First-in-class cancer telomere targeting agent
THIO is recognized by telomerase and incorporated into telomeres in cancer cells. Once incorporated, THIO compromises the telomere structure and function, leading to ‘uncapping’ of the chromosome ends and thus resulting in rapid tumor cell death.
Low doses of THIO, followed by anti-PD-L1 or anti-PD1 therapy, completely eliminated advanced tumors in preclinical models in vivo, and produced cancer cell specific immune memory, where the immune system continued to be active against the cancer cells after extended periods of time, with no additional treatment.
These results demonstrate how the THIO-produced telomere stress increases innate sensing and adaptive anti-tumor immunity, which provides a strong rationale for sequentially combining our telomere-targeted therapy with immunotherapy (Mender et al., 2020).
Sources & Literature
Mender et al., Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity, Cancer Cell (2020), https:// doi.org/10.1016/j.ccell.2020.05.020 https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30270-1
Mender et al. A novel telomerase substrate precursor rapidly induces telomere dysfunction in telomerase positive cancer cells but not telomerase silent normal cells. Oncoscience. 2015 Aug 22;2(8):693-5. https://www.ncbi.nlm.nih.gov/pubmed/26425659
Mender, et al. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine. Cancer Discovery. 2015 Jan;5(1):82-95. https://www.ncbi.nlm.nih.gov/pubmed/25516420
Mender et al. Telomerase-Mediated Strategy for Overcoming Non-Small Cell Lung Cancer Targeted Therapy and Chemotherapy Resistance. Neoplasia 2018 Aug;20(8):826-837. https://www.ncbi.nlm.nih.gov/pubmed/30015158
Reyes-Uribe et al. Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene. 2018 Jul;37(30):4058-4072. https://www.ncbi.nlm.nih.gov/pubmed/29695835
Sengupta et al. Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors. Mol Cancer Ther. 2018 Jul;17(7):1504-1514. https://www.ncbi.nlm.nih.gov/pubmed/29654065
Shay JW, Wright WE. Telomeres and telomerase: three decades of progress. Nat Rev Genet. 2019 May;20(5):299-309. https://www.ncbi.nlm.nih.gov/pubmed/30760854
Zhang et al. Induction of Telomere Dysfunction Prolongs Disease Control of Therapy-Resistant Melanoma. Clin Cancer Res. 2018 Oct 1;24(19):4771-4784. https://www.ncbi.nlm.nih.gov/pubmed/29563139
Zhang G, Shay JW. Inducing rapid telomere irreparable damage in telomerase-expressing cancers. Oncotarget. 2018 Nov 9;9(88):35803-35804. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254679/