Imaging bladder cancer: Correlation with histopathologic findings

Objectives Bladder cancer (BCa) is the 5th common malignancy with recurrence rate of >50%, mandating long-term surveillance. CT, MR and F-18-FDG have serious limitations and low sensitivity in detection of recurrent papillary tumors. C-11-Choline is sensitive for BCa but suffers from short t½ of C-11. VPAC1, a genomic biomarker is expressed in high density on BCa cells. Goal is to target VPAC1 with Cu-64-TP3805 (Kd=3.1x10.-9M) and TP4303 for imaging BCa.

Methods TP3805 was labeled with Cu-64 for digital autoradiography (DA) or with a near infrared fluorophore (TP4303) for optical imaging (OI). Formalin-fixed paraffin sections from a tissue microarray of 100 patients 75M, 70.2±11 yrs. (45-89), and 25F, 71.4±9.3 yrs. (54-89) with high grade BCa (stage pT1-T4b) and 5 normal subjects (3M, 2F), were obtained from institutional tissue library and incubated at 22oC for 15 min, either with Cu-64-TP3805 (10±2 µCi) or TP4303 (1 nm). After PBS washes, tissues were air dried, DA was performed (IS-4000 R Bruker) and OI was carried out (FX-Pro, Bruker). ROI analysis was performed and signal to noise ratio (SNR) were calculated. Data were correlated with histologic findings.

Results All histologically malignant and healthy tissues had 100% corroboration with Cu-64-TP3805 and TP4303 uptake. The Cu-64-TP3805 mean SNR was 4.9±1.3, (1.9-10.7) and 2.1±0.4, (1.4-2.7) for malignant and benign tissue, respectively (p=0.01). The TP4303 mean SNR was 4.7±1.6, (2.4-8.5) and 1.4±0.9, (0.3-2) for malignant and benign tissue, respectively (p=0.02). Malignant tissues with low SNR had denuded, inflammatory or necrotic cells by histology, and accounted for a low SNR. These cells do not express VPAC1. Aggressive BCa samples had higher uptake than lower grade BCa samples on both DA and OI.

Conclusions Cu-64-TP3805 demonstrates strong binding to BCa tissue. This together with its lack of urinary excretion in humans, renders Cu-64-TP3805 worthy of investigations to image BCa in humans.

Research Support NIH, R01 CA157372-01 (MLT)