Issue Date: August 20, 2007
One Pill, Many Uses
AFTER TAKING in the hype of recent years over "designer drugs" and "targeted therapies," cancer sufferers can be excused for expecting the magic bullet: one single pill tailored especially for them that can bring their disease to its knees. And indeed, drugs like Genentech's breast cancer treatment Herceptin and Novartis' leukemia drug Gleevec, each of which addresses a specific genetic mutation, have proven to be amazingly effective at stopping cancer in its tracks—but only for a while.
Eventually, those targeted therapies stop working in many patients because the disease either learns to resist the drug or finds a way to spread despite being kept in check at its origins. The protein drug Herceptin, for instance, does a good job of keeping breast cancer at bay, but a portion of patients wind up with brain metastasis, and the big, floppy antibody can't get past the blood-brain barrier. Likewise, a slew of follow-on drugs to Gleevec are in development because, at some point, cancer cells become impervious to its effects.
It is becoming increasingly clear that cancer is not just the result of one errant gene. It may start that way, but inevitably, other proteins get pulled in to keep the disease going. Curing cancer, or at least managing it, will require understanding and then interrupting the complex network of proteins the disease uses to survive. In the end, patients are more likely to be looking at a cocktail of pills rather than a magic bullet.
Researchers are hoping that drugs blocking Met, a tyrosine-kinase receptor that is implicated in many cancers, will be a staple of that cancer-fighting cocktail. For some patients, a straight Met inhibitor might suffice. But more often, a Met inhibitor would work best when mixed with other cancer therapies, ranging from targeted drugs to traditional agents such as chemotherapies.
In the pantheon of tyrosine-kinase receptors implicated in cancer, Met comes off as a particularly sinister protein. "Met is one of the highest and most frequently occurring gene products in tumors," says George Vande Woude, research director of the Van Andel Institute, a cancer research center in Grand Rapids, Mich.
Vande Woude's lab discovered the gene in 1984, when he was head of the molecular oncology section at the National Cancer Institute's Cancer Research & Development Center, Frederick, Md. Along with researchers from institutes across Italy, the U.K., and Japan, Vande Woude has played a significant role over the past 20-some years in unraveling Met's complex web of activities.
AS IT TURNS OUT, Met is a quiet character in healthy cells. It is critical during the development of an embryo, when it regulates the growth of tissues and organs. Once a mammal is mature, the protein's activity is basic. Day-to-day, Met supports bone marrow function, pops up to help repair the liver in the case of cirrhosis, and is a key player in wound repair.
But when switched on by its ligand, human growth factor (HGF), in a cancer setting, Met can instigate a laundry list of bad deeds. Like many other well-studied tyrosine-kinase receptors and their ligands, Met plays "a direct role" in leading some types of cells down a cancerous path, says Ravi Salgia, director of the thoracic oncology research program and associate professor of medicine at the University of Chicago. Moreover, it helps those cancer cells proliferate and invade adjacent tissues.
In fact, Met is short for "metastatic." Initially, the protein was named for the "methyl" in N-methyl-N-nitronitrosoguanidine, the gene-damaging agent that a postdoc in Vande Woude's lab had used to transform a human cell line, leading to the discovery of Met. A decade later, studies underscoring its role in helping disease spread led researchers to decide Met should stand for metastatic instead.
A growing body of research is showing how Met conspires to keep cancer alive even after drugs have controlled it. Met seems to play a key role in enabling cells to develop a resistance to drugs targeting other tyrosine-kinase receptors. These treatments include AstraZeneca's Iressa and Genentech's Tarceva, both of which block the epidermal growth factor receptor (EGFR).
For example, researchers at Dana-Farber Cancer Institute, in Boston, have shown that some lung cancer patients who have developed a resistance to Iressa have extra copies of the Met gene. Tests in cells suggest that resistance to Iressa and other EGFR inhibitors can be reversed by introducing a Met inhibitor.
