Grant: Project Grant

Based on the conservative estimate that ~10 percent of human cancers employ the Alternate Lengthening of Telomere (ALT) mechanism as a telomere maintenance strategy, more than twenty thousand new cancer cases and eight thousand deaths can be attributed to ALT cancers in Canada. ALT is found in the most clinically challenging cancer types, such as pediatric and adult brain cancers, soft tissue sarcoma and osteosarcoma. Importantly, clinical data suggest that ALT tumors have distinct clinical behaviors from their ALT-negative counterparts. While recent advances in the molecular studies of the ALT mechanism have led to a better understanding of this atypical telomere maintenance pathway, the development of clinical interventions has been restricted by the lack of targets that advanced beyond the experimental stages. Malignant transformation and continuous growth of ALT tumors are hampered by telomere maintenance-related disadvantages that are necessary to promote the innate properties of the ALT recombination mechanism. These factors create global structural vulnerabilities in the ALT genome, extended beyond the telomere, which could be therapeutically targeted. Accordingly, our preliminary data showed increased ALT-specific cytotoxicity of G-quadruplex ligands, related to the ALT genomic structural defects, and encouraged further development of this novel treatment strategy. Our studies focus on understanding the structural and biological differences resulting from the unique ALT mechanism that is absent in non-transformed cells, and exploiting them for therapeutic development. The selective targeting of ALT chromatin structure is predicted to exhibit favorable therapeutic efficacy and safety. Furthermore, early phase clinical trials of G-quadruplex ligands suggested that treatment-related adverse effects are in general manageable. Our positive data will provide the mechanistic basis for designing and further developing this novel anti-cancer strategy.