Cancer drug development is a classic good news, bad news story. The good news is that scientists have developed hundreds of compounds that can kill tumor cells very efficiently. The bad news is that most of those compounds are almost as good at killing healthy cells. As a result, modern oncology is a tricky balancing act, striving to kill the tumor without killing the patient. It often fails.
To address that problem, researchers have tried a variety of strategies to deliver drugs specifically to tumors. Antibodies are a popular choice, but they can be hard to manufacture and deliver. In recent years, investigators have turned their attention to small peptides, some of which are capable of binding tumor cells with exquisite specificity. As scientists continue to study these tumor-targeting peptides, contract research organizations (CROs) and other service companies are increasingly catering to this emerging niche.
Cutting out the carbs
One of the great advantages of peptides is that they are easy to synthesize. Unfortunately, many of the structures that are specific to tumor cells are carbohydrates, not peptides. “We can just order DNA or oligonucleotides or peptides ... but carbohydrates we always have to make the manual way, and it’s very expensive and time-consuming,” explains Michiko Fukuda, PhD, a professor in the tumor microenvironment lab at the University of California, Sanford-Burnham Medical Research Institute in Santa Barbara, Calif.
Rather than try to synthesize tumor-targeting carbohydrates, Fukuda and her colleagues decided to use phage display to find peptides that could mimic certain carbohydrate binding properties. In one recent study, they focused on selectin, which normally binds carbohydrates during tumor cell metastasis. Screening a phage display library of small peptides with a selectin probe identified a peptide that binds selectin. When the researchers injected labeled versions of this peptide into mice with tumors, the peptides homed specifically to the tumors and inhibited metastasis.
Though the team had originally aimed for selectin, they missed slightly; in mice, the new peptide turns out to bind a protein called annexin A1 rather than selectin. But work in other labs demonstrated that annexin A1 is a specific marker for the surfaces of tumor vasculature. Other cells in the body express the protein, but don’t export it to the surface, so an annexin A1-binding peptide injected into the bloodstream should only see its target inside tumors. That explained the specificity Fukuda and her colleagues had seen.
Annexin A1’s expression pattern also suggested a drug-targeting strategy. The “peptide was conjugated with [an] anticancer drug and injected into tumor-bearing mice, and it worked very well without any side-effects, because the targeting is so specific,” says Fukuda. She and her colleagues published those results in December 2011.1
That paper was one of a spate of recent findings that are starting to soften longstanding skepticism about tumor-targeting peptides. “When I started [these] studies people were saying that a peptide is not good for targeting, or even [that] targeting is not a primary interest in pharmaceutical companies,” says Fukuda. She adds that “I think now people think that peptides [are] a really good method.”
Finding the right hook-up
As interest in tumor-targeting peptides has increased, so has the number of potentially useful peptides. Indeed, researchers working in drug development—as well as basic cell biology—can now choose from a whole family of cell-penetrating peptides (CPPs) with different specificities. “The field is growing, and we see more and more requests,” says Miguel Castro, PhD, CEO of Bio-Synthesis in Lewisville, Tex., a company that synthesizes cell-penetrating peptides for researchers in numerous industry and academic labs. Castro adds that “it’s very clear that the activity does work, and [it’s] a very good and strong tool to use.”
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CPPs aren’t just a laboratory curiosity anymore, either. Companies such as CDG Therapeutics in Chicago, Ill. have been taking CPP-coupled drugs into clinical trials against different types of tumors, and the initial results look promising. “Big pharmaceuticals, they are looking at this very carefully. They have a keen interest in applying it,” says Castro.
Though the early news is good, drug developers still face many hurdles in trying to turn CPPs into cures. Besides finding small peptides that bind and enter tumor cells, researchers must also figure out how to exploit that activity to treat the tumor, as the peptides themselves are generally not toxic. The most popular approach is to link the peptide to a small molecule or biologic drug that actually does the dirty work, but not just any linkage will do.