More details of the complex network of interactions between Met and various proteins continue to emerge. Just last month, a paper from researchers at Massachusetts Institute of Technology highlighted a link between Met and a mutated form of EGFR in an aggressive brain cancer (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0705158104). Several groups are studying whether Met overexpression in breast cancer causes patients to develop a resistance to common treatments such as aromatase inhibitors and estrogen suppressors.
With such a broad set of duties in cancer survival, Met is an obvious drug target. In addition to developing Met inhibitors that target tumors directly caused by Met, researchers see opportunities to apply inhibitors in situations where cancer cells have invaded other tissues or have become resistant to other treatments. For example, "you can imagine all sorts of scenarios whereby you could use a Met inhibitor as a postsurgical or post-chemo adjuvant to control metastasis," says Stephen Burley, chief scientific officer at San Diego-based SGX Pharmaceuticals, which is developing a Met inhibitor.
Indeed, the protein's potential "to increase the invasive nature of primary tumors and help those tumors become more metastatic is a very important biological concept that is driving the interest in Met," says Mike Morrissey, president of R&D at Exelixis, a South San Francisco-based biotech firm that is developing two compounds targeting Met.
FURTHERMORE, Met is fairly unusual in its ubiquity. "Probably 10 to 15% of all solid tumors, all of the nonblood tumors, have this Met mutation or overexpression," says Charles Baum, Pfizer's vice president of oncology. That's a pretty healthy portion, he adds, particularly since other kinases targeted by successful drugs are active in a limited number of tumors.
For example, overexpression of Her2, the target of Herceptin, is directly linked to certain breast cancers. Likewise, a genetic quirk increases the activity of the bcr-abl receptor, a target of Gleevec, causing a kind of leukemia. But, Baum notes, those receptors are not implicated in many other malignancies.
Given Met's vast medical and commercial potential, the drug industry is finally starting to take notice. "In 2001, I went to the American Association for Cancer Research meeting, and there were maybe one or two posters on the Met/HGF axis in oncology," says Terri Burgess, director of oncology research at Amgen. "This past year, there were hundreds, and every major pharma company has a footprint."
Companies are employing various weapons to take down Met. The arsenal includes small molecules targeting Met; antibodies against Met; antibodies targeting its ligand, HGF; and, earlier in the pipeline, small interfering RNAs that silence the gene's activity.
The most popular approach to blocking Met, it appears, is the use of small molecules. In addition to companies such as Exelixis, ArQule, SGX, and Pfizer that have publicly discussed their small molecules in development, nearly every major drugmaker seems at least to be dipping a toe in the Met waters.
A quick search of the blog KinasePro (kinasepro.wordpress.com), a well-respected site on kinase chemistry, reveals that Vertex Pharmaceuticals, Amgen, and Bristol-Myers Squibb, among others, have all filed patents on at least one small molecule targeting Met. Meanwhile, GlaxoSmithKline, as part of a broad drug development deal inked in 2002, has an option to license Exelixis' two Met inhibitors after they have made it through Phase II trials. And Merck & Co. has completed preclinical trials of a Met inhibitor.
"There's no doubt it's a very attractive and now extremely popular target," SGX's Burley says. "And I don't think this is a fad. I think this is based on very good scientific data."
THE LANDSCAPE of small molecules targeting Met divides into two terrains: agents that aim to be highly selective, highly potent inhibitors of the protein and agents that hit multiple protein kinases implicated in cancer, including Met.
Exelixis, which is the furthest along in the clinical development of small-molecule inhibitors of Met, is in the latter camp. The company had originally been developing a drug that hit only Met. But in 2003, researchers discovered that kidney cancer in patients with von Hippel-Lindau disease, caused by a genetic mutation that affects roughly 1 in 40,000 people, was driven by overexpression of both Met and another protein kinase, vascular endothelial growth factor (VEGF).
