Over the past few decades, there has been significant improvement in the five-year survival rates of cancer patients due to improved use to traditional chemotherapeutics that rely on DNA damage as primary mode of action. However, the improvement in patient survival has led to the emergence of late effects due to these treatments, which includes development of new second cancers due to the mutations induced in normal cells during therapy.
Direct apoptosis inducers can target various components of the apoptotic pathway, thereby leading to apoptosis in tumour cells. Many cancer cells have a defective apoptotic pathway, which leads to resistance to traditional chemotherapy agents that induce apoptosis indirectly, and it is hoped that direct apoptosis inducers may overcome this. The direct apoptosis inducing agents that will be the focus of this study include death receptor antagonists (such as TRAIL), BH3 mimetics and SMAC mimetics/IAP antagonists.
Since these agents do not rely on DNA damage as their primary mode of proapoptotic action, we hypothesized that these agents would not lead to DNA damage in surviving cells, thereby reducing the risk of developing new therapy-induced cancers. However, it was shown by Lovric & Hawkins (2010) that TRAIL can induce DNA damage in surviving cells and this DNA damage required caspases and caspase-activated DNase (CAD).
One aim of this project is to investigate the mutagenic potential of other classes of direct apoptosis inducers, such as BH3-mimetics and Smac mimetics. The second aim of this project is to investigate the mechanism by which TRAIL provokes mutations in the surviving cells. The final aim of the project is to test the ability of any direct apoptosis inducers found to be non-mutagenic to co-operate with low (less mutagenic) doses of chemotherapy agents to kill stem cells or leukemia cells without causing potentially oncogenic mutations.