on May 3, 2017
`
`http://science.sciencemag.org/
`
`Downloaded from
`
`vival for the patients. But periodic imaging of
`the tumor’s blood flow did suggest that at least
`part of sorafenib’s effects were due to its ability
`to block angiogenesis. “Tumor vascularization
`was decreased” in patients who received the
`drug, Escudier says.
`Sutent, identified about 5 years ago by Julie
`Cherrington, then at SUGEN Inc. in South San
`Francisco, California, and her colleagues, is
`also moving quickly through clinical testing.
`(SUGEN has since been acquired by Pfizer.)
`This drug also targets a broad set of tyrosine
`kinases. The fact that it inhibits the protein pro-
`duced by the KIT oncogene suggested that it
`might be a good drug for treating GIST. “GIST
`cells are totally addicted to that [KIT] signal”
`for growth, says George Demetri of Harvard’s
`Dana-Farber Cancer Institute in Boston, who
`led the phase III clinical trial of Sutent for
`GIST reported at the meeting.
`One proof of that came with the discovery
`that this kind of tumor responds to the anti-
`cancer drug Gleevec, which inhibits both KIT
`and another kinase that drives a leukemia
`called CML. The current trial included more
`than 300 GIST patients for whom Gleevec no
`longer worked. Again the results were so strik-
`ing that the trial was unblinded early so that the
`controls could receive treatment.
`Sutent delayed the time of tumor progres-
`sion on average from 1.5 to 6.3 months and
`also significantly reduced the death rate, even
`at this early stage of analysis. And like
`sorafenib, Sutent may be effective against kid-
`ney tumors. Robert Motzer of Memorial
`Sloan-Kettering Cancer Center in New York
`City described the results of two smaller stud-
`ies, including 169 patients with metastatic kid-
`ney cancer. Roughly two-thirds of the patients
`responded to the drug with either tumor
`shrinkage or delayed progression.
`In addition, Kathy Miller of Indiana Uni-
`versity, Indianapolis, reported that in a small
`phase II trial, about 14% of breast cancer
`patients who failed previous chemotherapy
`treatments responded to Sutent. “It doesn’t
`sound like much, but in this group of heavily
`pretreated patients, this is very good,” she says.
`Not all the large studies of second-
`generation antiangiogenesis drugs reported at
`ASCO produced clear results, however. The
`drug known as PTK/ZK, which is being
`developed by Novartis and Schering, targets
`most of the same tyrosine kinases as
`sorafenib and Sutent. Although it did produce
`a 12% increase in progression-free survival in
`a trial including nearly 1200 patients with
`metastatic colon cancer, that improvement
`did not attain statistical significance.
`As for Avastin, the f irst-generation
`angiogenesis inhibitor continues to show
`promise. Although it is currently approved
`only for treating colon cancer, results pre-
`
`CREDIT:B.ESCUDIER/INSTITUTE GUSTAVE ROUSSY
`
`C a n c e r
`
`Encouraging Results for Second-
`Generation Antiangiogenesis Drugs
`
`The strategy of denying growing tumors a blood supply continues to show clinical
`promise as new and improved drugs move through the pipeline
`
`The development of cancer drugs that stifle
`tumor growth by blocking the formation of
`the blood vessels they need seems to have
`turned the corner. Early last year, the U.S.
`Food and Drug Administration approved the
`first cancer drug, an antibody called Avastin,
`that is specifically designed to
`prevent this tumor angiogenesis,
`as the new blood vessel growth is
`called. Avastin may soon have
`company, if presentations last
`week at the annual meeting of the
`American Society of Clinical
`Oncology (ASCO) in Orlando,
`Florida, are any indication.
`One advanced clinical trial
`showed that a new antiangiogene-
`sis drug called sorafenib signifi-
`cantly slows metastatic kidney
`cancer, and another drug, known as
`Sutent, proved its mettle in treating
`a digestive system cancer called
`GIST (gastrointestinal stromal
`tumor). In contrast to Avastin,
`which must be injected because it’s
`a protein, both of these drugs are
`small molecules that can be taken
`in pill form. Perhaps even more
`important, the new drugs take aim
`at multiple molecular targets, only
`some of which are related to blood-
`vessel growth. The results from this novel drug
`class “mark the dawn of a new era in anti-
`angiogenesis therapy,” says William Li,
`director of the Angiogenesis Foundation in
`Boston, Massachusetts.