As Castro explains, therapeutic proteins generally have multiple potential linking sites on their surfaces, so investigators have to decide how many sites they want to connect CPPs to: “When you conjugate them, depending on what you want to do you may want to conjugate as much as you can, or you may want to find an ideal number where you don’t hinder the activity of the enzyme or the protein.”
For that reason, researchers who send their peptide synthesis work out may want to search for a contractor with specific experience in tumor-targeting peptides. “Whereas the peptide itself can be done by anybody ... having a little more experience in [cancer targeting] may be more helpful to the researcher,” says Castro.
The master key
At least one family of peptides, though, could allow drug developers to send compounds into tumors without having to link them to anything. That was what Erkki Ruoslahti, PhD, one of Fukuda’s colleagues at the Sanford-Burnham Institute, discovered two years ago. While screening phage libraries for peptides that would bind tumor vasculature, Ruoslahti’s team discovered a peptide called iRGD that activates a general transport mechanism in blood vessels.2
“iRGD and other peptides like it, they activate a bulk transport pathway that takes in anything that is around and transports it out of the blood vessels and through tissue,” says Ruoslahti. When the researchers delivered iRGD and various anti-cancer drugs simultaneously to mice with tumors, the drugs migrated very efficiently into the tumors and killed them.
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While evidence in the mouse system suggests that iRGD homes specifically to tumor tissue, Ruoslahti cautions that there could be cryptic receptors for the peptide in other tissues, which could lead to off-target effects. However, that possibility also suggests that modified iRGD-like peptides could be developed to increase the drug permeability of other types of tissues. So far, the researchers have found a peptide that targets atherosclerotic plaques, and they are studying other motifs as well. “While we haven’t rigorously proven it, we think that those peptides work the same way in different targets that iRGD works in tumors,” says Ruoslahti.
Since the initial mouse experiments, the iRGD work has been picked up by CendR Therapeutics in Del Mar, Calif., a spinoff company that is now preparing to take iRGD-based therapies into clinical trials.
The iRGD results are also part of what Ruoslahti sees as a growing trend in tumor targeting, in which researchers are increasingly aiming for tumor vasculature instead of trying to develop peptides that bind directly to tumor cells. “[Tumor cells] really aren’t available to probes as well as is the vasculature, so I think a main improvement in the past ten years or so has been the realization that it’s much better to target the tumor vasculature at least initially,” says Ruoslahti.
A big box of tissues
Whether linking compounds to peptides or using the peptides as an adjuvant, companies developing the new therapies will likely need the services of a good CRO. While numerous companies provide contract drug development services for the industry, those specializing in oncology have often carved out special niches for themselves. Crown Bioscience in Santa Clara, Calif., for example, owns a unique repository of tumor grafts derived from actual patient biopsies. In the company’s graft system, “you have the actual tumor environment, intact, of a human patient,” explains Laura Sailor, senior vice president of business development at Crown.
Crucially, the tumors have been isolated from patients in Asian countries where cancer chemotherapy is not widely available yet. That means the tumors are susceptible to a whole range of compounds, just as newly diagnosed tumors will be in the clinic. “It’s naive, so you can push it to metastasis, you can push it to resistance,” says Sailor.
The system should also provide good predictions for clinical trials in Asia, where many companies are now focusing major efforts. “The clinical trials are a little bit easier over there, and the market’s way, way bigger,” says Sailor.
Crown is not the only CRO pursuing the peptide-targeting business, of course. Companies such as Pharmatech in Denver, Colo. have also been working on peptide-based projects, while JPT Peptide Solutions in Berlin, Germany offers a range of services that extends from peptide synthesis to contract research.
While interest in tumor-targeting peptides hasn’t seen the type of sudden boom that has characterized many other biotechnologies, researchers and service providers continue to see promising results from the field. For drug developers, that can only be good news.
About the Author
Originally trained as a virologist, Alan Dove is now a science journalist whose work appears regularly in a variety of trade and scientific journals and online publications. He also co-hosts the popular podcast “This Week in Virology.”
References
1. Hatakeyama S, et al. Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide. Proc Natl Acad Sci USA. 2011;108(49):19587-92.
2. Sugahara KN, et al. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science. 2010; 328(5981):1031-5.
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