Targeting telomerase in cancer cells using degrader-based platforms

• Main Author: Lim, Natalie Bao Ying
• Other Authors: Phan Anh Tuan
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2021
• Subjects: Science::Chemistry
• Online Access: https://hdl.handle.net/10356/148039
• Institution: Nanyang Technological University

Telomeres progressively shorten during each cell division as a result of the “end replication problem”. A hallmark of cancer is unrestricted cell proliferation, which correlates to the maintenance of telomere length through the activation of telomerase or telomerase-independent recombination mechanisms. Strategies targeting telomerase as an anti-cancer approach have emerged over the years since the expression of telomerase is high in cancer cells, but low or undetectable in normal somatic cells. Current approaches targeting telomerase are largely achieved using telomerase inhibitors that work by modulating its activity via temporary inhibition. Since a sustained interaction is required with the intended target, higher drug dosages are often needed for complete inhibition, which might result in undesirable side effects. On the contrary, degrader-based platforms that control the abundance of the disease-implicated RNA or protein target have emerged as alternative therapeutic approaches. In this work, a degrader-based platform using gapmer antisense oligonucleotide (ASO) has been successfully constructed to reduce telomerase activity in cancer cells. The high in vivo stability, efficient cellular uptake, and high knockdown efficacy of our gapmer ASO against hTR demonstrate their potential as a new class of degrader-based platforms for cancer therapy.