Tumor Paint Lights Up Cancer Cells, Facilitates Surgery

Roxanne Nelson

July 02, 2014

It sounds like something out of a futuristic medical novel: before the surgeon begins to operate, an injected substance magically lights up all of the cancer cells. The surgeon can see precisely where the tumor begins and ends, which increases the chances of removing it all without damaging the surrounding healthy tissue.

This scenario could happen sooner rather than later. An innovative substance known as "tumor paint" has been tested in canine cancer patients at an academic center, and the results are promising. Tumor paint is also now being evaluated in a phase 1 human trial.

Dr. James Olson

Tumor paint was developed by James Olson, MD, PhD, and colleagues at Seattle Children's Hospital and the University of Washington. The hope is that it will enable surgeons to see tumors live during surgery at better resolution than preoperative scans or direct intraoperative observation, which would improve the likelihood that they will remove all malignant cells without damaging healthy tissue. The experimental technique has been tested in brain, prostate, breast, colon, skin, and other cancers.

The impetus for tumor paint came after Richard Ellenbogen, MD, chair of the Department of Neurological Surgery at the University of Washington, spent 12 hours removing a brain tumor from a 17-year-old girl. Even with 25 years of experience and the best tools available, he had difficulty differentiating between malignant and healthy tissue. "He thought that what he left behind was normal brain tissue, but it turned out to be cancerous," Dr. Olson said in an interview. The case "proved that the tools just aren't available to help surgeons distinguish cancer from normal brain."

That day, Dr. Olson and Dr. Ellenbogen decided to put together a team to create a molecule that would light up the cancer cells.

A Quarter Century in the Making

However, the product cells was actually 25 years in the making. When he was a PhD candidate in pharmacology at the University of Michigan, Dr. Olson helped develop a radioactive drug that would light up brain cancers on PET scans. After he defended his thesis, one of his professors asked what he would want to do next.

 
Okay, Buck Rogers, so what are you really going to do?
 

"I told him that now that we figured out how to get radioactivity into the tumors, we needed to figure out a way to get light into tumors, so surgeons could see where the cancer cells are when they're operating," Dr. Olson explained. "And to that, the professor asked, 'okay Buck Rogers, so what are you really going to do?' "

Dr. Olson ran into his professor last year and reminded him of that conversation. "I showed him the story of what we were doing and how we were getting light into the cancer cells," he told Medscape Medical News. "That was a fun reunion."

When Dr. Olson first came up with the idea, technology hadn't advanced to the point where it could become a reality. But after the disheartening case with the 17-year-old girl, Dr. Olson knew that the time had come. The main problem was finding a substance that could be used an illuminating agent.

Not long after that case, a neurosurgery resident, Patrik Gabikian, MD, began working in Dr. Olson's lab.

Dr. Gabikian found a report from a lab in Alabama that was studying scorpion venom; it appeared that the toxin could bind to brain tumor cells. "Importantly, the substance that it bound to was not in normal brain," said Dr. Olson. "I thought that this could be our target."

Chlorotoxin (CTX) is a 36-amino acid peptide found in the venom of the deathstalker scorpion (Leiurus quinquestriatus) that can cross the blood–brain barrier, which is generally a major hurdle for drug developers.

It works by blocking small-conductance chloride channels. It also binds to matrix metalloproteinase-2, which is upregulated in gliomas and related cancers but is not normally expressed in brain.

Dr. Olson chose to use Cy5.5, a fluorescent molecular beacon that emits photons in the near-infrared spectrum. Because photons of this wavelength are minimally absorbed by water or hemoglobin, these beacons are well suited for intraoperative imaging.

The resulting compound, known as CTX:Cy5.5, was subsequently injected into a human brain tumor that was grafted onto the back of a mouse. "If it lights up, we figured we were on to something," he said. "If not, then it was back to the drawing board."

In less than an hour, the tumor glowed, brightly and distinctly from the rest of the mouse.

"We were literally dancing in the halls," Dr. Olson laughed. "It's quite rare when something works that fast, and in your very first test."

Subsequent studies were also successful. In more than 50 mice, all tissues sent to pathology tagged as cancer based on the CTX:Cy5.5 signal were cancerous, and all adjacent normal tissue was histologically normal. Current technology, such as MRI, can distinguish tumors from healthy tissue only if more than 1 million cancer cells are present. But CTX:Cy5.5 could identify tumors with fewer than 2000 cancer cells, making it 500 times more sensitive than MRI under operating conditions.

First Human Trial

With the fundamental research completed, Dr. Olson realized that tumor paint had outgrown his lab. Blaze Bioscience, founded in 2010 to develop and commercialize the technology, entered into a licensing agreement with the Fred Hutchinson Cancer Research Center in Seattle.

 
I was surprised that no one had invented it already.
 

"Jim Olson was looking for someone to transfer his vision into reality," Heather Franklin, CEO and president of Blaze, told Medscape Medical News. "I immediately realized that this was a technology that should be out there. In fact, I was surprised that no one had invented it already. So we started the company together."

Franklin, who is the former senior vice president of business development and alliance management at ZymoGenetics, was able to bring some of her colleagues from that company on board.

In late December 2013, Blaze announced the initiation of the first human trial looking at a tumor paint product candidate called BLZ-100. In this product, the CTX peptide was synthesized using standard solid-phase methods and, after refolding, the peptide was conjugated to an indocyanine green derivative.

