Date of Award
Spring 5-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Pharmaceutical Sciences
First Advisor
Dr. Sun Yang
Second Advisor
Dr. Kamaljit Kaur
Third Advisor
Dr. Reza Mehvar
Fourth Advisor
Dr. Jennifer Totonchy
Fifth Advisor
Dr. Miao Zhang
Abstract
Interferon-gamma (IFN-γ), a well-studied pro-tumorigenic cytokine in melanoma, has been shown to upregulate programmed death‐ligand 1 (PD‐L1) on the melanoma cell. The interaction between PD-L1 and its receptor PD-1 inactivates T-lymphocytes, allowing melanoma cells to escape from immune surveillance. Immune checkpoint inhibitors targeting PD-1/PD-L1 have been shown to prevent immunosuppression and exhibited significant clinical benefits in improving patient survival across a broad range of cancer types including melanoma. Of note, our preliminary RPPA study showed that one of the significantly upregulated genes induced by IFN-γ was cyclooxygenase-2 (COX-2). COX-2 catalyzes the first rate-limiting step in the conversion of arachidonic acid to prostaglandins, including PGE2 which leads to inflammation. It is well documented that COX-2 plays an important role in tumor development and progression in many cancers. Particularly, studies have demonstrated that COX-2 expression in melanoma tumors positively correlates with PD-L1 expression. In this study, we first determined the role of COX-2- mediated PGE2 production in IFN-γ-induced melanoma progression and PD-L1-mediated immunosuppression.
Moreover, our previous studies demonstrated that novel nNOS inhibitor HH044, effectively inhibited IFN-γ-induced PD-L1 expression both in vitro and in vivo. Another objective of this study was to determine whether nNOS-mediated nitric oxide (NO) signaling interacts with the COX-2-PGE2-PD-L1 signaling axis in melanoma. Our overall hypothesis is that in combination with COX-2 inhibitors, nNOS inhibitors may synergistically reduce melanoma tumor growth and extend mouse survival. In addition, the translational potential of our novel nNOS inhibitor in clinical practice and the effects on nNOS inhibition on the melanoma tumor microenvironment were further assessed.
In summary, this study determined the underlying mechanisms by which IFN-γ stimulates melanoma progression and examined the anti-melanoma activity of novel combination therapy using nNOS inhibitors with COX-2 inhibitors and immunotherapy for melanoma treatment.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Recommended Citation
Patel, AR. Development of Pharmaceutical Inhibitors Targeting nNOS for Melanoma Treatment. [dissertation]. Irvine, CA: Chapman University; 2025. https://doi.org/10.36837/chapman.000627
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