Poster S12 - Characterizing the Efficacy and Safety of a Novel Ribonucleotide Reductase Inhibitor (TMU27a) in Different Cancer Models

Saturday, October 26, 2024

10:00 AM - 11:00 AM EST

Location: Exhibit Hall E, F & G

Presenting Author(s)

Hailey Brady

Undergraduate research assistant
University of Michigan
Milan, Michigan, United States

Co-Author(s)

TB

Taylor Baker

Graduate Student
Case Western Reserve University, United States

Primary Investigator(s)

RK

Ruth Keri

Professor at Cleveland Clinic Lerner College of Medicine
Cleveland Clinic Lerner Research Institute, United States

Introduction: Ribonucleotide reductase (RNR) is the rate-limiting enzyme controlling nucleotide production. Upregulation of RNR is vital to support tumor cell proliferation, making it a prime target for inhibition by chemotherapy treatments. Currently, Gemcitabine (GEM) is a standard first-line treatment for various aggressive types of cancer. However, GEM causes significant toxicities (i.e. myelosuppression) because it is a nucleoside analog – its metabolites indiscriminately cause DNA end-chain termination and inhibit various off-target enzymes. We hypothesize that a non-nucleoside RNR inhibitor would achieve the same therapeutic benefits of GEM without the severe side effects.

Materials and

Methods: We identified TMU27a (TMU) as a first-in-class, non-nucleoside RNR inhibitor following in silico binding and validation assays. triple-negative breast cancer, pancreatic cancer, and leiomyosarcoma cell lines are all sensitive to TMU, as TMU causes significant double-strand DNA breaks and chromosomal instability. This excessive genomic damage causes growth repression and cancer cell death.

Results, Conclusions, and Discussions: Notably, pancreatic and breast gemcitabine-resistant cell lines and xenograft models are also sensitive to TMU, indicating that TMU overcomes gemcitabine resistance. Several xenograft studies demonstrate that TMU suppresses tumor growth without impacting mouse weights, suggesting strong drug efficacy in the absence of overt toxicities. Moreover, there is no evidence of myelosuppression with TMU treatment. Together, these data indicate that TMU is an efficacious and safer alternative to GEM, reinforcing the potential of TMU as a novel drug candidate for treating various cancers, including those that develop GEM resistance.

Acknowledgements (Optional):