Response to angiotensin blockade with irbesartan in a patient with metastatic colorectal cancer

Abstract

Background: A patient suffering from metastatic colorectal cancer, treatment-related toxicity and resistance to standard chemotherapy and radiation was assessed as part of a personalized oncogenomics initiative to derive potential alternative therapeutic strategies.

Patients and methods: Whole-genome and transcriptome sequencing was used to interrogate a metastatic tumor refractory to standard treatments of a patient with mismatch repair-deficient metastatic colorectal cancer.

Results: Integrative genomic analysis indicated overexpression of the AP-1 transcriptional complex suggesting experimental therapeutic rationales, including blockade of the renin-angiotensin system. This led to the repurposing of the angiotensin II receptor antagonist, irbesartan, as an anticancer therapy, resulting in the patient experiencing a dramatic and durable response.

Conclusions: This case highlights the utility of comprehensive integrative genomic profiling and bioinformatics analysis to provide hypothetical rationales for personalized treatment options.

Keywords: AP-1 complex; RNA expression analysis; chemo-refractory colon cancer; irbesartan; mismatch repair defective; personalized medicine.

Figure 1.

Pathology and positron emission tomography—computed tomography (PET/CT) scans. Hematoxylin and eosin staining (A, left) shows moderately differentiated colonic adenocarcinoma; immunohistochemistry for MLH1 shows loss of staining in tumor cell nuclei with retained staining in background inflammatory cells (centre); c-JUN immunohistochemistry shows strong expression in the tumor cells, note the normal colonic epithelium features staining of the crypt bases only (right). Pretreatment PET/CT scans (B–E) demonstrate fludeoxyglucose (FDG) uptake in the L3 spinous process (B) and in multiple lymph node areas including left supraclavicular, left mediastinal, retrocrural, retroperitoneal, para-aortic and bilateral iliac regions (C). Five weeks after treatment initiation with irbesartan (D and E). FDG activity has resolved in the affected areas.

Figure 2.

CNV and expression analysis. CNV plots of chromosomes 3 and 10 in the colonic adenocarcinoma (A); single copy loss in a region containing PIK3CA (left); single copy loss of approximately 20 kb deletes exons 1 and 2 of PTEN (right and inset). Density plots showing relative gene expression levels compared with colon adenocarcinoma (B) for FOS (left) and JUN (right). Green curve indicates expression range in tumor tissue, blue curve depicts expression range in normal tissue, yellow line shows relative expression level in patient tumor tissue, and pink line indicates relative expression level in normal compendium.