THIO is a Telomerase-Mediated Approach to Fighting Cancer

Telomerase is present in 90% of human cancer cells and contributes significantly to proliferative abilities and immortality of cancer cells. MAIA Biotechnology is developing a Telomerase-Mediated Approach to Fighting Cancer.

Telomerase is either absent or shows low activity in normal cells. THIO(6-thio-dG) is recognized by telomerase and incorporated into telomeres. Once incorporated, it compromises telomere structure and function, leading to ‘uncapping’ of the chromosome ends resulting in rapid tumor cell death.

MAIA Biotechnology, Inc. is a cutting-edge, early stage biotech company, dedicated to developing targeted cancer therapies with novel mechanisms of action that are intended to meaningfully improve and extend the lives of patients with cancer. A privately-held company based in Chicago and Houston, MAIA is led by a passionate, principled and dynamic Management Team with significant drug development experience, committed to advancing promising agents into trials in humans in the next 3-5 years.

MAIA is leveraging the following research to develop its anti-cancer system called THIO. At a recent conference, anti-aging expert Aubrey de Grey stated the THIO approach to fighting cancer looked very promising.

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.

Abstract – A novel telomerase substrate precursor rapidly induces telomere dysfunction in telomerase positive cancer cells but not telomerase silent normal cells

Although telomerase is an almost universal target for cancer therapy, there has been no effective telomerase targeted inhibitor that has progressed to late stage human clinical trials. Recently, we reported that a telomerase-mediated telomere-disrupting compound, 6-thio-2′-deoxyguanosine (6-thio-dG), was very effective at targeting telomerase positive cancer cells while sparing telomerase silent normal cells. 6-thio-dG, a nucleoside analogue of the already-approved drug 6-thioguanine, is incorporated into telomeres by telomerase, resulting in disruption of the telomere-protecting shelterin complex. This disruption leads to Telomere dysfunction-Induced Foci (TIFs) formation and rapid cell death for the vast majority of cancer cells. Since most chemotherapies eventually fail due to drug acquired resistance, novel drugs such as 6-thio-dG, as a single first line agent or in the maintenance setting, may represent an effective new treatment for cancer patients.

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.

Abstract – Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine
The relationships between telomerase and telomeres represent attractive targets for new anticancer agents. Here, we report that the nucleoside analogue 6-thio-2′-deoxyguanosine (6-thio-dG) is recognized by telomerase and is incorporated into de novo-synthesized telomeres. This results in modified telomeres, leading to telomere dysfunction, but only in cells expressing telomerase. 6-Thio-dG, but not 6-thioguanine, induced telomere dysfunction in telomerase-positive human cancer cells and hTERT-expressing human fibroblasts, but not in telomerase-negative cells. Treatment with 6-thio-dG resulted in rapid cell death for the vast majority of the cancer cell lines tested, whereas normal human fibroblasts and human colonic epithelial cells were largely unaffected. In A549 lung cancer cell-based mouse xenograft studies, 6-thio-dG caused a decrease in the tumor growth rate superior to that observed with 6-thioguanine treatment. In addition, 6-thio-dG increased telomere dysfunction in tumor cells in vivo. These results indicate that 6-thio-dG may provide a new telomere-addressed telomerase-dependent anticancer approach.

SIGNIFICANCE – Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine
Telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials. In the present study, we demonstrate a small-molecule telomerase substrate approach that induces telomerase-mediated targeted “telomere uncapping,” but only in telomerase-positive cancer cells, with minimal effects in normal telomerase-negative cells.

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.

Reyes-Uribe et al. Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene. 2018 Jul;37(30):4058-4072.

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/

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