The study, published in the July 15, 2007 issue of Cancer Research, shows that the tumor paint can help surgeons distinguish between cancer cells and normal brain tissue in the operating room.
The paint is a scorpion-derived peptide called chlorotoxin that is linked to the molecular beacon Cy5.5. Until now there has been no way to allow surgeons to see tumors "live" during surgery.
Chlorotoxin:Cy5.5 is a fluorescent molecular beacon that emits photons in the near infrared spectrum. This illumination gives surgeons a better chance of removing cancerous cells during surgery without injuring surrounding healthy tissue. This is particularly significant in the brain, where approximately 80% of malignant cancers recur at the edges of the surgical site. Current technology, such as magnetic resonance imaging (MRI) can distinguish tumors from healthy tissue only if more than 1 million cancer cells are present. But Cy5.5 can identify tumors with fewer than 2000 cancer cells, making it 500 times more sensitive than MRI under operating conditions.
"My greatest hope is that tumor paint will fundamentally improve cancer therapy," said James M. Olson, MD, PhD, of Seattle Children's Hospital and The Hutchison Center who is the senior author of the study. "By allowing surgeons to see cancer that would be undetectable by other means, we can give our patients better outcomes."
Olson led the team that included neurosurgeons, engineers and biologists. The bioconjugate, Chlorotoxin:Cy5.5 which, when injected, emits a near- infrared light, was created in his laboratory at the Hutchinson Center. In mouse models, the team demonstrated that they could light up brain tumors as small as 1 millimeter in diameter without lighting up the surrounding normal brain tissue. In a prostate cancer model, as few as 200 cancer cells traveling in a mouse lymph channel could be detected.
Chlorotoxin:Cy5.5 is applicable to many cancers, but is especially helpful to surgeons operating on brain tumors. Not only would it reveal whether they'd left behind any bits of tumor, it would also help them avoid removing normal tissue. Chlorotoxin:Cy5.5 begins binding to cancer cells within minutes. The Chlorotoxin:Cy5.5 signal lasts for 14 days, illuminating cancer cells. Contrast agents currently in use only last for a few minutes.
"I feel fortunate to be working with gifted scientists to bring this revolutionary imaging technique from the laboratory to the bedside," said Richard Ellenbogen, MD, pediatric neurosurgeon, Seattle Children's Hospital and co-investigator on the study. "This development has the potential to save lives and make brain tumor resection safer."
Surgery remains a primary form of cancer therapy. Despite advances in surgical tools, surgeons currently rely on color, texture or blood supply to differentiate tumor from normal tissue, a distinction that is often subtle and imperfect. The limitations of this method contribute to cancer growth or patient mortality that is potentially preventable. The tumor painting technique combines a visual guide for the surgeon with the potential for significant improvement in accuracy and safety.
Tumor painting has been successfully tested in mice and the pilot safety trials are complete. Olson and his team are preparing the necessary toxicity studies before seeking approval from the Food and Drug Administration to begin clinical trials. Chlorotoxin:Cy5.5 could be used in operating rooms in as little as 18 months. All clinical studies will have consenting adult participants.
Olson and his team believe that Chlorotoxin:Cy5.5 has the potential to be used in the future as a non-invasive screening tool for early detection of skin, cervical, esophageal, colon and lung cancers. It is also useful in identifying positive lymph nodes which could mean a significant advancement for breast, prostate and testicular cancers.
Children's and the Hutchison Center's role as leading research institutions is underscored by their membership in the Pediatric Brain Tumor Consortium (PBTC), a group of 10 medical centers selected by the National Cancer Institute (NCI). The consortium's members were chosen by the NCI based on their experience, dedication to research and quality of patient care.
Other Children's and Hutchison Center, and University of Washington researchers on the team include Mandana Veiseh, PhD; Patrik Gabikian, S-Bahram Bahrami, PhD; Omid Veiseh, Miqin Zhang, Robert C. Hackman, MD; Ali C. Ravanpay, Mark R. Stroud, PhD; Yumiko Kusuma, Stacey J. Hansen, Deborah Kwok, Nina M. Munoz, PhD; Raymond W. Sze, MD; William M. Grady, MD; and Norman M. Greenberg, PhD.
About Seattle Children's Hospital Research Institute, Seattle, Wash.
At the forefront of pediatric research, the Seattle Children's Hospital Research Institute at Children's Hospital and Regional Medical Center in Seattle conducts research under nine major centers and is internationally recognized for its discoveries in cancer, genetics, health services, immunology, pathology, infectious disease and vaccines. Consistently ranked as one of the best children's hospitals in the country by U.S. News & World Report, Children's serves as the pediatric referral center for Washington, Alaska, Montana and Idaho. Children's has been delivering superior patient care for 100 years, including advancing new discoveries and treatments in pediatric research, and serving as a primary teaching, clinical and research site for the Department of Pediatrics at the University of Washington School of Medicine.
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