On October 18, 2022 Iterion Therapeutics, Inc., a venture-backed, clinical-stage biotechnology company developing novel cancer therapeutics, reported that results from a preclinical murine study of tegavivint in beta-catenin activated hepatocellular carcinoma (HCC) will be featured in a poster presentation and discussion session at the 34th European Organisation for Research and Treatment of Cancer (EORTC), National Cancer Institute (NCI), and American Association for Cancer Research (AACR) (Free AACR Whitepaper) Symposium (ENA 2022). ENA 2022 is being held October 26-28, 2022, in Barcelona, Spain (Press release, Iterion Therapeutics, OCT 18, 2022, View Source [SID1234622106]).
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Tegavivint is a potent and selective first-in-class small molecule inhibitor of Transducin Beta-like Protein One (TBL1), a novel downstream co-factor in the Wnt/beta-catenin signaling pathway. Increased expression of beta-catenin and TBL1 are associated with metastasis and poor prognosis in a broad range of tumor types, including HCC. Up to 50% of HCC patients have tumors driven by activating beta-catenin and canonical Wnt pathway mutations. Tegavivint targets TBL1 and prevents TBL1/beta-catenin complex formation, specifically inhibiting nuclear beta-catenin’s oncogenic transcriptional activity without disrupting key cell membrane functions that are linked to toxicity common to other drugs in this pathway.
The poster presentation, entitled, "The TBL1 inhibitor, Tegavivint, suppresses tumour growth and enhances T-cell infiltration in preclinical murine β-Catenin mutant hepatocellular carcinoma," will be presented on Wednesday, October 26, 2022, between 12:00-20:00 CET, during the Molecular Targeted Agents 1 session (poster board number PB043; abstract number 53) by Thomas Drake, M.B.Ch.B., B.Med.Sci, principal investigator of the study from the Cancer Research UK Beatson Institute. The poster reports on research studying the therapeutic potential for tegavivint in a genetically engineered C57BL/6J mouse model (GEMM) of beta- cateninexon3 mutant HCC (reference) in both early and late-stage disease. The results include evidence for direct anti-tumor activity and immunomodulatory effects on the ‘cold’ immune microenvironment.
The study found that inhibition of TBL1 in early-stage disease significantly reduced the number of tumor-initiating clones compared with vehicle controls. Treatment of established beta-cateninexon3 activated tumors with tegavivint inhibited tumor growth and resulted in a reduced tumor burden compared with vehicle controls. Additionally, in mice with established tumors, tegavivint treatment increased CD3+ T-lymphocyte tumor infiltration, with prominent increases in intratumoral CD8+ T-cells. Importantly, no off-target effects were observed in intestinal tissue, which is dependent on canonical Wnt signaling to maintain tissue homeostasis.
"Hepatocellular cancer is the third leading cause of death worldwide with approximately half of all patients harboring a Wnt/beta-catenin mutation that is correlated with poor prognosis and resistance to checkpoint inhibitor therapy," said Rahul Aras, Ph.D., CEO of Iterion. "The research presented at ENA 2022 suggests that tegavivint’s ability to inhibit TBL1 and thereby nuclear beta-catenin’s oncogenic activity has the potential to reduce tumor growth and activate an immune response in previously ‘cold’ HCC tumors. These data add to a growing body of literature suggesting nuclear beta-catenin inhibition may be beneficial in treatment of HCC and Iterion is now planning to initiate a company-sponsored clinical trial investigating the potential for tegavivint in this patient population."