`Despite their chemical differences, Avastin
`and the new drugs share a common purpose:
`starving tumors of blood. Avastin is designed
`to bind to and block the activity of an
`angiogenesis-promoting protein called vascu-
`lar endothelial growth factor (VEGF).
`Sorafenib, which is being developed by Bayer
`Corp. and Onyx Pharmaceuticals, and Sutent,
`under development by Pfizer Corp., also block
`VEGF action, but in a different way. The recep-
`tors through which VEGF works are so-called
`tyrosine kinases, which add phosphate groups
`to certain proteins. The new drugs block this
`kinase activity, thus inhibiting receptor action.
`In addition, they inhibit other tyrosine
`kinase enzymes within cells. This means the
`drugs may block tumor cell growth directly, as
`well as by inhibiting angiogenesis. “These are
`
`like Gattling guns; Avastin is like a sniper,” is
`how Li puts it.
`Sorafenib was originally identified on the
`basis of its ability to inhibit a tyrosine kinase
`called Raf, a member of a major cellular
`growth control pathway—one that often
`contributes to the run-
`away cell division of
`cancer cells due to
`mutations that cause
`it to be overactive. But
`the drug also inhibits
`additional tyrosine
`kinases, including the
`receptors for VEGF
`and
`for platelet-
`derived growth factor
`(PDGF) and the prod-
`ucts of the KIT and
`FLT-3 oncogenes.
`Sorafenib, which
`was discovered 4 years
`ago, moved quickly
`through animal and
`preliminary clinical
`studies. By early
`2004, investigators
`had begun a large
`phase III trial of the
`drug’s effectiveness in
`patients with metasta-
`tic kidney cancer. This double-blind trial
`included some 900 patients at multiple med-
`ical centers who had not responded to previ-
`ous therapy and who were given either
`sorafenib or a placebo.
`At the ASCO meeting, Bernard Escudier
`of the Institute Gustave Roussy in Villejuif,
`France, reported that sorafenib “very signifi-
`cantly” increased the length of time before
`the treated patients’ cancers grew visibly,
`from 3 months in the placebo group to
`6 months. “This was the best data we have
`seen in kidney cancer with any drug so far,”
`Escudier says. The improvement was so
`striking that the review committee for the
`trial unblinded the results early so that the
`controls could also receive the drug.
`Despite the drug’s targeting of multiple
`tyrosine kinases, side effects, which included
`rashes, hair loss, nausea, diarrhea, and high
`blood pressure, were relatively mild. Still to be
`determined, however, is whether the delayed
`progression will translate into improved sur-
`
`Slow flow. Blood flow to a kidney
`tumor (top, green) is reduced (bot-
`tom) by an angiogenesis inhibitor.
`
`1248
`
`27 MAY 2005 VOL 308 SCIENCE www.sciencemag.org
`Published by AAAS
`
`NOVARTIS EXHIBIT 2061
`Par v. Novartis, IPR 2016-01479
`Page 1 of 2
`
`

`

` on May 3, 2017
`
`http://science.sciencemag.org/
`
`Downloaded from
`
`N E W S FO C U S
`
`good news at the ASCO meeting. In another
`phase III trial, described by Alan Sandler of
`Vanderbilt University School of Medicine in
`Nashville, Tennessee, the addition of Avastin to
`a chemotherapy regimen slowed tumor pro-
`gression in patients with one form of nonsmall
`cell lung cancer.
`Although second-generation antiangio-
`genesis drugs such as sorafenib and Sutent,
`unlike Avastin, have shown promise when
`given alone, researchers are also beginning to
`test the drugs in combination with other thera-
`pies. The idea, they say, is to mix drugs that hit
`different aspects of the pathological changes
`that drive tumor growth. An antiangiogenesis
`drug might be combined, for example, with a
`drug that blocks the cell growth–stimulating
`activity of epidermal growth factor. “We’re
`getting smarter,” Demetri says. “We’re going
`to be able to profile the tumor and pick and
`choose [anticancer] drugs just like we
`pick and choose antibiotics for treating life-
`threatening infections.”
