Abstract 5412: Developing combination therapies for telomerase-overexpressing cancers

Abstract Cancer heterogeneity poses a significant medical challenge, necessitating therapies tailored not only to individual patients but also to the unique cancer clones that exist within diverse microenvironmental contexts. Despite this diversity, nearly all cancer cells share a reliance on telomeres to maintain genomic stability. The telomerase (hTERT) gene is hyperactive in many cancers and has been identified as a potential target for treatment. While this has led to the development of multiple telomerase-targeting approaches, disappointingly, none have been approved in clinical applications yet. To circumvent this concern, our team has applied a genetic approach called synthetic dosage lethality (SDL), to exploit hTERT overexpression to identify potential targets to treat cancer. SDL is a genetic concept, where a normally non-lethal gene inactivation kills cells only in the context of overexpression of another gene like hTERT. Our laboratories have used lentiviral-based pooled CRISPR/Cas9 and pooled shRNA-screening platforms to systematically query the genome and recently identified several SDL partners of hTERT. Through extensive validation using pooled in vivo CRISPR/Cas9 screens across multiple cell lines, tumor xenografts, and patient-derived organoids, we identified RMT1, an RNA 2'-O-methyltransferase, as a prominent SDL partner of hTERT. In collaboration with the AtomWise and Thoth Biosimulations companies, we have developed novel inhibitors for RMT1 that preferentially suppress hTERT-overexpressing cell lines growth and viability. We have also performed a large-scale screen of FDA-approved small molecule inhibitors with the goal of repurposing these drugs to target hTERT-overexpressing cancers. Subsequently, we plan to apply these therapies in combination to amplify the efficiency of treatment against cancers, yielding preclinical evidence to support the development of novel cancer therapies. Since hTERT activity is essential in all cancer cells, our findings introduce a transformative approach to overcoming cancer cell heterogeneity by targeting the SDL interactions of hTERT. This strategy also capitalizes on the ubiquitous overexpression of hTERT in all cancer types, enabling the selective eradication of hTERT-dependent malignancies. Citation Format: Vincent Maranda, Frederick S. Vizeacoumar, Yue Zhang, Liliia Kyrylenko, Andrew Freywald, Franco J. Vizeacoumar. Developing combination therapies for telomerase-overexpressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5412.