"It's a very elegant system by which tumors have two different, very coordinated means to survive and thrive," Morrissey says. While Met helps cancer cells grow, proliferate, and migrate, VEGF -better known as the target of Genentech's antibody Avastin-enables the growth of the blood vessels that feed the tumor's growth. Thus, a compound that blocks both the tumor and the vasculature that supports its growth "should have very potent activity," he adds.
The discovery caused Exelixis to switch gears, and the firm's Met program morphed into one targeting multiple protein kinases. Thus, XL-880, the most advanced Met inhibitor in Exelixis' portfolio, was designed to also block VEGF receptor (VEGFR).
Phase I data indicate the strategy is working. Patients with a range of tumor types seemed to tolerate the drug, and the disease either stabilized or regressed in 39 of the 45 study participants with measurable disease as their best response. For five of those patients, the tumors demonstrated a partial response to the drug—that is, they shrank by at least 30%. For one of the patients, the drug kept the disease at bay for more than two years. The drug is now in Phase II trials in papillary renal cell carcinoma, gastric cancer, and head and neck cancer.
Exelixis is finishing Phase I studies of a second compound, XL184, which???in addition to Met and VEGFR???hits Ret tyrosine kinase, a protein involved in kidney and nervous system functions. The drug is set to enter Phase II trials for treatment of thyroid cancer later this year. Lung and brain cancer studies are also planned.
While Exelixis is trying to curb disease by barring multiple protein kinases involved in cancers, ArQule is among the companies trying to create a potent, highly selective Met blocker. The firm believes its lead inhibitor, ARQ197, stands out from competing compounds by binding to a different site on the Met receptor.
Most kinase inhibitors dock in the same pocket as the energy-transfer nucleotide adenosine 5´-triphosphate (ATP), an obvious choice because ATP binds to the active site of all kinases. Yet this universal activity also creates a challenge when it comes to selectivity, because an inhibitor could easily turn out to be a key that fits many locks, causing myriad off-target side effects. The hurdle isn't insurmountable; several ATP-competitive inhibitors have become successful drugs. But it's one that ArQule is attempting to avoid by offering a molecule that does not compete with ATP.
"We believe that ARQ197 may be binding to a part of the Met receptor that is close to the ATP-binding site, but it is clear from a number of preclinical studies that it is not competitive with ATP," says Stephen A. Hill, ArQule's chief executive officer.
Early data from Phase I trials, designed to determine a dosing schedule for ARQ197, are encouraging, Hill says. Of 35 patients with a variety of solid tumors, three had a partial response, while 18 experienced a stabilization of their disease.
ArQule is considering several clinical strategies for ARQ197. Perhaps the fastest route to market is to pursue an indication where Met is a significant driver of tumors, such as certain muscle sarcomas and pediatric kidney tumors, that lack other treatments, Hill notes.
THE OTHER STRATEGY is to devise a trial proving that the drug can keep cancer from metastasizing. Doctors conducting the earlier trial of ARQ197 observed that only a small portion of patients had new lesions, a sign that the drug is keeping the disease from spreading. ArQule is exploring combining its Met inhibitor with Herceptin to reduce the rate of brain metastasis in breast cancer patients.
Lastly, ArQule is interested in using ARQ197 to prevent or reverse cancer cells' resistance to other drugs, such as Tarceva.
SGX is also zeroing in on pure Met inhibition with its lead molecule, SGX523. The company deployed its structure-based drug discovery platform to select and optimize SGX523 and the follow-on drugs in its pipeline. Unlike ArQule's compound however, SGX523 is an ATP competitor for the Met receptor.
"Despite competing with ATP for binding, the compound is 1,000 times as selective for Met than the more than 200 protein kinases tested by SGX," Burley says. He believes this potency should quash any concern that ATP competition would lead to off-target effects. "I think we've effectively disposed of the debate regarding the promiscuity of ATP-competitive compounds," Burley notes. "We've proven that earlier prejudices were just not founded."
The drug's potency and selectivity are a direct result of its design, Burley says. "Kinases are very plastic," he notes. Small-molecule inhibitors can accept different conformations and work by "locking" them into an inactive conformation. SGX523 in particular stabilizes Met in a unique shape that the firm believes is the basis of the drug's "exquisite activity," Burley says.
