"Lighting Up" Tumors With Scorpion Venom, Laser Imaging Technology

Glioma Researchers Make Headway in Test of Breakthrough Intraoperative Fluorescent Imaging Method

A clinical trial testing a novel tumor-specific peptide conjugated to a fluorescent molecule, is showing significant promise in enabling neurosurgeons to detect and abstract dangerous gliomas intraoperatively. When used in conjunction with a compact imaging device developed at Cedars-Sinai, the fluorescent molecule can be seen during surgeries, with the hope that such visualization will lead to improved extent of tumor removal.

Tumor Paint BLZ-100, a product of Blaze Bioscience, Inc., is a synthetic version of a peptide found in the venom of the deathstalker scorpion, which has a very high affinity to human gliomas. When activated by laser in the near-infrared part of the spectrum, it emits a glow invisible to the human eye, which the specially designed camera captures.

The imaging system, termed Synchronized near-InfraRed Imaging System (SIRIS) was developed at Cedars-Sinai. The camera uses special image collection techniques and software for image processing to detect very low levels of fluorescence required to see the Tumor Paint adequately. The SIRIS is being used in conjunction with intravenously administered BLZ-100, to determine if it can enable neurosurgeons to delineate brain tumors from healthy tissue in real time.

The Phase 1 trial, funded by Blaze Bioscience, started in January 2015 and is enrolling patients at both Cedars-Sinai and a site in Australia. Several additional trials of BLZ-100 have been initiated in the United States, all using the SIRIS imaging system to help identify the BLZ-100. If the findings continue to pan out this approach may be a significant breakthrough in cancer research, according to researchers at the Cedars-Sinai Maxine Dunitz Neurosurgical Institute and Department of Neurosurgery.

Synchronized near-InfraRed Imaging System (SIRIS)

"We are very excited about our preliminary findings," said Chirag G. Patil, MD, MS, director of the Center for Neurosurgical Outcomes Research and the clinical trial’s principle investigator. "Identifying something that can bind selectively only to cancer cells addresses a major hurdle in cancer research. This system has the potential to become an enormous scientific breakthrough, especially as it relates to intraoperative detection and resection of malignant brain tumors in real time."

Gliomas are among the most lethal malignant brain tumors, with patients typically surviving about 15 months after diagnosis. Based on research, survival statistics increase with complete removal of the tumor, but it is impossible to visualize with the naked eye where tumor stops and brain tissue starts. Current imaging systems do not provide such a definitive view.

"Gliomas have tentacles that invade normal tissue and present big challenges for neurosurgeons: Taking out too much normal brain tissue can have catastrophic consequences, but stopping short of total removal gives remaining cancer cells a head start on growing back," said Keith L. Black, MD, chair and professor of the Department of Neurosurgery. "That's why we have worked to develop approaches that will provide a clear distinction during surgery between diseased tissue and normal brain."

Black is also director of the Maxine Dunitz Neurosurgical Institute, the Johnnie L. Cochran Jr. Brain Tumor Center, and is the Ruth and Lawrence Harvey Chair in Neuroscience.

In preclinical studies, the experimental system clearly delineated tumor tissue from normal brain tissue. Also, with near-infrared light's ability to penetrate deep into the tissue, BLZ-100 might be able to identify metastatic lesions that are separate from the main tumor that otherwise might evade detection.

Pramod Butte, PhD, research scientist and assistant professor in the Department of Neurosurgery, said the tumor-imaging process consists of two parts: deploying a fluorescent "dye" that sticks only to cancer cells, and using a laser and a special camera to make an invisible image visible.

To get the dye to the tumor, it is linked to the peptide, chlorotoxin. Chlorotoxin ignores normal tissue but seeks out and binds to malignant tumor cells. It first was derived from the venom of a desert-living yellow scorpion, leiurus quinquestriatus, also known as the deathstalker. Adam Mamelak, MD, FACS, FAANS, professor of neurosurgery at Cedars-Sinai, has studied the synthetic version of chlorotoxin and its tumor-targeting properties for more than a decade.

"Injected intravenously, the chlorotoxin seeks out the brain tumor, carrying with it indocyanine green, which has been used in a variety of medical imaging applications," Butte said. "When we shine a near-infrared laser on the tissue, the tumor glows. But the glow emitted by the tumor is invisible to the human eye."

The camera device, designed in Butte's lab, solves this problem by capturing two images and combining them on a high-definition monitor.

"Now that we’re proving the tumor-targeting ability of the fluorescent peptide complex can reliably visualize malignant cells using the SIRIS platform, our belief is that this approach may someday improve our ability to surgically remove gliomas without harming healthy tissue" Butte said.

Caption for top and bottom photo: Researchers aim to determine if Tumor Paint BLZ-100, derived from scorpion venom and used in conjunction with an imaging device developed at Cedars-Sinai, may be used to allow neurosurgeons to effectively detect and map gliomas.