Telomere maintenance

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. Nat Comms 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, however the landscape of ALT-targeting drugs is not well established. The interrogation of genes involved in ALT may reveal new biomarkers for targeted treatment of these aggressive tumors.

Thus far, we have screened >800 human sarcoma tumor samples to identify frequency of ALT in various sarcoma sub-entities. Following this stratification, we have employed integrative multi-omics analysis to identify genetic alterations that separate ALT-positive tumors from the ALT-negative tumors to identify ALT-associated aberrations that may be targetable directly or via secondary dependencies. Using a large panel of rare sarcoma cell lines and patient-derived xenografts, we are validating the "druggability" of candidate alterations and mechanistically characterizing those using phospho-proteomics to lay the groundwork for nominating ALT-specific targets for evaluation in the clinical setting. Moreover, we are developing methods to address the impact of heterogeneity in telomere maintenance mechanisms using machine learning tools (Belova et al. 2023 biorXiv) and spatially resolved technologies (Frank et al. Nucleic Acids Res 2022).