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.
","abstract_html":"<p>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.</p> <p>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.</p> <p>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.</p>","abstract_has_math":false,"creators":["Patel, Anika R"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Pharmaceutical Sciences","degree_department":null,"school":null,"contributors":["Dr. Sun Yang","Dr. Kamaljit Kaur","Dr. Reza Mehvar","Dr. Jennifer Totonchy"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-05-01T07:00:00Z","date_published":"2025-05-01T07:00:00Z","updated_at":"2026-07-24T01:38:43Z","subjects":["melanoma","neuronal nitric oxide synthase (nNOS)","interferon-gamma (IFN-γ)","targeted therapy","programmed death-ligand 1 (PD-L1)","celecoxib","Cancer Biology","Immunotherapy","Medicinal Chemistry and Pharmaceutics","Other Pharmacy and Pharmaceutical Sciences","Pharmaceutics and Drug Design","Pharmacology","Skin and Connective Tissue Diseases"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/39","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Dr. Sun Yang","Dr. Kamaljit Kaur","Dr. Reza Mehvar","Dr. Jennifer Totonchy"]},{"key":"dc:creator","label":"Author","values":["Patel, Anika R"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2027-04-30T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmaceutical Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["melanoma","neuronal nitric oxide synthase (nNOS)","interferon-gamma (IFN-γ)","targeted therapy","programmed death-ligand 1 (PD-L1)","celecoxib","Cancer Biology","Immunotherapy","Medicinal Chemistry and Pharmaceutics","Other Pharmacy and Pharmaceutical Sciences","Pharmaceutics and Drug Design","Pharmacology","Skin and Connective Tissue Diseases"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/39"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:source","label":"Dc Source","values":["Patel, AR. Development of Pharmaceutical Inhibitors Targeting nNOS for Melanoma Treatment. [dissertation]. Irvine, CA: Chapman University; 2025. https://doi.org/10.36837/chapman.000627"]},{"key":"dc:title","label":"Title","values":["Development of Pharmaceutical Inhibitors Targeting nNOS for Melanoma Treatment"]}]}],"canonical_facts":{"dc:contributor":["Dr. Sun Yang","Dr. Kamaljit Kaur","Dr. Reza Mehvar","Dr. Jennifer Totonchy"],"dc:creator":["Patel, Anika R"],"dc:date.available":["2027-04-30T07:00:00Z"],"dc:description.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.
"],"dc:identifier":["https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/39"],"dc:source":["Patel, AR. Development of Pharmaceutical Inhibitors Targeting nNOS for Melanoma Treatment. [dissertation]. Irvine, CA: Chapman University; 2025. https://doi.org/10.36837/chapman.000627"],"dc:subject":["melanoma","neuronal nitric oxide synthase (nNOS)","interferon-gamma (IFN-γ)","targeted therapy","programmed death-ligand 1 (PD-L1)","celecoxib","Cancer Biology","Immunotherapy","Medicinal Chemistry and Pharmaceutics","Other Pharmacy and Pharmaceutical Sciences","Pharmaceutics and Drug Design","Pharmacology","Skin and Connective Tissue Diseases"],"dc:title":["Development of Pharmaceutical Inhibitors Targeting nNOS for Melanoma Treatment"],"thesis:degree_discipline":["Pharmaceutical Sciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T01:38:43Z"}