NEWS | I N D E P T H
“Without numerical targets we’re afraid progress could stall.”
128
BIOMEDICINE
Targeting copper to treat breast cancer Business obstacles threaten to delay the phase III trial of a copper-depleting drug By Ken Garber
I
n 2007, a woman facing an almost certain death sentence took a chance on a drug that needed a second chance itself. The woman had stage IV breast cancer that had spread to her liver. Chemotherapy had eliminated her primary tumor, and surgeons had removed the liver metastases, leaving her in a status called “no evidence of disease” (NED). But oncologists cannot eliminate microscopic distant metastases—and this woman had the “triple negative” subclass of breast cancer, which is particularly aggressive and prone to bouncing back. Patients like her usually relapse within a year, with death following swiftly. So, as part of a 2-year clinical trial of advanced breast cancer patients, the woman began taking a drug that mops up copper, thought to play a role in tumor growth (Science, 15 January 2010, p. 331). The drug, tetrathiomolybdate (TM), had already failed a series of previous cancer clinical trials, but this new trial has since been extended several times and there is still no sign of cancer in the woman after 8 years. The full trial results are equally striking, as Weill Cornell Medical College (WCMC) oncology fellow Eleni Nackos reported last month at the annual meeting of the American Society of Clinical Oncology (ASCO). At a median follow-up of nearly 5 years, 62 other women in the 75-patient TM trial also had no detectable cancer. Among them were 12 of the 15 other women with stage IV triple negative breast cancer, whose typical median survival is months, with NED status only a temporary reprieve. Though these are extremely small numbers and the study had no placebo arm, University of Chicago oncologist Olufunmilayo Olopade says she was “blown away” by the data presented at ASCO. “What was so compelling about this study was that they were looking [at] women who were at high risk of recurrence,” she adds. sciencemag.org SCIENCE
10 JULY 2015 • VOL 349 ISSUE 6244
Published by AAAS
Downloaded from www.sciencemag.org on July 10, 2015
2009 until this past March. Women are had just one female professor and one fe36% of total faculty in the United States, male teaching assistant. Now, 18 of the de44% in the United Kingdom, 36% in Gerpartment’s 75 faculty members are women. many, and 33% in France, according to “The university’s affirmative actions led to a study by science policy experts Sotaro a natural increase in women faculty,” says Shibayama of the University of Tokyo, Narie Sasaki, a molecular cell biologist and Aldo Geuna of the University of Turin who helped craft some of the initiatives. in Italy. Hamaguchi and others worry that a lack To help close the gap, since 2006 Japan’s of similar support elsewhere is contribut5-year plans for science and technology ing to a female brain drain. Women make have included numerical goals for female up close to 60% of the Japanese citizens recruitment. The plan adopted in 2006, working in Western countries as students, for instance, called for women to make up teachers, and researchers, according to a 25% of the researchers recruited into the Ministry of Foreign Affairs survey. And anoverall scientific workforce by 2011. It also ecdotes suggest that the overseas female set goals for specific fields, including 30% Japanese scientists are among the cream of in health, 30% in agriculture, 20% in the the crop. Over the past decade, for instance, natural sciences, and 15% in engineering. the Howard Hughes Medical Institute The current plan, adopted in 2011, upped (HHMI) has awarded its prestigious grants the overall recruitment goal to 30%. And to just three Japanese scientists working in in 2013, the government’s Gender Equality the United States, and all are women. Bureau urged that the 30% goal apply to That might be a statistical fluke, says university presidencies and other leaderone of the HHMI scholars, plant biologist ship positions, not just the rank and file. Keiko Torii of the University of WashingThe target date is 2020, but so far, Japan is ton in Seattle. But she thinks Japan does not on track to meet these goals. need “some strong government initiative The new draft plan, … to promote women in for the years 2016 science as well as help through 2020, drops them and their husgender targets in favor bands balance families of so-far unspecified and careers.” strategies to advance CSTI’s Harayama, who women. That approach spent a decade on the Hisako Ohtsubo, Nihon University alarms some advocates. faculty of Tohoku UniOhtsubo, for one, says versity in Sendai, shares “numerical targets are definitely necessary” those concerns. But she worries that overfor advancing women. She and a number of emphasizing numerical targets might lead to colleagues are also pushing to expand other institutions simply filling slots with women supportive measures. For example, earlier without addressing the many other issues plans have encouraged