Inflammation and cancer treatment

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Targeting NOS2 and COX2 to Improve Conventional, alternative and Immunotherapeutic. The importance of NOS2 and COX2 in ER- breast and other cancer as driver of outcome suggest that there is opportunity to target these proteins to for cures. A clinical trial on chemoresistent and metaplastic breast cancer by Dr. Jenny Chang at Houston Methodist shows remarkable responses in these patients with extremely poor prognosis (PMID: 34910551). This breakthrough and the biology described above suggest that targeting NOS2 as well as COX2 are powerful targets to treat clinically challenging tumors. Using the aggressive 4T1 murine model, which mimics clinically challenging TNBC similar to that in humans, we found that simultaneous targeting NOS2/COX2 led to a 47% high response with 25% complete tumor regression and 40% of those were found to have resistance to rechallenge (PMID: 36375380). These results showed that NOS2/COX2 inhibition dramatically altered the immune response leading to the development of immune memory. Like the spatial orientation analysis in the human, it was found that COX2 inhibition impacted primarily T-cell such as CD8 Teff leading to activation and penetration into the tumor. Targeting NOS2 increases B cell and repolarize myeloid cells macrophage and neutrophils. These finding in the murine model were remarkably consistent with clinical trial of Dr. Chang's. In the murine model dual inhibition showed reduction of metastasis by >100 fold in survival surgery and enhancement of Taxol response. Taken together, these results show that targeting NOS2 and COX2 has powerful impact on the immune system and will be important consideration in immune based and conventional therapy. COX2 inhibitors have been used in treatment and prevention with mixed results. NSAIDs used in conjunction with radiation was shown to improve outcome. In cohort of TNBC, we found that high COX2 but not NOS2 correlated with poorer outcome suggesting that COX2 may impede radiotherapy in TNBC. Radiation of 4T1 model with NSAID showed dramatic improvement in tumor regrowth delay (PMID: 38912586). Inhibition of COX2 in tumor focus radiation show that there was local increase in Type I interferons and STING response. These results show that combination of focal radiation and NSAID provide a local reverse of immune response. Our previous work using NOS inhibitor L-NAME in murine models shows that local increase in IL2, IL12, and IFN (PMID: 25990221). While systemic delivery of these IFN type I/II and IL-2 are challenging due to their strong determinantal side effects. Radiation with NSAID or NOS inhibitor with tumor focal irradiation provides a unique method to change the immune response without side effects of systemic delivery. Taken together targeting NOS2 and COX2 result in a profound change in the antitumor immune response may powerful synergize conventional, target therapy, alternative and other immune therapy.