A new orally active inverse agonist of estrogen-related receptor gamma (ERRү) called DN200434 shows promise with regard to the diagnosis and treatment of anaplastic thyroid cancer (ATC), as well as other poorly differentiated thyroid cancers, according to the results of a study published in Clinical Cancer Research.
“We recently reported that the selective ERRү inverse agonist GSK5182 enhances NIS [Na+/I− symporter]-mediated radioiodine uptake in ATC cells with either KRAS or BRAF mutations, promoting enhanced radioiodine therapy responsiveness in vitro,” wrote authors, led by Thoudam Debraj Singh, Department of Medical Oncology Laboratory, All India Institute of Medical Sciences (AIIMS), New Delhi. “Toward discovering novel ERRү inverse agonists, we also reported several lead optimization studies including 4-hydroxytamoxifen analogue synthesis and biological evaluation. This finding provided a rationale for exploring new ERRү inverse agonists that effectively enhance NIS function in vivo and show potential for clinical translation to patients with ATC.”
In the current study, the authors once again found that DN200434–ERRү complex crystallographic studies demonstrated that DN200434 binds to key ERRү binding pocket residues via four-way interactions. Additionally, DN200434 upregulated iodide-handling genes and reestablished radioiodine avidity in ATC tumor lesions, which was verified using 124I-PET/CT. DN200434 amplified ATC tumor radioiodine therapy susceptibility, thus inhibiting growth.
Per histology findings, patients with ATC exhibited increased ERRү expression in tumors vs normal tissue, thus indicating that ERRү could be a therapeutic target for ATC.
About 30% of patients with thyroid cancer are refractory to radioiodine therapy because of insufficient sodium iodide symporter expression and function in ATCs. To date, DN200434 is the most cell active and only orally bioavailable inverse agonist of ERRү.
Data regarding the effects of DN200434 on radioiodine uptake in CAL62 cells harboring KRAS gene mutations were utilized to elucidate the biological potential of DN200434. These cells have been previously used to evaluate the therapeutic efficacy of various other agents and are amenable to cellular cytotoxicity induction and iodide-handling gene restoration.
DN200434 triggered a dose- and time-dependent rise in radioiodine incorporation in CAL62 cells, which was inhibited to basal levels via KClO4—an NIS-specific inhibitor. This finding indicates that higher radioiodine uptake was associated with DN200434-modulated NIS function. Moreover when compared with GSK5182, DN200434 was stronger at inducing increased radioiodine avidity.
Singh et al. hypothesized that enhanced radioiodine avidity could also be due to iodide-handling gene restoration, including NIS, TPO, TG, and TSHR. DN200434 ameliorated iodide-handling gene expression at both mRNA and protein levels.
The authors found that DN200434-treated cells exhibited downregulated Glut-1 and Glut-4 expression levels, as well as decreased F-18-FDG uptake. These findings suggest that DN200434 holds unique potential to reinduce differentiation of poorly or undifferentiated ATC cells.
“Clearly, novel therapeutic strategies are needed for patients with ATC and an effective means of restoring radioiodine efficacy against ATC and other thyroid cancers would be most welcome,” said Stephen Lai, M.D., Ph.D., professor of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, In an interview with Cancer Network. “The authors have provided some elegant functional and structural preclinical studies to support the continued translation of their compound into the clinical setting.”