Late last year, Pfizer launched a phase I trial of a new monoclonal antibody against cancer. The target: the insulin-like growth factor 1 (IGF-1) receptor. Pfizer's drug was the first in a cavalcade of such agents now in development, including both monoclonal antibodies and small molecules.
"In the last 5 years, or even 3 years, the pharmaceutical industry has ... rediscovered the IGF receptor as a potential target," said Michael Pollak, M.D., a professor of oncology at McGill University in Montreal.
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Essential for Transformation
Since then, further research has established the importance of the IGF-1 receptor in biology, especially cancer biology. In 1987, Pollak showed that the receptor is present in human tumor samples. (He also speculated that blocking the receptor might work against cancer.) In 1993, Argiris Efstratiadis, M.D., Ph.D., of Columbia University in New York, created IGF-1 receptorknockout mice that were born half the size of normal mice. This result established the receptor as the key growth factor that regulates cell and body size. Later that year, Renato Baserga, M.D., of Thomas Jefferson University in Philadelphia, showed that mouse fibroblasts with inactivating IGF-1 receptor mutations could not be transformed by powerful oncogenes. "Other receptors can transform cells," says Baserga today, "but the absence of the receptor that fails to transform cells seems to be pretty much unique to the IGF receptor."
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Epidemiologic studies also helped establish the importance of IGF-1. In 1998, Physicians' Health Study researchers reported in Science that men with high IGF-1 blood levels run a greater risk of prostate cancer. Similar results for breast cancer in premenopausal women in the Nurses' Health Study were released the same year, and a solid association in colorectal cancer appeared in 1999. Confirming reports followed. "We're not dealing with BRCA1-type huge risks," stressed Pollak, but the studies helped establish the IGF-1 receptor as a potential therapeutic target.
This confluence of scientific research happened at a time of cultural change stemming from the success of the targeted drugs trastuzumab (Herceptin) and imatinib (Gleevec). Suddenly tyrosine kinase inhibitors were hot targets for big pharma and biotech. The IGF-1 receptor was one of the very first receptor tyrosine kinases to be cloned, and companies are now aggressively pursuing drugs and small molecules that target it (see table, p. 791).
IGF-1 ReceptorTargeted Drugs In Development
* Patent applications filed but programs unconfirmed.
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Insulin Resistance
Drug firms had a valid reason for hesitating for so long: They worried about accidentally hitting the insulin receptor with inhibitors. The two receptors are 70% homologous, with almost identical catalytic domains. So researchers were concerned that anticancer drugs might also block insulin receptor signaling and cause diabetes.
Another worry was that IGF-1 receptors are expressed in normal tissues throughout the body, unlike other kinase targets. "It's fairly homogeneously expressed, and I think that concerns people," said Douglas Yee, M.D., an IGF researcher at the University of Minnesota. And some drug companies are suspicious of a receptor that seems to be involved in so many cancers. "There's data from prostate cancer, in colon cancer, in breast cancer, in myeloma," said Yee. "People are a little leery of the fact that it's so widely expressed [across tumor types]."
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Some of the preclinical data are encouraging. Antibodies, small molecules, and antisense against the IGF-1 receptor, as well as dominant negative mutants, have all worked in mice to block tumor growth, with little or no toxicity. "As a target, the IGF-1 receptor is almost ideal, because ... there are just so many reasons why cells, especially transformed cells, depend on the IGF-1 receptor [for] their survival," said Robert Aiken, M.D., a neurooncologist at Beth Israel Medical Center in New York.
Efficacy in humans is not a given, however. Although the IGF-1 receptor is overexpressed in many cancers, it is not amplified like Her2/neu is in some breast cancers. And though IGF-1 receptor signaling clearly does block apoptosis, "it is not as strong in stimulating proliferation of cells, except when it stimulates angiogenesis," said Derek LeRoith, M.D., Ph.D., an IGF researcher at the National Institute of Diabetes and Digestive and Kidney Diseases. In many xenograft models, blocking the receptor inhibits tumor growth but often does not shrink tumors. Combination with chemotherapy is much more effective, but single-agent activity in humans must first be demonstrated.
