCR), immunohistochemistry, immunofluorescence, global proteomics, and animal studies.
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