Targeting perturbed telomere maintenance in sarcoma

Telomeres are nucleotide sequences composed of 5'-TTAGGG-3' tandem repeats that play an important role in maintaining genomic integrity by protecting the ends of chromosomes from DNA damage by means of the telomere-shelterin complex. Replication of telomeres is carried out by telomerase. To achieve replicative immortality, approximately 85% of cancers reactivate TERT expression. The remaining 15% cancers maintain telomere length via a telomerase-independent mechanism termed alternative lengthening of telomeres (ALT). Our previous work (Chudasama et al.2018) and that of others has established ALT as a frequent feature in sarcomas that contributes to tumor progression. Being a cancer cell-specific process, ALT represents an attractive therapeutic target. The interrogation of genes involved in ALT may reveal new biomarkers for targeted treatment of these aggressive tumors. We are employing integrative omics analysis, CRISPR/Cas9 based genome-editing and drug sensitivity screens to investigate ALT occurrence and ALT-associated aberrations in tumors and relevant model systems for functional and mechanistic study of ALT process to nominate compounds that selectively target ALT positive sarcomas.

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