A Spontaneous Melanoma Mouse Model Applicable for a Longitudinal Chemotherapy and Immunotherapy Study

Assessing Longitudinal Treatment Efficacies and Alterations in Molecular Markers Associated with Glutamatergic Signaling and Immune Checkpoint Inhibitors in a Spontaneous Melanoma Mouse Model

“…TGS mice are immunocompetent hairless spontaneous metastatic melanoma-prone mice that were developed from crosses between the TG-3 and SKH-1 to allow tumor progression to be monitored easily without the inconvenience of fur ( Eddy et al, 2023 ). TG-3 and TGS mice have similar onset and progression of melanoma.…”

“…In the published low-dose troriluzole (1.7 mg/kg) study, male mice responded to all treatment modalities, with the most reduction in tumor progression from baseline in the monotherapy of troriluzole (12%) or anti–PD-1 (0%) treatment arm compared with that in vehicle treatment (65%) ( Eddy et al, 2023 ). In this study, at the higher dose of troriluzole (25 mg/kg), the greatest reduction in tumor progression from baseline was observed in male mice treated with single-agent troriluzole (69%) or anti–PD-1 (46%) than in those treated with vehicle (91%) ( Figure 2 b).…”

“…Tumor development, progression, and immune dysfunctions in these mice resemble those observed in patients with melanoma ( Alb et al, 2012 ; Eddy and Chen, 2021 , 2020 ; Mairhofer et al, 2015 ; Prokopi et al, 2021 ; Zhu et al, 2000 ). In the earlier study, the functional inhibition of mGluR1 by troriluzole and anti–PD-1 yielded antitumor responses but also showed a sex-biased response in male mice ( Eddy et al, 2023 ). A report on a glioblastoma allograft study showed greater efficacy and higher tolerability of troriluzole at 25 mg/kg ( Medikonda et al, 2021 ).…”

“…Previously, in a long-term therapeutic study using troriluzole, an inhibitor of glutamatergic signaling and anti–PD-1, an immune checkpoint inhibitor in a spontaneous melanoma-prone mouse model, TGS (TG-3/SKH-1), a model system reported to have a physiologically relevant and immunocompetent tumor–host environment, was reported ( Eddy et al, 2023 ). Melanoma in these mice is driven by the ectopic expression of a neuronal receptor, mGluR1 (protein and Grm1 [mouse gene]).…”

“…Melanoma in these mice is driven by the ectopic expression of a neuronal receptor, mGluR1 (protein and Grm1 [mouse gene]). TGS mice harboring 2 copies of the disrupted Grm1 gene have onset of melanoma within 1.5–2 months and succumb to heavy tumor burden by 4–5 months (homozygous mice), whereas TGS mice with 1 copy of the disrupted Grm1 allele show onset of melanoma within 4–5 months and succumb to melanoma by 10–12 months (heterozygous mice) ( Eddy et al, 2023 ). The melanoma in heterozygous or homozygous TGS mice is histologically indistinguishable.…”