Abstract LB303: Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer

Abstract The deposition of the extracellular matrix (ECM) is associated with poor prognosis and therapy response in gastric cancer. An elevated extracellular matrix (ECM) and interstitial fluid pressure in gastric cancer limits the targeting of HER2-expressing gastric cancer cells when radioimmunotherapy (RIT) with 64Cu-trastuzumab (64Cu-TRZ) is utilized. Here we used Losartan (LOS), which is an antihypertensive drug, to downregulate ECM and interstitial fluid pressure in gastric cancer mice model. After 40 mg/kg of LOS treatment, a 2-fold higher Alexa-647-TRZ uptake significantly enhanced 64Cu-TRZ uptake by positron emission tomography (PET) imaging, LOS treatment decreased the tumor volume, and enhanced the survival rate. LOS-treated samples showed reduced SERPINE1 mRNA expression compared with the controls, as determined by qRT-PCR. Downregulated mRNA expression of TGFβ-1, and upregulated mRNA expression of MMP-2 in LOS-treated samples were observed. The corresponding protein expression of SERPINE1 was confirmed using western blotting. We also confirmed that silencing of SERPINE1 increased MMP2 activity. We revealed that the enhanced therapeutic effect of 64Cu-TRZ via LOS was due to the downregulation of SERPINE1, which degrades the ECM through MMP2. Our novel combinational therapy of using 64Cu-TRZ with LOS is highly effective for treatment of gastric cancer. Citation Format: Javeria Zaheer, Joycie Shanmugiah, Hyeongi Kim, Jin Su Kim. Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB303.