The ongoing phase 1 trial is being conducted in Australia in patients with basal cell carcinoma, squamous cell carcinoma, or amelanotic melanoma.

"We are now looking at safety and at different dosing groups," Franklin said. "We thought that skin cancer was a very good place to start. We want to be in a setting where we can clearly see if the drug is working and also, for now, where the patients are not very sick."

The primary objective is to evaluate the safety and tolerability of BLZ-100 after a single intravenous injection that is administered prior to surgery. The study will also examine the pharmacokinetics of BLZ-100 and the fluorescent signal from skin tumors.

"Tumor paint went from the lab into trials in less than 2 years," she noted. "We are continuing to work with Dr. Olson's lab in developing other optide-based product candidates."

Dogs Aglow

Although the technology is on the cusp of human trials, canine patients have been reaping the benefits. A clinical trial of tumor paint in 27 dogs that were undergoing surgical excision of malignant tumors has already been completed at the College of Veterinary Medicine, Washington State University (WSU), Pullman.

"These are real cancer patients, they are people's pets who developed cancer spontaneously, not in a lab," said Dr. Olson. "Some of the results have been stunning; in 1 case, they were able to save the dog's leg."

Many types of canine tumors resemble human disease, including sarcomas, breast and lung cancers, mucosal squamous cell cancers, and gliomas. The diversity of tumor size and type, surrounding tissue, and patient body mass make dogs an excellent model with which to predict the clinical characteristics of BLZ-100, including tumor penetration, background staining, and effective imaging dose.

Although the canine trial was a clinical trial for veterinary medicine, it is considered part of the preclinical trial paradigm for human medicine, explained William S. Dernell, DVM, MS, professor and chair in the Department of Veterinary Clinical Sciences at WSU. "It's good that we can contribute in that manner but, for us, it's a true clinical trial," he said.

The researchers are now in the process of organizing a phase 2 trial. Blaze is providing funding for the continuation of the work in the interim period between phase 1 and phase 2.

As the research continues, it will be a little more focused. First and foremost, we wanted to make sure that there weren't any overt toxicities associated with the product and that it didn't cause any unexpected problems, Dr. Dernell told Medscape Medical News. "We determined that."

The canine trial allowed researchers to see that product uptake did occur in the tumors and to evaluate the tumor types in which BLZ-100 was most advantageous. "We also wanted to see which tumor type in dogs would be the optimal type for use in humans," he said. "And in this initial study, we did find that out."

Another focus of the canine trial was to determine which tool could be used for intraoperative imaging. "We had companies interested in having their devices tested in that arena," he explained. With the dogs, "we were able to get real-time data."

They found that they could get intraoperative images with fluorescence, and could differentiate tumor from normal tissue. "We made a lot of changes and adjustments; it was kind of a proof-of-principle project," he said. "But we didn't make any real changes in the standard surgical procedure, based on whether or not there was uptake, so as not to compromise the patient."

The best uptake and differentiation was seen in soft tissue sarcomas, which are relatively common in dogs. "The behavior of these tumors are similar in dogs and humans, so this could be very helpful," Dr. Dernell explained. "This is what we will put our focus on in the next trial. We also plan to use the tool to make some intraoperative decisions and then back those decisions up with pathology. This will ensure us that the product is doing what we really want it to do."

The researchers are more comfortable doing that now that there are supportive data. Dr. Dernell explained that even if there is an error, such as when pathology finds a tumor where there was no uptake of the product, the patient really hasn't been compromised. "That's because we have a lot good options to fall back on, such as doing a second smaller surgery," he said. "The hope is that the data will be of benefit to the design and functioning of human clinical trials."

Lights, Cameras, Action

For BLZ-100 to be of use, an imaging system is needed. Although there are many infrared imaging systems in use, they are not optimized to the concentration and amount of indocyanine green in this product.

Researchers at Cedars-Sinai Medical Center in Los Angeles have recently developed an experimental tumor-imaging system using a standard charge-coupled device (CCD) camera to visualize low levels of dye attached to the tumors. The 2-in-1 camera system simultaneously captures white light and near-infrared images, and combines these images on a high-definition video monitor.

A proof-of-concept study recently published showed that it is possible to use a standard CCD to record fluorescence from brain tumors using BLZ-100 (Neurosurg Focus. 2014;36(2):e1).

"We needed a sophisticated imaging system that could do high resolution and that was tiny enough to be connected to endoscopes," lead author of that study, Pramod Butte, MBBS, PhD, said in an interview. "We are using a single camera and most systems use 2 cameras."

In an ideal world, Dr. Butte pointed out, it would be possible to detect a single cell. "We can now start looking at cells that are clusters," he said. "If there are a few cells left behind, we need to get them out."

 
The one thing that they cannot resist is the neurosurgeon.
 

Surgery is the one thing that tumors can't develop resistance to. "Tumors can be resistant to radiotherapy and chemotherapy, but the one thing that they cannot resist is the neurosurgeon," Dr. Butte said with a chuckle. "But to have a complete resection, you need to see the tumor."

The camera allows surgeons to get a high-resolution picture in real time. "It can also go places no microscope can go," he said. "And no tumor gets left behind. It can detect a 1 mm tumor that is buried 3 mm deep into the tissue, so satellite lesions aren't missed."

Dr. Butte said he is hoping that human clinical trials for the imaging system will begin this fall, after the safety trials for BLZ-100, currently ongoing in Australia, have been completed.

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