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Yes / Cochrane Incentive Grant from the National Institute for Health Research (NIHR)

Chemotherapy resistance in human epithelial ovarian cancer (EOC) is a significant reason for the high rate of death among patients. We hypothesized that chemotherapy- resistant EOC cells will be killed by novel drug treatments in non-adherent culture conditions. The objective of this study was to test the efficacy of novel drugs to affect platinum resistant EOC cell viability. To achieve this, the cell killing efficacy of several drugs were tested on drug-resistant EOCs growing in non-adherent cultures. Both EOC cell lines and primary EOC cells isolated from patient ascites were used for these studies. Two different classes of drugs were tested including multikinase inhibitors (dorsomorphin and LDN-193189), and an understudied class of novel chemotherapeutic agents called glycosylated antitumor ether lipids (GAELs). EOC cells were treated with the drugs at different doses alone or in combination with cisplatin. Because GAELs exhibited promising results in resistant EOC cells, the mechanism of GAEL-induced cell-death was evaluated. / October 2016

Drug resistance is a serious problem in health care in general, and in malaria treatment in particular, rendering many of our previously considered ‘wonder drugs’ useless. Recently, large sums of money have been allocated for the continuous development of new drugs to replace the failing ones. We seem to be one step behind the evolution of antimalarial resistance; is it possible to get one step ahead? Are interventions which slow down the evolution and spread of drug-resistant malaria parasites achievable? In this thesis, I address these issues with experimental data, using the well-established rodent malaria model Plasmodium chabaudi to understand the selective advantages and disadvantages drug-resistant parasites endure within a vertebrate host and the selective pressures various drug treatment regimes exert on these parasites. Competitive interactions between drug-resistant and drug-sensitive parasites were observed within the host, with resistant parasites having a competitive disadvantage in the absence of drug treatment. The frequency of resistant parasites at the start of the infection was an important determinant of the strength of selection: the lower their frequency, the stronger the competitive suppression in non-treated hosts and the greater their competitive release following drug treatment. Genetically similar genotypes, one resistant and one sensitive, showed similar dynamics following drug treatment. Multiplicity of infection did not have an effect on the within-host dynamics: a larger number of co-infecting susceptible genotypes did not lead to greater competitive suppression or release of resistant parasites. Lastly, various drug treatment regimes were compared. Conventional drug treatment resulted in the greatest selective advantage for drug-resistant parasites, while less aggressive treatments were equally as effective, or even better, at improving host health and reducing overall infectiousness. These studies demonstrate that altering the within-host ecology of drug-resistant parasites by administering drugs and hence removing the drug-sensitive competitors has a large influence on the transmission potential of drug-resistant parasites. Furthermore, this thesis provides proof of principle that other drug treatment regimes different from those currently in use could better control drug-resistant parasites, without compromising other treatment goals. In the case of malaria, less drugs may mean extending the useful lifespan of that drug.