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Dabogratinib (TYRA-300), an FGFR3 Isoform-Selective Inhibitor: Preclinical and Initial Clinical Evidence of Antitumor
Jacqueline H Starrett1, Eric L Allen1, Melissa Neal1
1Tyra Biosciences, Carlsbad, California.
Abstract:
Despite recent advances in the treatment of fibroblast growth factor receptor 3 (FGFR3)-altered metastatic urothelial carcinoma, there is no approved precision therapy that selectively targets FGFR3 while sparing other FGFR isoforms. Dabogratinib (TYRA-300)-a rationally designed selective FGFR3 inhibitor-was evaluated in vitro and in vivo. We also report three patient cases from the ongoing first-in-human, phase I/II SURF301 study (NCT05544552). Dabogratinib elicited a dose-dependent reduction in downstream signaling across three bladder cancer cell lines harboring an FGFR3 fusion, mutation, or gatekeeper resistance mutation. In a xenograft model driven by an FGFR3S249C-activating mutation, dabogratinib treatment resulted in dose-dependent tumor growth inhibition with tumor regression observed at the highest doses. These preclinical findings are supported by the three case reports from the SURF301 study, which demonstrate early clinical activity in patients with advanced metastatic urothelial carcinoma with an FGFR3 fusion or activating mutation.
Insights
Dabogratinib shows promise as a targeted therapy for FGFR3-altered metastatic urothelial carcinoma (mUC). Preclinical and early clinical data suggest it effectively inhibits FGFR3 signaling and reduces tumor growth in mUC patients.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Metastatic urothelial carcinoma (mUC) treatment has advanced, yet lacks targeted therapies for FGFR3 alterations.
- Existing treatments do not selectively inhibit FGFR3 without affecting other FGFR isoforms.
Purpose of the Study:
- To evaluate dabogratinib (TYRA-300), a selective FGFR3 inhibitor, in preclinical models and early clinical trials.
- To assess the efficacy of dabogratinib in FGFR3-altered bladder cancer.
Main Methods:
- In vitro and in vivo studies using bladder cancer cell lines with FGFR3 alterations.
- Xenograft models with FGFR3 activating mutations were used to assess tumor growth inhibition.
- Phase I/II SURF301 study (NCT05544552) evaluating dabogratinib in advanced mUC patients.
Main Results:
- Dabogratinib demonstrated dose-dependent reduction in downstream signaling in FGFR3-altered bladder cancer cell lines.
- Significant tumor growth inhibition and regression were observed in a xenograft model with FGFR3 S249C mutation.
- Early clinical activity was noted in three advanced mUC patients with FGFR3 alterations in the SURF301 study.
Conclusions:
- Dabogratinib exhibits potent preclinical anti-tumor activity against FGFR3-altered urothelial carcinoma.
- Early clinical data from the SURF301 study support dabogratinib's potential as a targeted therapy for mUC with FGFR3 alterations.
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