tilarginine (L-NMMA)

P=N/A, N=130, Active, not recruiting, VA Office of Research and Development | Recruiting --> Active, not recruiting | Trial completion date: Oct 2025 --> Oct 2027 | Trial primary completion date: Oct 2025 --> Oct 2027

Targeting this modification with nitric oxide synthase (NOS) inhibitors such as L-NAME, L-NMMA and 1400w restore sensitivity of MEK inhibitor, promotes dendritic cell activation, and enhances CD8+ T cell infiltration in preclinical models such as immunogenic mouse models and individual patient derived, primary melanoma cells. We also explore the emerging role of S-nitrosylation in regulating macrophage-mediated immune surveillance and propose translational strategies for combining redox modulation with targeted and immune therapies. These insights offer a compelling framework for overcoming therapeutic resistance and reprogramming the tumor immune microenvironment to activate the cytotoxic T-cells and enhance the responses to immunotherapy in NRAS-driven cancers.

P1, N=90, Completed, New York Medical College | Active, not recruiting --> Completed

P1, N=12, Active, not recruiting, The Methodist Hospital Research Institute | Trial completion date: Dec 2024 --> Dec 2025

We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed a post-treatment reversal of epithelial-to-mesenchymal transition and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a unique strategy to decrease chemoresistance and improve clinical outcomes in MpBC.

P1, N=12, Active, not recruiting, The Methodist Hospital Research Institute | Trial completion date: Dec 2023 --> Dec 2024

Cells were also treated with 10 μM of NOS2 inhibitor l-NMMA and 10 μM of N-acetyl cysteine (NAC), a free radical scavenger·H2O2 (100 μM) treated and untreated cells were used as positive controls and negative control respectively...The low levels of NO and MPO regulates gastrointestinal tract homeostasis and overcomes the inflammatory response of NLRP3. The ROS also plays crucial role in macrophage polarization hence alter the immune responses duing H. pylori pathogenesis.

L-NMMA, a pan nitric oxide synthase inhibitor, can mitigate TAMo-mediated inhibition of T cell proliferation without affecting TCM -like cell generation...Thus, the terminally differentiated TAMo subset (CD300LGhigh ACElow ) mainly contributes to TCM -like cell development. Taken together, these findings establish the significance of TAMos in boosting T-cell antitumor immunity.

NOS inhibitor, L-NMMA, was used to evaluate the role of nitric oxide in M-MDSC-mediated T cell suppression...Conclusions Glioma-derived factors recruit and induce CCR2+/CX3CR1+ myeloid cells to a CD4/8+ T cell suppressive state that can be partially ameliorated by iNOS inhibition. While additional M-MDSC-mediated immune suppressive mechanisms need to be identified, targeting M-MDSCs holds promise as an effective approach to improve immune-directed interventions in GBM.

Glioblastomas remain a challenging therapeutic target. iNOS inhibitors exhibit substantial potential as treatment options for oncologic lesions, and they have demonstrated a safe toxicity profile in humans for other pathological conditions. Research endeavors should be focused on investigating their potential effects on brain tumors.

P1, N=12, Active, not recruiting, The Methodist Hospital Research Institute | Trial completion date: Jan 2023 --> Dec 2023

HFD mice had a pro-inflammatory profile with a significantly faster tumor growth and higher expression of iNOS in tumor and adipose tissues. Treatment with the docetaxel/L-NMMA combination resulted in a more significant anti-tumor effect in HFD mice, likely through remodeling of TME. Spatial analysis, including CODEX and immunophenotyping are being conducted to determine the TME influence in obesity associated TNBC and the effect of NOS inhibition.