funding agencies that can hold them back. to create grants for women who rejoin the Harayama notes that CSTI is sponsoring workforce after raising children and to restudies examining how and why women lax age limits for young investigator grants, choose certain career paths. One prelimiso as not to disadvantage women who take nary result is that young women who extime out for maternity leave. cel in science are gravitating toward fields Advocates point to some institutions such as health care and teaching, which as a model. At Nagoya University, Hamaprovide credentials—such as teaching cerguchi created a scheme to recruit one or tificates or medical licenses—that offer a two promising female principal investipassport back into the workforce after gators each year without regard to their time off raising children. “Young women specialty, putting them on track to fill facare being very pragmatic in choosing caulty positions as older professors retire. A reer paths,” she says. mentoring program encourages senior feHarayama also suspects many women male faculty to share tips with newcomers, avoid leadership positions because they and the university organizes leadership don’t find the prospect of working within seminars to prepare women for higher Japan’s male-dominated, opaque decisionpositions. It also keeps its day care cenmaking hierarchies very attractive. “We need ter open for particularly long hours, and changes in the establishment,” she says. helps provide care for sick kids. The center How the final plan might encourage even sends taxis to pick up children from those changes won’t be clear until later nearby schools. this year. But Harayama predicts it will Supporting women “had a snowball efinclude “more concrete actions” to create fect,” Hamaguchi says. In 2006, for examan academic community in which more ple, Nagoya’s graduate biology department women scientists can shine. ■
diate plans to test TM in cancer patients, its CEO acknowledges, and for now will not sublicense the drug. TM, easily synthesized in the lab, has a long history as a copper chelator—a compound that binds and inactivates ionic copper. In veterinary medicine, it cures copper poisoning in sheep, which are very sensitive to copper in their food. Around 1990, George Brewer, a University of Michigan (UM) physician and Limiting copper in geneticist, began testthe body may prevent ing TM in people with breast cancer, imaged Wilson disease. here (pink) in a colored The cancer conmammogram, from nection emerged afspreading or returning. ter work by several research teams showed Yet the promise of copper depletion apthat copper boosts angiogenesis, the crepears tarnished—not by clinical results ation of new blood vessels, which solid tubut by corporate strategy. WCMC oncolomors need to grow and metastasize. Brewer, gist Linda Vahdat, who led the trial, now with colleagues at UM, gave TM to female wants to proceed with a larger, phase mice genetically engineered to develop III trial of TM for triple negative breast breast tumors. None of the treated animals cancer. But the rights to treating cancer became cancerous, whereas more than half with TM are held by a Swedish biotech of control mice did. Under a microscope, company that is developing the drug insays Brewer, he could see dormant, precanstead for Wilson disease, a rare inherited cerous cells in the treated mice “just sitting disease of copper accumulation. The comthere, not growing because they couldn’t pany, Wilson Therapeutics, has no immedevelop a blood supply.”
Cancer’s copper connections
PHOTO: EPHYR / SCIENCE SOURCE
D
ozens of human enzymes incorporate or utilize copper, taking advantage of the metal’s readiness to donate or accept electrons to catalyze key biochemical reactions. Tumors, however, may be especially dependent on the metal. Copper, for example, promotes angiogenesis, the growth of blood vessels that can feed an expanding tumor, and depleting it may keep cancer in check (see main story, p. 128). Nancy Hynes at the Friedrich Miescher Institute in Basel, Switzerland, also reported in 2014 in Science Signaling that copper binds and activates the enzyme Memo, which enables tumor cells to move independently and thus metastasize. And in 2014, a Duke University group reported in Nature that copper is required for signaling by the mutant BRAF protein, which drives half of melanomas and many other cancers. Duke has recently launched a phase I clinical trial that combines an anticopper drug with a BRAF inhibitor in melanoma patients. Yet another role for the metal emerged when Janine Erler at the University of Copenhagen found that a copper-containing enzyme called lysyl oxidase-like 2 creates a collagen scaffold for cancer cells to occupy as they spread. In a clinical trial of a copper chelator in breast cancer patients, the enzyme’s level fell. “All of these mechanisms might be at play,” says pharmacologist Donita Brady of the Duke group. “And maybe what we’ll find is that particular cancer types are more susceptible to particular copper-dependent processes.” —K.G.
