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Assessing Longitudinal Treatment Efficacies and Alterations in Molecular Markers Associated with Glutamatergic
Kevinn Eddy1,2, Kajal Gupta3, Mohamad Naser Eddin1
1Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, USA.
Abstract:
Previous work done by our laboratory described the use of an immunocompetent spontaneous melanoma-prone mouse model, TGS (TG-3/SKH-1), to evaluate treatment outcomes using inhibitors of glutamatergic signaling and immune checkpoint for 18 weeks. We showed a significant therapeutic efficacy with a notable sex-biased response in male mice. In this follow-up 18-week study, the dose of the glutamatergic signaling inhibitor was increased (from 1.7 mg/kg to 25 mg/kg), which resulted in improved responses in female mice but not male mice. The greatest reduction in tumor progression was observed in male mice treated with single-agent troriluzole and anti-PD-1. Furthermore, a randomly selected group of mice was removed from treatment after 18 weeks and maintained for up to an additional 48 weeks demonstrating the utility of the TGS mouse model to perform a ≥1-year preclinical therapeutic study in a physiologically relevant tumor-host environment. Digital spatial imaging analyses were performed in tumors and tumor microenvironments across treatment modalities using antibody panels for immune cell types and immune cell activation. The results suggest that immune cell populations and cytotoxic activities of T cells play critical roles in treatment responses in these mice. Examination of a group of molecular protein markers based on the proposed mechanisms of action of inhibitors of glutamatergic signaling and immune checkpoint showed that alterations in expression levels of xCT, γ-H2AX, EAAT2, PD-L1, and PD-1 are likely associated with the loss of treatment responses. These results suggest the importance of tracking changes in molecular markers associated with the mechanism of action of therapeutics over the course of a longitudinal preclinical therapeutic study in spatial and temporal manners.
Insights
This study enhanced melanoma treatment in mice by increasing glutamatergic signaling inhibitor dosage, improving female responses. Combined therapy with troriluzole and anti-PD-1 showed the best tumor reduction in males.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Previous research utilized the TGS (TG-3/SKH-1) mouse model to assess glutamatergic signaling inhibitors and immune checkpoint inhibitors for melanoma treatment.
- A significant sex-biased therapeutic efficacy was observed, with male mice responding better to the initial treatment regimen.
Purpose of the Study:
- To evaluate the impact of an increased dosage of a glutamatergic signaling inhibitor on melanoma treatment outcomes in the TGS mouse model.
- To assess the long-term utility of the TGS model for preclinical therapeutic studies.
- To investigate the role of immune cell populations, activation, and molecular markers in treatment response and resistance.
Main Methods:
- The study involved an 18-week treatment period with modified dosages of glutamatergic signaling inhibitors and anti-PD-1 in TGS mice.
- A subset of mice continued observation for an additional 48 weeks post-treatment.
- Digital spatial imaging and analysis of molecular protein markers (xCT, γ-H2AX, EAAT2, PD-L1, PD-1) were employed.
Main Results:
- Increasing the glutamatergic signaling inhibitor dose improved treatment responses in female mice but not males.
- The combination of troriluzole and anti-PD-1 demonstrated the greatest reduction in tumor progression in male mice.
- Digital spatial imaging revealed that immune cell populations and T cell cytotoxic activity are crucial for treatment efficacy.
- Alterations in specific molecular markers correlated with the loss of treatment response.
Conclusions:
- The TGS mouse model is suitable for longitudinal preclinical therapeutic studies.
- Immune cell dynamics and specific molecular markers are critical indicators of treatment response and resistance in melanoma.
- Longitudinal tracking of molecular markers is essential for understanding therapeutic mechanisms and optimizing treatment strategies.
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