Grant: CIHR Fellowship

My project attempts to change what is one of the most frustrating aspects of cancer chemotherapy, especially for patients with advanced metastatic disease, namely the all-too-often limited benefits in prolonging survival or achieving cure. These limited benefits are still the norm even when tumours are induced to significantly shrink by exposing patients every few weeks to the highest doses of chemotherapy they can tolerate i.e. 'maximum tolerated doses' (MTDs), which can cause very toxic side effects. One reason to account for this is that there resides within tumours low numbers of what are known as 'cancer stem cells' (CSCs). These cells tend to be highly resistant to MTD chemotherapy in contrast to the 'bulk' population of non-CSCs. So conventional chemotherapy spares CSCs during tumour shrinkage allowing them to repopulate the tumour mass after therapy. Our group has been working on an investigational therapeutic concept known as low-dose 'metronomic' chemotherapy (MC) where the chemotherapy is given frequently with no prolonged breaks (e.g. daily oral drugs). Despite less toxicity, and hence no need for breaks, it can be remarkably effective in preclinical studies even when treating advanced metastatic disease in mice. Based on several observations there is reason to think that this counterintuitive therapeutic outcome is based on the possibility that MC targets the CSC subpopulation. My project is designed to confirm this hypothesis by comparing the effects of several MTD vs potent MC regimens in mice models of advanced metastatic ovarian cancer, using three independent assays to detect CSCs. Some experiments will also involve assessing the impact of adding an 'antiangiogenic' drug that targets the tumour's growing vasculature to MC since such combinations can cause remarkable anti-tumour effects. The results of these experiments could change the perception about chemotherapy and CSCs, and foster more aggressive clinical trial development of MC.