SCIENCE sciencemag.org
The mouse work led to a series of human trials of TM in various types of cancers, with disappointing results. Instead of abandoning the drug, Brewer concluded that that copper depletion would be more effective against the microtumors that seed metastases, which differ biologically from the primary tumor. He tried to convince a biotech company, Attenuon, to use TM to prevent recurrence in cancer patients in remission, but the company instead enrolled people with bulk tumors. These trials, too, failed. Meanwhile, aware of the UM mouse work and studies linking copper to angiogenesis and metastasis, Vahdat organized the current phase II trial. Like Brewer, she concluded that the drug was best deployed in people at risk of recurrence, and she raised money for the small trial from private foundations and cancer nonprofits. At ASCO, Nackos reported that the drug reduced copper in patients’ blood by about half, with few serious side effects. That may have triggered several antitumor mechanisms (see sidebar). For example, TM treatment lowered the number of bone marrow–derived, angiogenesis-promoting cells in blood, probably because copper is needed to activate growth factors important to those cells. TM’s “real value is to prevent metastasis,” Vahdat says. “And that’s by changing the tumor microenvironment … It’s a totally different way to treat cancer.” To mount a phase III trial, Vahdat sought Wilson Therapetics’ version of TM because it only needs to be taken once a day. Wilson will provide it at cost, but the company will not fund the trial. And Vahdat’s recent application for a $10 million grant from a U.S. Department of Defense program devoted to breast cancer was rejected. Wilson Therapeutics CEO Jonas Hansson says he has closely followed Vahdat’s phase II trial, which he calls “promising.” His company is now reviewing all the literature on TM and cancer. “We are in the evaluation phase,” Hansson says. “We just can’t give these rights [to TM] away, because we ourselves want to understand it first.” The impasse with Wilson had left Vahdat increasingly frustrated. “They have laserlike focus on Wilson’s disease, because that’s what their investors have invested in,” she says. “But they are interested in cancer, and I think ultimately when the timing is right for them, that they will look into it. It’s just that I’m ready and raring to go right now.” ■ Ken Garber is a writer based in Ann Arbor, Michigan. 10 JULY 2015 • VOL 349 ISSUE 6244
Published by AAAS
129
“Without numerical targets we’re afraid progress could stall.”
128
BIOMEDICINE
Targeting copper to treat breast cancer Business obstacles threaten to delay the phase III trial of a copper-depleting drug By Ken Garber
I
n 2007, a woman facing an almost certain death sentence took a chance on a drug that needed a second chance itself. The woman had stage IV breast cancer that had spread to her liver. Chemotherapy had eliminated her primary tumor, and surgeons had removed the liver metastases, leaving her in a status called “no evidence of disease” (NED). But oncologists cannot eliminate microscopic distant metastases—and this woman had the “triple negative” subclass of breast cancer, which is particularly aggressive and prone to bouncing back. Patients like her usually relapse within a year, with death following swiftly. So, as part of a 2-year clinical trial of advanced breast cancer patients, the woman began taking a drug that mops up copper, thought to play a role in tumor growth (Science, 15 January 2010, p. 331). The drug, tetrathiomolybdate (TM), had already failed a series of previous cancer clinical trials, but this new trial has since been extended several times and there is still no sign of cancer in the woman after 8 years. The full trial results are equally striking, as Weill Cornell Medical College (WCMC) oncology fellow Eleni Nackos reported last month at the annual meeting of the American Society of Clinical Oncology (ASCO). At a median follow-up of nearly 5 years, 62 other women in the 75-patient TM trial also had no detectable cancer. Among them were 12 of the 15 other women with stage IV triple negative breast cancer, whose typical median survival is months, with NED status only a temporary reprieve. Though these are extremely small numbers and the study had no placebo arm, University of Chicago oncologist Olufunmilayo Olopade says she was “blown away” by the data presented at ASCO. “What was so compelling about this study was that they were looking [at] women who were at high risk of recurrence,” she adds. sciencemag.org SCIENCE
10 JULY 2015 • VOL 349 ISSUE 6244
Published by AAAS
Downloaded from www.sciencemag.org on July 10, 2015
2009 until this past March. Women are had just one female professor and one fe36% of total faculty in the United States, male teaching assistant. Now, 18 of the de44% in the United Kingdom, 36% in Gerpartment’s 75 faculty members are women. many, and 33% in France, according to “The university’s affirmative actions led to a study by science policy experts Sotaro a natural increase in women faculty,” says Shibayama of the University of Tokyo, Narie Sasaki, a molecular cell biologist and Aldo Geuna of the University of Turin who helped craft some of the initiatives. in Italy. Hamaguchi and others worry that a lack To help close the gap, since 2006 Japan’s of similar support elsewhere is contribut5-year plans for science and technology ing to a female brain drain. Women make have included numerical goals for female up close to 60% of the Japanese citizens