改善胰腺癌对氯沙坦的反应：机制洞见及对个体化治疗的意义

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, with a 5-year overall survival of ~13%. Delayed diagnosis, limited response to current treatments, and the predominance of locally advanced or metastatic disease contribute to poor outcomes. Leveraging our preclinical findings in PDAC murine models, we showed that adding losartan-an angiotensin II type-1 receptor (AT1) blocker-to FOLFIRINOX followed by chemoradiation doubled R0 resection rates to ~70% in locally advanced PDAC in a phase II trial (NCT01821729) (PMID: 31145418). However, the patient-response was variable. Here we recapitulated this variability in orthotopic PDAC mouse models and revealed the underlying mechanism. Methods and Results: To investigate potential causes of the variable response, we mapped AT1 expression using light-sheet microscopy in AT1 reporter mice bearing orthotopic PDAC. We observed abundant AT1 throughout the tumor microenvironment. To define its functional relevance, we generated Agtr1a knockout (KO) PDAC cell lines and inducible KO mouse models. AT1 deletion in either cancer cells or stromal cells (but not alpha-SMA⁺ myCAFs or pericytes) significantly reduced tumor growth. Because losartan is a pro-drug that needs activation by liver enzymes CYP3A4 and CYP2C9, we next examined its metabolism. We subcutaneously administered two major losartan metabolites, EXP3179 and EXP3174, to orthotopic PDAC-bearing mice and found that EXP3174 mediated the anti-tumor effects of losartan. Mass spectrometry of plasma samples revealed that while some tumor-bearing mice efficiently converted losartan to its active metabolite, others showed limited or no conversion. To determine the cause, we assessed CYP2C9 and CYP3A4 activity in liver microsomes from non-metastatic PDAC-bearing mice. CYP2C9 activity was markedly reduced and inversely correlated with tumor burden, providing a mechanistic basis for differential losartan activation. Ongoing work aims to determine whether PDAC patients likewise display variable plasma levels of losartan and EXP3174. Conclusion: These findings identify impaired hepatic metabolism as a key driver of variable losartan responses in locally advanced PDAC. Mass-spectrometry-based assessment of losartan and EXP3174 levels may help determine which patients can effectively activate the drug. Given losartan's safety and low cost, its oral administration remains appropriate for most patients; however, in individuals with compromised CYP2C9 activity, administration of the active metabolite - EXP3174 may represent a more effective therapeutic option.