As evidence implicating stem cells in cancer mounts, drug makers are taking notice. GlaxoSmithKline (GSK) in December formed a strategic alliance worth up to $1.4 billionwith OncoMed Pharmaceuticals, of Redwood City, California. The dealgives GSK an option to license four of OncoMed's antibody candidatesdeveloped to target cancer stem cells, one of which is scheduled toenter clinical trials in June.
The GSK-OncoMed pact is the firstmajor deal focused on cancer stem cell R&D, which is undergoingexplosive growth. John Bates, the director of Biopharm Reports, inCambridge, UK, says the number of companies devoted to this researchhas grown from 17 in April 2007 to nearly 40 today. What's more,patents covering developments in cancer stem cells doubled to about 70in 2007, he adds. The problem is that not everyone even believes thattargeting cancer stem cells will yield therapeutic benefits.
GeorgeSchreiner, CEO with Raven Biotechnologies in San Francisco, attributesthe burst of commercial interest to recent evidence of cancer stemcells in solid tumors. Scientists have suspected since the 1950s thatthe cells play a role in blood tumors, such as acute myeloid leukemia,but their existence in solid tumors became evident only in 2003. That'swhen Michael Clarke, currently associate director of StanfordUniversity's Institute for Stem Cell and Regenerative Medicine, and histhen post-doc, Mohamed Al-Hajj, claimed to find cancer stem cells inbreast tumors. The cells had two markers that are now synonymous withcancer stem cells: high expression of the antigen CD44 and lowexpression of antigen CD24. Isolated on the basis of these markers, thehuman cells were cultured and introduced into immunocompromised mice.Clarke and Al-Hajj found that only a few of the cells could spawnaggressive, metastatic tumors in the animals. Those findings bolstereda theory that solid tumors arise from a small population of cancer stemcells that, like normal stem cells, have the capacity for self-renewal.Clarke and his colleague Max Wicha, the director of the University ofMichigan Comprehensive Cancer Center, founded OncoMed to pursueclinical opportunities in cancer stem cells in 2004. They now sit onthe company's scientific advisory board.
Findings in otherlaboratories have since suggested cancer stem cells exist in varioustumors, including those of the brain, head and neck, prostate, andcolon. Scientists further postulate that cancer stem cells resistcurrent drug therapies and repair DNA after radiation treatment moreefficiently than their differentiated, daughter cells. That explainswhy solid tumors often recur after treatment, Schreiner explains. "Whathappens is the stem cells survive and repopulate to form a new tumor,"he says. "And because they transmit their resistance to daughter cells,the new tumors are much harder to treat." Some researchers now believethe only way to cure cancer is by killing the stem cells that give riseto it.
OncoMed is one of a handful of companies preparing totest compounds against cancer stem cells in the clinic. In the GSKdeal, OncoMed receives an undisclosed, up-front payment in cash andequity investment, with $1.4 billion more tied to achieving milestones.Royalties on product sales would follow. OncoMed's lead candidate, ahumanized monoclonal antibody (mAb) OMP-21M18, targets "a cancer stemcell pathway with broad applicability across multiple solid tumors,"says Paul Hastings, the company's CEO.
Other companies preparingfor clinical trials this year include Arius Research in Toronto, whoselead humanized IgG1 mAb targets a variant form of CD44 found inleukemia, breast, colon and prostate cancer cells. Also, RavenBiotechnologies has two mAbs in preclinical development: RAV17 (whichtargets the pancreatic assigned tumor marker PAN), which Schreiner saystargets prostate as well as pancreatic cancer cells, and RAV18 (whichtargets ADAM-9), for colon and lung cancer. Raven is now preparing tomerge with VaxGen, a San Francisco-based vaccine manufacturer, pickingup needed cash reserves from a company with a depleted pipeline butplenty of manufacturing assets. Reflecting a broader trend in cancerdrug development, most compounds targeting cancer stem cells aremonoclonal antibodies, Bates says (see Table 1).MAbs predominate because they target antigens on the cell surfacerather than processes inside the cell as small molecules do.
Thechief safety concern with targeting cancer stem cells, Clarke warns, isthat these mAbs might also attack normal stem cells that replenishdamaged tissues. "The main thing is to ensure that we eliminate themalignant cancer stem cells only without affecting the normal stemcells," he says. "Whether we'll be able to do this is the billiondollar question that everyone wants to answer."
Meanwhile, ascommercial entities grow up around it, skeptics question the validityof targeting cancer stem cells. Current thinking holds that a tinypopulation of stem cells can explain why cancers recur even whenexisting treatments kill off up to 99% of a given tumor. According toBert Volgestein, a professor of oncology at Johns Hopkins University inBaltimore, tumors can be completely eradicated only if those small—andpresumably drug-resistant—stem cell fractions are destroyed.
Thetumor fraction contributed by stem cells ranges from a low of 0.1% to ahigh of 40%, and some reports have described tumors made entirely ofstem cells. But Vogelstein also admits that if a tumor containing alarge fraction of stem cells were almost completely eliminated bytreatment, this would undermine the logic of targeting stem cells asthe last, drug-resistant holdouts from which aggressive metastatictumors would likely emerge refractive to treatment.
GSK's interestin OncoMed comes from a desperation "to tap into oncology space, anarea in which it is particularly weak," says Sho Matsubara, an analystwith London-based Standard and Poor's Equity Research Division. Also,GSK's sales are assumed to decline in coming years, due to genericcompetition (Matsubara estimates a 7% drop annually for the next fiveyears). It does have a compound of its own that may have shrunk breasttumors by attacking cancer stem cells. According to evidence describedat the San Antonio Breast Cancer Symposium on December 17, six weeks'treatment with GSK's Tyverb (lapatinib), a small molecule used inconjunction with Xeloda (capecitabine) for late-stage breast cancer,slashed the number of stem cells by more than half among 30 womenstudied. Two-thirds of the women were reportedly cancer-free afterfollow-up treatment.
But others remain cautious as, in someinstances, claims pointing to the existence of cancer stem cells haveturned out to be wrong upon closer inspection. "More studies are neededto confirm that cancer stem cells were in fact targeted by Tyverb,"Bates notes. "We need further evidence to show that cancer stem cellsin humans have been fully characterized. And we need ways todemonstrate that a particular subpopulation of cells has been reducedby treatment," he notes.
Ultimately, the best evidence will come from more studies that show killing cancer stem cells improves patientsurvival, Bates says. For fast-moving cancers such as pancreatictumors, the evidence may come sooner. In the case of slow-movingcancers, such as prostate, accumulating the necessary evidence couldtake more time, he points out.
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