recruitment. The plan adopted in 2006, working in Western countries as students, for instance, called for women to make up teachers, and researchers, according to a 25% of the researchers recruited into the Ministry of Foreign Affairs survey. And anoverall scientific workforce by 2011. It also ecdotes suggest that the overseas female set goals for specific fields, including 30% Japanese scientists are among the cream of in health, 30% in agriculture, 20% in the the crop. Over the past decade, for instance, natural sciences, and 15% in engineering. the Howard Hughes Medical Institute The current plan, adopted in 2011, upped (HHMI) has awarded its prestigious grants the overall recruitment goal to 30%. And to just three Japanese scientists working in in 2013, the government’s Gender Equality the United States, and all are women. Bureau urged that the 30% goal apply to That might be a statistical fluke, says university presidencies and other leaderone of the HHMI scholars, plant biologist ship positions, not just the rank and file. Keiko Torii of the University of WashingThe target date is 2020, but so far, Japan is ton in Seattle. But she thinks Japan does not on track to meet these goals. need “some strong government initiative The new draft plan, … to promote women in for the years 2016 science as well as help through 2020, drops them and their husgender targets in favor bands balance families of so-far unspecified and careers.” strategies to advance CSTI’s Harayama, who women. That approach spent a decade on the Hisako Ohtsubo, Nihon University alarms some advocates. faculty of Tohoku UniOhtsubo, for one, says versity in Sendai, shares “numerical targets are definitely necessary” those concerns. But she worries that overfor advancing women. She and a number of emphasizing numerical targets might lead to colleagues are also pushing to expand other institutions simply filling slots with women supportive measures. For example, earlier without addressing the many other issues plans have encouraged funding agencies that can hold them back. to create grants for women who rejoin the Harayama notes that CSTI is sponsoring workforce after raising children and to restudies examining how and why women lax age limits for young investigator grants, choose certain career paths. One prelimiso as not to disadvantage women who take nary result is that young women who extime out for maternity leave. cel in science are gravitating toward fields Advocates point to some institutions such as health care and teaching, which as a model. At Nagoya University, Hamaprovide credentials—such as teaching cerguchi created a scheme to recruit one or tificates or medical licenses—that offer a two promising female principal investipassport back into the workforce after gators each year without regard to their time off raising children. “Young women specialty, putting them on track to fill facare being very pragmatic in choosing caulty positions as older professors retire. A reer paths,” she says. mentoring program encourages senior feHarayama also suspects many women male faculty to share tips with newcomers, avoid leadership positions because they and the university organizes leadership don’t find the prospect of working within seminars to prepare women for higher Japan’s male-dominated, opaque decisionpositions. It also keeps its day care cenmaking hierarchies very attractive. “We need ter open for particularly long hours, and changes in the establishment,” she says. helps provide care for sick kids. The center How the final plan might encourage even sends taxis to pick up children from those changes won’t be clear until later nearby schools. this year. But Harayama predicts it will Supporting women “had a snowball efinclude “more concrete actions” to create fect,” Hamaguchi says. In 2006, for examan academic community in which more ple, Nagoya’s graduate biology department women scientists can shine. ■
diate plans to test TM in cancer patients, its CEO acknowledges, and for now will not sublicense the drug. TM, easily synthesized in the lab, has a long history as a copper chelator—a compound that binds and inactivates ionic copper. In veterinary medicine, it cures copper poisoning in sheep, which are very sensitive to copper in their food. Around 1990, George Brewer, a University of Michigan (UM) physician and Limiting copper in geneticist, began testthe body may prevent ing TM in people with breast cancer, imaged Wilson disease. here (pink) in a colored The cancer conmammogram, from nection emerged afspreading or returning. ter work by several research teams showed Yet the promise of copper depletion apthat copper boosts angiogenesis, the crepears tarnished—not by clinical results ation of new blood vessels, which solid tubut by corporate strategy. WCMC oncolomors need to grow and metastasize. Brewer, gist Linda Vahdat, who led the trial, now with colleagues at UM, gave TM to female wants to proceed with a larger, phase mice genetically engineered to develop III trial of TM for triple negative breast breast tumors. None of the treated animals cancer. But the rights to treating cancer became cancerous, whereas more than half with TM are held by a Swedish biotech of control mice did. Under a microscope, company that is developing the drug insays Brewer, he could see dormant, precanstead for Wilson disease, a rare inherited cerous cells in the treated mice “just sitting disease of copper accumulation. The comthere, not growing because they couldn’t pany, Wilson Therapeutics, has no immedevelop a blood supply.”