Safety in Numbers
Toxicity is the other issue, because the IGF-1 receptor is present throughout the body. But "there is a certain threshold at which the receptor numbers have to be above in order to start getting a mitogenic signal," said Ludwig. By bringing receptor numbers below that threshold, he reasoned, a drug should preferentially kill cancer cells. A drug would also affect normal cell receptors, "but those are at a low level anyway," said Ludwig.
Whereas IGF-1 signaling is crucial in fetal and childhood development, its role in adult biology is less clear. Researchers hope that any treatment side effects will be benign. "Receptors in adult tissues, we and others have shown, are actually at a lower level than ... in the embryo, fetus, or children, so they seem to be there for maintenance," said LeRoith. "If you're lucky ... you'll block the tumor, but you'll only have minimal side effects on normal tissues, except for those tissues that are rapidly turning over, such as bone marrow and the gut."
Baserga said he thinks that inhibitors should preferentially target cancer cells, based on cell culture data. "Cells in monolayers, which are normal cells usually, when you give them an antisense or a drug against the IGF-1 receptor, you have 10% inhibition," he said. "If you treat them in anchorage independence, you ... inhibit 99%." Anchorage independence is thought to model metastasizing cancer cells. In many mouse xenograft models, IGF-1 receptor blockers do work especially well against metastases.
Diabetes remains a theoretical issue, even if the new drugs don't block the insulin receptor. That's because insulin receptors and IGF-1 receptors tend to heterodimerize, and monoclonal antibodies will block such "hybrid receptors" in addition to single IGF-1 receptors. Hitting hybrid receptors "is bad," said Baserga, although, he added, they may not be plentiful enough to make a difference. Others say it's good to hit hybrid receptors in cancer because they transmit mainly IGF-1 receptor signals, not insulin receptor signals. "Most people think that the hybrid receptor is actually a better IGF receptor than it is an insulin receptor," said Yee.
Into the Clinic
Companies developing monoclonal antibodies are hopeful that they won't just block the IGF-1 receptorthey will get rid of it by means of cell internalization followed by degradation. "Receptor levels are very important," said Ludwig. "If you could bring that down to that threshold level, you might actually revert [the cell] to a more normal phenotype." Baserga agreed that receptor internalization is critical. "What you have to do is really downregulate the receptor so that the cells die," he said. "If you give ... an inhibitor that inhibits the IGF-1 receptor without downregulating it, you may stop growth, but then it resumes when you stop the treatment."
That's one knock against small-molecule inhibitors, which do not appear to cause this receptor internalization. Another problem is that small molecules, compared with monoclonal antibodies, are harder to make specific for IGF-1 receptor. But Novartis' Cancer Cell paper last year featured small molecules an order of magnitude more specific for IGF-1 receptor than for the insulin receptor in cell culture. These drugs worked well in mouse xenograft models. Pills targeting the IGF-1 receptor suddenly seemed like a real possibility.
Then, in February or early March of 2005, Novartis ran into toxicity problems in primate studies of its small molecules and discontinued development of the drugs, several sources outside the company told JNCI. "It broke my heart," said one researcher. (The toxicity was not thought to be mechanism related.) Novartis scientist Francesco Hofmann, Ph.D., denied these accounts. "The program is still alive," Hofmann said in mid-April. "Those compounds are still alive."
Monoclonal antibodies do not appear to have caused toxicity problems in animals. Pfizer's human trial in multiple myeloma is continuing, and companies such as ImClone are quickly moving their drugs toward clinical studies. Based on animal models, Ludwig said, "nothing we have seen thus far would prevent us from pursuing clinical development of this drug."
Many researchers inside and outside the IGF field eagerly await results. "The questions are clear, and we need to get the answers," said Pollak. "Some people are optimistic the trials will work; others are pessimistic. But ... I cannot find a person who would say, These trials do not need to be done. There's a general consensus that it would be scientific negligence not to proceed."
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