一种新型iNOS抑制剂作为炎性乳腺癌的靶向治疗策略

Nitric oxide (NO), generated by inducible nitric oxide synthase (iNOS), has been implicated in tumor progression, metastasis, and therapy resistance. Our completed phase Ib/II clinical trial in metastatic and locally advanced triple negative breast cancer showed that combination therapy with the pan NOS inhibitor LNMMA and standard chemotherapy elicits potent antitumor activity. Mechanistically, LNMMA targets the breast cancer stem cell (BCSCs) population enhancing their susceptibility to chemotherapy. We have developed a new iNOS inhibitor TDIMER co formulated with a calcium channel antagonist to mitigate the hemodynamic effects associated with systemic iNOS inhibition. We hypothesize that TDIMER can be effective for the treatment of inflammatory breast cancer (IBC), a rare and highly aggressive subtype with high recurrence rates and poor prognosis. In vitro studies were performed using SUM149 IBC cells. iNOS expression was confirmed by RT-qPCR and western blot. TDIMER efficacy was assessed, alone or with docetaxel, and compared to LNMMA, through cell proliferation, apoptosis and cell migration assays. BCSCs (CD44⁺/CD24⁻ /low ) were identified by flow cytometry after treatment with TDIMER or LNMMA in combination with docetaxel. In vivo studies using non-tumor bearing NSG mice were conducted to determine TDIMER dose toxicity and effect on blood pressure (BP). Mice received TDIMER (40 mg/kg oral gavage on day 1, 20 mg/kg oral gavage on days 2-5) or in combination with the calcium channel blocker amlodipine (10 mg/kg IP injection on days 1-5). Mice treated with PBS were used as control. BP was measured daily with BP-2000 (Visitech Systems). Animals were euthanized on day 5 for histopathological analysis and assessment of biochemical markers (ALT, AST, BUN) in serum samples. TDIMER treatment demonstrated superior efficacy over LNMMA, with a markedly lower IC₅₀ in SUM149 cells. TDIMER more effectively reduced cell viability, and delayed migration relative to LNMMA. Combination therapy with TDIMER and docetaxel induced the highest levels of apoptosis and reduced BCSCs, suggesting potent activity against chemo resistant tumor-initiating cells. In vivo toxicity studies demonstrated that TDIMER treatment did not produce histopathological alterations or significant elevations in serum ALT, AST, or BUN levels, confirming a favorable safety profile. Furthermore, no significant changes in BP were observed across experimental groups, underscoring TDIMER's advantage in achieving potent iNOS inhibition without the need for coadministration of antihypertensive agents. Ongoing studies are aimed to elucidate the antitumor efficacy of TDIMER in xenograft mouse models of IBC. Overall, our findings support continued preclinical development of TDIMER as a novel iNOS targeted therapy for IBC patients.