Cancer’s copper connections
PHOTO: EPHYR / SCIENCE SOURCE
D
ozens of human enzymes incorporate or utilize copper, taking advantage of the metal’s readiness to donate or accept electrons to catalyze key biochemical reactions. Tumors, however, may be especially dependent on the metal. Copper, for example, promotes angiogenesis, the growth of blood vessels that can feed an expanding tumor, and depleting it may keep cancer in check (see main story, p. 128). Nancy Hynes at the Friedrich Miescher Institute in Basel, Switzerland, also reported in 2014 in Science Signaling that copper binds and activates the enzyme Memo, which enables tumor cells to move independently and thus metastasize. And in 2014, a Duke University group reported in Nature that copper is required for signaling by the mutant BRAF protein, which drives half of melanomas and many other cancers. Duke has recently launched a phase I clinical trial that combines an anticopper drug with a BRAF inhibitor in melanoma patients. Yet another role for the metal emerged when Janine Erler at the University of Copenhagen found that a copper-containing enzyme called lysyl oxidase-like 2 creates a collagen scaffold for cancer cells to occupy as they spread. In a clinical trial of a copper chelator in breast cancer patients, the enzyme’s level fell. “All of these mechanisms might be at play,” says pharmacologist Donita Brady of the Duke group. “And maybe what we’ll find is that particular cancer types are more susceptible to particular copper-dependent processes.” —K.G.
SCIENCE sciencemag.org
The mouse work led to a series of human trials of TM in various types of cancers, with disappointing results. Instead of abandoning the drug, Brewer concluded that that copper depletion would be more effective against the microtumors that seed metastases, which differ biologically from the primary tumor. He tried to convince a biotech company, Attenuon, to use TM to prevent recurrence in cancer patients in remission, but the company instead enrolled people with bulk tumors. These trials, too, failed. Meanwhile, aware of the UM mouse work and studies linking copper to angiogenesis and metastasis, Vahdat organized the current phase II trial. Like Brewer, she concluded that the drug was best deployed in people at risk of recurrence, and she raised money for the small trial from private foundations and cancer nonprofits. At ASCO, Nackos reported that the drug reduced copper in patients’ blood by about half, with few serious side effects. That may have triggered several antitumor mechanisms (see sidebar). For example, TM treatment lowered the number of bone marrow–derived, angiogenesis-promoting cells in blood, probably because copper is needed to activate growth factors important to those cells. TM’s “real value is to prevent metastasis,” Vahdat says. “And that’s by changing the tumor microenvironment … It’s a totally different way to treat cancer.” To mount a phase III trial, Vahdat sought Wilson Therapetics’ version of TM because it only needs to be taken once a day. Wilson will provide it at cost, but the company will not fund the trial. And Vahdat’s recent application for a $10 million grant from a U.S. Department of Defense program devoted to breast cancer was rejected. Wilson Therapeutics CEO Jonas Hansson says he has closely followed Vahdat’s phase II trial, which he calls “promising.” His company is now reviewing all the literature on TM and cancer. “We are in the evaluation phase,” Hansson says. “We just can’t give these rights [to TM] away, because we ourselves want to understand it first.” The impasse with Wilson had left Vahdat increasingly frustrated. “They have laserlike focus on Wilson’s disease, because that’s what their investors have invested in,” she says. “But they are interested in cancer, and I think ultimately when the timing is right for them, that they will look into it. It’s just that I’m ready and raring to go right now.” ■ Ken Garber is a writer based in Ann Arbor, Michigan. 10 JULY 2015 • VOL 349 ISSUE 6244
Published by AAAS
129
