Gene expression biomarker imaging to detect lymph node metastases

Abstract

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Objectives: Lymph node metastasis is a poor prognostic indicator for cancer patients. We utilized adenoviral vectors (Ad)that express imaging reporter genes (firefly luciferase or herpes thymidine kinase (sr39tk) gene) under cell- or cancer-specific promoter to detect nodal metastases.

Methods: The Mucin-1 expressing KPL breast tumors were implanted in mammary fat pads and the PSA-positive LAPC-9 prostate xenografts, expressing lymphatic endothelial growth factor VEGF-C were implanted subcutaneously or intraprostatically in SCID mice. Cancer-selective muc1 promoter and prostate-specific PSA promoter was used to target breast and prostate cancer, respectively. A two-step transcriptional amplification (TSTA) method was employed to augment the expression of imaging reporters. Nodal metastasis was targeted by injecting the selective Ad in the lymphatic-rich paws or peritumorally. BLI and PET were conducted.

Results: The cancer-specific AdMuc1-TSTA-fl specifically detected metastasis by BLI in the axillary nodes, ipsilateral to the implanted KPL tumors. Similarly, prostate-specific AdTSTA-fl directly visualized prostate cancer metastases in axillary or pelvic peri-aortic nodes of subcutaneous or prostatic tumors, respectively. Moreover, sentinel lymph node (SLN) metastases were readily detected by AdTSTA-sr39tk mediated PET by using 18F-FHBG as tracer.

Conclusions: Ad can enter lymphatic circulation and transport to the SLNs. Transduction of metastatic tumor cells and the subsequent cell-restricted expression of imaging reporter gene lead to specific diagnostic imaging signals. These findings suggest that the transcriptionally-targeted Ad can be an effective diagnostic imaging agent to detect SLN metastasis and improved patient care.

Research Support: NCI, PCF