Editors' ChoiceCancer Imaging

Spotlight on Cancer

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Science Translational Medicine  26 Mar 2014:
Vol. 6, Issue 229, pp. 229ec54
DOI: 10.1126/scitranslmed.3009018

A particularly challenging battle in the war against cancer is the one waged against the spread of micrometastases—drug-resistant cells left behind after chemotherapy that evade detection until it is too late—when they have formed multiple nodules that choke vital organs. To catch and kill these micromets earlier, Spring and colleagues developed a dual imaging and treatment platform that targets, monitors, and destroys tumor cells disseminated throughout the body.

The authors designed an “immunoconjugate” composed of a toxic chromophore called benzoporphyrin derivative (BPD) and an antibody targeted to epidermal growth factor receptor (EGFR) called cetuximab. Conjugating BPD to cetuximab causes self-quenching of BPD that substantially lowers its background fluorescence and toxicity to minimal levels. However, when the BPD-cetuximab conjugates bind to EGFR (which is highly up-regulated on cells of many types of tumors), they are internalized, simultaneously blocking critical tumor cell signaling pathways and triggering dissociation of the conjugate. Dissociation leads to unquenching of the BDP, causing it to fluoresce brightly and light up the tumor cells. Spring et al. administered the conjugate to mice with peritoneal micrometastases and then monitored the glowing tumor cells over the course of 2 weeks using a microendoscope. The BPD-cetuximab conjugate was specific for tumor tissue, whereas the gold-standard BPD liposomal formulation, verteporfin, was nonspecific and had lower fluorescence. Near infrared (NIR) light could also be applied via the same catheter to transfer high levels of energy from the chromophore to kill the tumor cells. This novel strategy—termed tumor-targeted, activatable photoimmunotherapy (taPIT)—was developed in tandem with an automated image analysis workflow to track down and destroy micrometastases in a mouse model of human epithelial ovarian cancer.

Other activatable contrast agents have been difficult to apply to micrometastases owing to their lack of tumor selectivity. The combination of photodynamic therapy with immuno-targeting and imaging allowed Spring et al. to kill drug-resistant cells with specificity and reduced side effects as compared with those of nontargeted or “always-on” chromophores. However, the requirement for NIR light makes the strategy problematic for harder-to-reach metastases, and background levels of BDP toxicity are not negligible. Nevertheless, both BPD and cetuximab are U.S. Food and Drug Administration–approved components that have been previously used synergistically in combination, which suggests that this approach is ready for translation.

B. Q. Spring et al., Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates. Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.1319493111 (2014). [Abstract]

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