`–JEAN MARX
`
`COUP’s international team of 37 scien-
`tists, led by Feigelson, found that the erup-
`tions unleashed by Orion’s stars are thou-
`sands of times stronger than the worst our
`sun can dole out today. The biggest flares
`probably extend out far enough to strike the
`disks of gas and dust around the young stars
`from which planets may form. No one
`knows the impacts of such giant magnetic
`short-circuits. But in one intriguing sce-
`nario, they churn circumstellar disks
`enough to keep newborn planets from spi-
`raling into their suns.
`If that happened in our solar system’s
`youth, it would be an ironic twist on our
`conception of x-ray flares as dangerous,
`Feigelson says: “They may have protected
`Earth from early destruction.”
`This statement became the catch phrase
`of a NASA briefing for reporters on 10 May,
`even though it stretches current theory,
`Feigelson readily admits. But for the first
`time, he says, the 13 papers* from COUP
`give theorists the data they need to under-
`stand the full range of high-energy tantrums
`from the youngest stars.
`
`The perfect target
`The Orion Nebula is ideal to study so many
`stars in one fell swoop, says astrophysicist
`Fabio Favata of the European Space
`Agency’s R&D center ESTEC in Noord-
`wijk, the Netherlands. “If you were to
`design a nebula from scratch as a target for
`
`* To appear in Astrophysical Journal Supplement
`Series, available at www.astro.psu.edu/coup
`
`sented at the ASCO
`meeting show that when
`given with more conven-
`tional chemotherapeutic
`drugs, Avastin can work
`on other cancers as well.
`In an earlier trial on
`patients with advanced
`breast cancer, Avastin
`combined with chemo-
`therapy did not produce a
`statistically significant
`improvement over the
`results of chemotherapy
`alone. But at the meet-
`ing, Indiana’s Miller, who also led the earlier
`study, reported on a new phase III trial in
`which Avastin was combined with the
`chemotherapy drug paclitaxel. This time, the
`news was good. Patients who got both drugs
`experienced significant increases in pro-
`gression-free survival and overall survival
`compared to those on paclitaxel alone.
`
`Quick reaction. A gastrointestinal tumor (left, dark areas) rapidly
`shrinks (right) after 1 week of treatment with the drug Sutent.
`
`Avastin may have worked better this time,
`Miller says, because those in the current trial
`had not previously been treated with
`chemotherapy and thus their cancers may have
`been less advanced than those in the earlier
`trial, who had all undergone—and failed—
`several rounds of chemotherapy. Genentech,
`the company that makes Avastin, got other
`
`A s t ro n o my
`
`Turbulent Orion Nebula Shows
`A Flare for the Dramatic
`
`A deep x-ray scan of a crowded star-forming cloud suggests that our solar system’s
`youth was far from serene
`
`On crisp winter nights, the stars of Orion, the
`Hunter, rule the Northern Hemisphere’s sky.
`But deep within the Orion Nebula, the constel-
`lation’s famous stellar nursery, conditions are
`anything but chilly. Fierce and persistent flares
`from baby stars pierce the nebula with x-rays,
`according to unprecedented studies released
`this month. The spasms light up the cloud “like
`an x-ray Christmas tree flashing on and off,”
`says astronomer Eric Feigelson of Pennsylva-
`nia State University, University Park.
`
`The pyrotechnics were revealed by the
`Chandra Orion Ultradeep Project (COUP),
`in which NASA’s Chandra X-ray Observa-
`tory stared at the nebula for nearly 2 weeks in
`January 2003. The penetrating scan captured
`the early lives of more than 1400 young stars,
`ranging from titans to dwarfs. The results
`turn back the clock to the infancy of our own
`sun, which may have formed in a similar
`nursery 4.6 billion years ago among siblings
`that have long since dispersed.
`
`Magnetic turmoil. Giant flares may spark turbulence in disks around newborn stars.
`
`CREDITS (TOP TO BOTTOM):A.VAN DEN ABBEELE AND Y.MELENEVSKY,DANA-FARBER CANCER INSTITUTE;CXC/M.WEISS
`
`www.sciencemag.org
`
`SCIENCE VOL 308 27 MAY 2005
`Published by AAAS
`
`1249
`
`NOVARTIS EXHIBIT 2061
`Par v. Novartis, IPR 2016-01479
`Page 2 of 2
`
`