SGX is now conducting studies in preparation for an Investigational New Drug Application that it expects to file with the Food & Drug Administration in the first quarter of 2008.
Pfizer, another company pursuing single-selectivity for Met, has been working on the target since inheriting relevant molecules in its acquisitions of Pharmacia, Sugen, and Agouron Pharmaceuticals. But the two molecules the firm settled on were discovered in its New London, Conn., labs, and are now being developed at its La Jolla, Calif., site.
Pfizer's lead candidate, PF-2341066, is in early-stage Phase I/II trials aimed at determining its tolerability and pharmacokinetic profile. A second Met inhibitor, "a slight variation" of PF-2341066, Baum says, is likely to enter Phase I trials next year.
Though it is still early days for PF-2341066, the preclinical work was encouraging, Baum says. The drug elicited solid inhibition of tumor growth in animal models and appears to be well-tolerated in humans.
The next step for PF-2341066 is Phase II trials in an indication, such as gastric cancers, where patients' tumors specifically have a Met mutation or overexpression. The idea is to use a population "most likely to benefit from giving the drug by itself," Baum says. "That's the cleanest way to test whether it can shrink tumors and have an effect on metastasis by itself." From there, the company can consider broader indications, such as cancers where Met is working synergistically with other kinases to provoke metastasis or drug resistance.
This vast drug development landscape is also helping to usher in more personalized treatment options. The first goal, says Salgia, the University of Chicago professor, is always to come up with a therapy that is effective in as many cancers as possible. But the next critical step is to identify which patients would benefit from that drug.
Salgia's lab is trying to unwind the many connections between Met and other kinases across different cancers to establish a better picture of how Met is involved in the disease. He is also working with companies developing Met inhibitors to help tease out the particular subset of patients who would benefit from their drug.
For example, Exelixis is conducting a Phase II trial of XL-880 on patients with papillary renal cell carcinoma. It wants to enrich the patient group with people who have either cancer-activating mutations in Met or an extra chromosome in the area where Met and HGF genes reside. Similarly, the company is looking for patients with an amplified Met gene in another trial of XL-880 in gastric cancer. "We're definitely trying to match the tumor genetics of the cancer with the pharmacology of our compounds," Morrissey says.
INDEED, nearly every company with a Met inhibitor in its pipeline appears to be incorporating pharmacogenomics into its clinical trial strategy. The ideal would be to develop a test early on in a drug's development that could streamline clinical trials and be available when the drug hits the market. But coming up with an easy way to test whether a Met inhibitor will work has many challenges.
"It's a matter of how easy it is to test a patient," Pfizer's Baum says. Ideally, a biopsy of a patient's tumor would be tested for a genetic mutation, but it's not always possible to get such a sample.
Given the general agreement that Met is a good target, the many molecules in development, and the resources devoted to finding the patients who will really benefit from them, it's hard not to get swept up in the excitement. Still, researchers caution that much more needs to be understood, even with drugs in the clinic. Vande Woude, for example, is working on understanding how Met may help cancer cells switch from simply proliferating to becoming invasive, a scenario that triggers metastatic disease.
And there is still much to learn about how well different drugs will interact with the Met receptor, an area of uncertainty that can be resolved only with hard data from patients.
"The expectations are very high, but we're not going to immediately jump from drug into patients and see remarkable cures," Vande Woude says. "Some of us strongly suspect that it is going to be a cocktail of drugs used not only to target one specific gene that may be prominent in disease but also to prevent other genes that can be selected under certain conditions from taking over." In the end, it will take a lot of testing to figure out which drugs work best in which patients. For that reason, the full potential of any of these targeted therapies is still years away.
Inhibiting Met "is not going to be an answer to everything," Salgia agrees. But he also believes there is plenty of room for many approaches to blocking the gene. "As an oncologist," he says, "I will take any drug effective against cancer."
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