Text

theses

Mouse models that reflect human disorders provide invaluable tools towards the translation of basic science discoveries to clinical therapies. However, many of these in vivo therapeutic studies are short-term and do not accurately mimic patient conditions. In this dissertation, we utilized a fully immuno-competent, transgenic mouse model, TGS, in which the spontaneous development of metastatic melanoma is driven by the ectopic expression of a normal neuronal receptor, metabotropic glutamate receptor 1 (mGluR1), as a model to assess longitudinal treatment response (up to 8-15 months) with an inhibitor of glutamatergic signaling, troriluzole, a prodrug of riluzole, plus an antibody against programmed cell death protein-1 (PD-1), an immune-checkpoint inhibitor. A sex-dichotomy in treatment response was observed where male mice benefited from a lower dose of troriluzole and when the dose of troriluzole was increased it rescued response rates in some female mice. We confirmed that troriluzole was successfully converted to its active metabolite, riluzole at 6-, 12-, and 18-weeks in systemic circulation. Our study suggests an emergence of resistant cell populations as a consequence of the long-term administration of troriluzole and/or anti-PD-1 that might be correlated with a loss of immune cell infiltrates, T-cell cytotoxicity, and difference in tumor-markers associated with the mechanism of action of riluzole/troriluzole and anti-PD-1. This work suggests that the TGS model is a responsive and tractable system for evaluating therapeutic regimens for melanoma in an immuno-competent setting. The main goal and conclusion from studies performed for this dissertation is that results from pre-clinical in vivo graft studies used in drug development which is required to obtain investigational drug approval to initiate a clinical trial need more rigorous scrutinizing since many of these in vivo studies are short-term and do not accurately reflect patient circumstances. Short-term in vivo graft studies are preclinical gold-standards to validate molecular targets identified in "OMIC" screens and in vitro studies but not necessarily adequate for accurately evaluating the long-term therapeutic outcomes in patients. The next best approach is to develop appropriate models to accurately predict therapeutic response in patients and use these models to rationally design treatment options for patients who develop resistance. 

http://dissertations.umi.com/gsnb.rutgers:12375

Ph.D.

Includes bibliographical references

doi:10.7282/t3-w3n5-jx79

The author owns the copyright to this work.