Anti-Cancer Technologies Licensed to Genentech
The approach of starving tumors of their blood supply, pioneered by Children's Judah Folkman, MD, has received another boost from biotechnology company Genentech, Inc. Two years ago, Genentech's drug Avastin?* (bevacizumab) became the first FDA-approved cancer treatment to specifically target angiogenesis, or blood vessel growth. Now, Children's has granted Genentech an exclusive license to anti-cancer technologies developed in the lab of Vascular Biology researcher Michael Klagsbrun, PhD.
These technologies, involving a cell receptor called neuropilin, share a similar mechanism of action with Avastin. Avastin curbs tumors by blocking a key stimulator of blood-vessel growth -- vascular endothelial growth factor, or VEGF -- from attaching to VEGF receptors on nearby blood vessels. It is currently approved for use in combination with chemotherapy in patients with first-line metastatic colorectal cancer, and is being tested in a variety of other cancers.
Back in 1998, Klagsbrun and colleagues reported in the journal Cell that VEGF binds not only to the VEGF receptor, but also to a co-receptor -- neuropilin, originally known for its role in guiding growing nerve fibers to their appropriate destinations. Further studies showed that neuropilin acts in combination with the VEGF receptor to enhance VEGF signaling and function. This made neuropilin a good target for trying to inhibit cancer growth, and several animal studies run by Klagsbrun's team show promise in hitting that target.
Klagsbrun believes that blocking VEGF from binding both to the high affinity VEGF receptor and to neuropilin may enhance anti-tumor efficacy. "Exploring this combination in blocking angiogenesis could be of real interest," he speculates.
Children's filed patents on the neuropilin discoveries beginning in 1997 (two have been granted; several others are pending), but they sat on the shelf until the recent renewal of interest in therapeutic angiogenesis inhibitors. Believing in the technology, Children's shouldered the expense of maintaining the patents each year. "We made a bet and stuck to it, because we believed these patents were going to be important," says Brenda Manning, Associate Director of Children's Intellectual Property Office (IPO). "And it turns out they are important."
Genentech already has a strong research program focused on neuropilins in collaboration with another firm, Renovis. Both Genentech and Klagsbrun's lab are investigating biological processes that direct the development of nerves and blood vessels alike. "We see Genentech's competence in the field of neuropilins as an exceptional asset," says IPO Director Don Lombardi.
Children's received a licensing fee from Genentech up front, with potential further payments contingent on successful product development. "The license enables Genentech to pursue several different alternative strategies and pick the best one," says Lombardi. "We believe it is a great validation of Michael's research." The license also includes rights to develop diagnostic products.
Klagsbrun is a leader in the field of growth factors and their receptors, in particular those that regulate angiogenesis. He purified basic fibroblast growth factor, the first known angiogenic molecule, in 1984. Recently, his lab showed that other agents involved in nerve guidance, semaphorins, are potent angiogenesis inhibitors.
Like VEGF, semaphorins bind to neuropilin, but their signals are inhibitory; in mouse experiments, they completely inhibited tumor metastasis. Klagsbrun's lab is now seeking a smaller version that might be attractive for commercial development. "It's interesting that something that keeps nerve cells from running around could be a powerful anti-angiogenic agent," he says.
* In Genentech-sponsored studies, the most serious adverse events associated with Avastin were gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The most common Grade 3-4 adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) were asthenia, pain, hypertension, diarrhea and leukopenia.