Roger Tsien, the UC San Diego professor who won the 2008 Nobel Prize for chemistry, has spent his career creating ways to help scientists look inside living cells, using fluorescent molecular tags that only bind to certain structures. Now his vision is to apply some of what he’s learned to help surgeons remove tumors by creating vivid color differences between a tumor and healthy tissue, and a technique to make more potent “smart bomb” cancer drugs.
The company founded to develop these technologies from the Tsien lab at UCSD is called Avelas Biosciences (pronounced UH-vell-us). It got started about a year ago with an undisclosed amount of seed capital from San Diego-based Avalon Ventures. Tsien and Kinsella go way back to the mid-90s, when they joined forces to start Aurora Biosciences, the company that eventually sold for almost $600 million to Vertex Pharmaceuticals in 2001. I heard about the new vision for Avelas a couple weeks ago during a visit with Tsien in his office at UCSD.
The basic idea is to hit cancer cells in a new way. Avelas makes peptide substrate molecules that are sort of like Legos that can be attached to whatever the scientist wants—an MRI contrast agent, a fluorescent tag, or a potent cell-killing agent. The peptides can be designed to latch specifically onto enzymes that are active in tumors, and if there’s a tag attached, it can provide a vivid image for a surgeon who’s trying to completely cut out a tumor without hitting any nearby nerve tissue, Tsien says.
And that’s just the start of how this might be useful. Tsien, and the co-founders of Avelas, are thinking hard about using this new platform of peptide substrates to also make cancer drugs. Today’s antibody drugs are usually made to hit a specific receptor on the surface of cancer cells, fitting like a key into a lock. Tsien referred to this as a “1 to 1” binding reaction, in which one drug molecule hits one target on cells. Instead, the Avelas peptides are aimed at hyperactive enzymes that make tumors go. The enzyme takes apart the peptide and its toxic cell-killing payload, and the enzyme repeats the process over and over again, creating an amplified anti-tumor effect, Tsien says.
If proven out in clinical trials, this notion could translate into lower doses, fewer side effects, and more efficient tumor-killing punch.
“This is a new targeting mechanism,” Tsien says. “I put it up there on the level with antibodies.”
This idea has been progressing in Tsien’s lab for the last six or seven years, and its commercial potential became clear about two years ago, he says. Once Kinsella became convinced it was time to spin this idea out into a company, two key people were brought aboard. Paul Finnegan, a former executive with Paramount BioCapital and Alexion Pharmaceuticals, was brought in as CEO because he had experience in both imaging and drug development. Tito Gonzalez, a former postdoc in Tsien’s lab and a veteran of Aurora and Vertex, signed on as vice president of R&D.
Like any company founded in a downturn, Avelas is under pressure to produce some commercially valuable results, sooner rather than later. So that’s why it is focusing first on imaging applications, Tsien says.
One idea is to start with MRI images. That tool is the best for whole body scanning for tumors, because it doesn’t expose the patient to any radiation that can accumulate and cause problems over time, and it provides high resolution images. But it’s not very sensitive, which requires a lot of gadolinium probes in a contrast agent to help a doctor see the difference between a tumor and healthy tissue. Radioactive tracers are very sensitive and easy to see, but pose a danger to the patient with accumulation over time, he says.
Avelas enters this picture with what it calls a fluorescent “Activatable Cell-Penetrating Peptide.” Tsien showed me on his laptop a picture of a surgeon looking at a tumor without any of these fluorescent-tagged peptides, and he asked me if I could tell the difference between the tumor and the healthy part (I couldn’t). Then he overlaid images with a blue dye for the tumor, and a green dye for the healthy parts, and it was crystal clear.
This kind of imaging has been used by a surgical collaborator, UCSD’s Quyen Nguyen, who has shown that the Avelas peptides enabled her to clearly define the boundaries of the tumor, and completely remove them surgically, which helped experimental mice live longer after surgery. This is one of the age-old problems with cancer surgery—failing to cut out the whole tumor can leave tiny metastases behind to flourish, while cutting too much out can cause disability in the patient.
“Surgeons fear that they are getting near some nerves. They are not that easy to distinguish,” Tsien says. “If you cut the patient’s nerves, the patient can lose motor function, gets paralyzed, lose sensation. That can be for the rest of your life.”
The demand for sharper contrast agents is growing as surgery becomes more roboticized, thanks to companies like Sunnyvale, CA-based Intuitive Surgical. Doctors who use laparoscopes mounted with cameras to perform operations have less and less ability to function on feel, and need to compensate by seeing better, Tsien says. Imaging for surgery, is “the low-hanging fruit,” Tsien says.
The bigger business opportunity, however, definitely lies in using the targeted peptides for cancer drugs. Just like you can attach a fluorescent tag to one of these peptides to help it light up on camera and tell you where the tumor is, you can attach a chemotherapy agent to create an anti-tumor smart bomb. The global market for cancer drugs was worth $66 billion in 2008, and is estimated to grow to $84 billion by 2012, according to research from Cowen & Company.
The precise imaging capability of the peptides will be used to guide Avelas through animal experiments to help determine first whether its cancer drugs are hitting the target as intended, Tsien says. The goal will be to get one of the cancer drug candidates through animal tests and into clinical trials in two to three years, R&D chief Gonzalez says.
“For most people, the imaging is a little crutch people use to help with developing a therapeutic,” Tsien says. “For us, the imaging may come first and pay off in its own right, and teach us how to do the therapeutic approach best.”
The big trick, of course, with cancer is finding a drug that only hits the cancer cells and doesn’t go “off-target” and hit healthy stuff, causing side effects. There is some off-target toxicity that needs to be dealt with, because some normal organs may have the enzyme activity that attracts the peptide drug, Tsien says. Avelas will have to pick its shots wisely in animal experiments, to focus on organs that have the enzyme activity in the right organs, like lung cancer, he says, but probably not brain cancer, because the peptides probably can’t cross the blood-brain barrier.
There are a couple of competitors out there with slightly different technologies. VisEn of Cambridge, MA is using a different kind of fluorescence for medical imaging, Finnegan, the CEO, says. Denmark-based PhotoCure uses a combination of light to activate drugs, which is a bit different.
Tsien, for his part, is continuing the push the envelope further with his fluorescent tags in his UCSD labs, studying things he considers interesting for cardiovascular disease, but which aren’t ready for a company yet. Naturally, he isn’t giving up his day job, especially now that as a Nobel Laureate, he joked he has gotten a precious parking spot near his lab.
But what really attracted Finnegan to this company in these early days? It was partly because Avelas has a platform technology that could give rise to a number of different kinds of opportunities. But more than that, it was about the people.
“Roger is so bright, and passionate about what he does. Everybody wants a piece of him, and yet he’s still generous with his time,” Finnegan says. “Being able to work with a Nobel Laureate, how many people really have the opportunity to do that?”
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