Journal of the National Cancer Institute Advance Access originally published online on May 13, 2008
JNCI Journal of the National Cancer Institute 2008 100(10):694-695; doi:10.1093/jnci/djn168
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© Oxford University Press 2008.
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Lapatinib Study Supports Cancer Stem Cell Hypothesis, Encourages Industry Research
Last year, scientists reported for the first time that the drug lapatinib (Tykerb) can cause complete tumor regression, possibly by killing cancer stem cells. Presented at the San Antonio Breast Cancer Conference on December 17, the findings showed that among 40 women with HER2-positive breast cancer who took lapatinib for 6 weeks—followed by 6 weeks of standard chemotherapy and trastuzumab—63% experienced a "pathologically complete response," meaning that there was no evidence of any remaining tumor. Jenny Chang, M.D., an associate professor at the Baylor College of Medicine in Houston, who led the study, said that 10%–20% of the women would probably have achieved a pathologically complete response with chemotherapy alone; this figure rises to 30% with chemotherapy and trastuzumab combined. "So, these are very exciting findings," she said. "We know that women with a pathologically complete response have the least likelihood of a recurrence." Chang's study is now undergoing peer review.
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There is substantial enthusiasm surrounding cancer stem cells. According to John Bates, Ph.D., who directs Biopharm Reports in Cambridge, UK, the number of companies devoted to this research grew from 17 in April 2007 to nearly 40 today. What's more, he added, patents covering developments in cancer stem cells doubled to about 70 in 2007.
The interest derives from evidence suggesting that cancer stem cells give rise to solid tumors. (There has been less success over the years in treating most solid tumors than blood cancers.) In a common analogy, cancer stem cells are compared to queen bees in a hive. It's only by killing them that cancer can be cured, many scientists believe. If these cells remain after treatment, tumors can return, just as beehives do when the queen bees aren’t destroyed. That hypothesis fuels hope that cancer stem cells—which resist current chemotherapy—might offer a new class of targets for drug development.
Still, Bates warns that the hypothesis has yet to be proven. "Cancer stem cells may be pivotally involved in the development and metastatic spread of cancer," he said. "But there's much more that needs to be done to confirm this in man."
Scientists have suspected since the 1950s that cancer stem cells play a role in blood tumors, such as acute myeloid leukemia. However, their possible existence in solid tumors was only found experimentally in 2003. That's when Michael Clarke, M.D., currently associate director of Stanford University's Institute for Stem Cell and Regenerative Medicine, and his then postdoc, Mohamed Al-Hajj, Ph.D., claimed to find cancer stem cells in breast tumors. The cells had two markers that are now synonymous with cancer stem cells: high expression of the antigen CD44 and low expression of antigen CD24. Isolated on the basis of these markers, the human cells were cultured and introduced into immunocompromised mice. Their results showed that only a few of the cells could spawn metastatic tumors. Since then, findings in other labs suggest the existence of cancer stem cells in more tumors, including those of the brain, head and neck, prostate, and colon.
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When Chang learned of Clarke's findings, she began looking at CD44 and CD24 expression profiles in breast tumor biopsy samples. What she found was that after 12 weeks of treatment with standard chemotherapy, the proportion of cells expressing the characteristic CD44/CD24 profile rose sharply compared with those of the other cancer cells in the tumor. And that, she said, suggested that chemotherapy had killed off most of the tumor cells while leaving the cancer stem cells behind.
Meanwhile, Max Wicha, M.D., the director of the University of Michigan Comprehensive Cancer Center in Ann Arbor, and his collaborators had begun to consider that self-renewal in cancer stem cells might be governed by HER signaling, which plays important roles in both normal and cancer cell proliferation. Self-renewal, the key property of stem cells, reflects their immortality. Unlike ordinary cells, which divide into two identical daughters, stem cells—both cancerous and noncancerous varieties—split into a pair of nonidentical entities: a daughter cell that loses the power of self-renewal and a new stem cell that retains this ability. After this division, the number of stem cells in the tissue (or tumor) remains unchanged because as one is lost, another is created.
The proposed links between stem cell renewal and HER signaling led Chang to lapatinib. The drug, made by GlaxoSmithKline, was being studied in clinical trials for women with HER2-positive breast cancer who had already been treated unsuccessfully with trastuzumab and other therapies. This is the indication for which lapatinib was approved by the U.S. Food and Drug Administration in 2007. Unlike trastuzumab, a monoclonal antibody that targets the HER2 gene only, lapatinib is a small molecule that also targets HER1. Scientists had found that HER2 needs HER1 to function properly, so GlaxoSmithKline reasoned that lapatinib, by targeting both, might be more effective than trastuzumab. (Chang points out, however, that the drugs haven’t yet been tested in a head-to-head comparison.)
Research was also showing that HER1 in particular was crucial to stem cell renewal. On the basis of that assumption, Chang speculated that lapatinib might target cancer stem cells, and so in 2004, she launched a clinical trial to test that hypothesis. It took 3 years to accrue the 40 patients upon which her current conclusions are based. Chang's clinical data are supported by tumor tissue analyses, which show that the CD44/CD24 expression profile was reduced in tumor biopsy samples after lapatinib exposure. "What we have here is a drug that—unlike chemotherapy—attacks the mother of all cancer cells: the stem cells," she said.
Others take a more cautious view, however. Bates, for instance, says that the best way to describe the lapatinib findings is to say that "a population of cells that are believed to be cancer stem cells were reduced [by treatment]." He added, "But it has yet to be shown conclusively that stem cells were targeted. It's important to realize this is an early study ... Further data are awaited."
Indeed, characterizing stem cells has become a major research thrust in the field. George Schreiner, M.D., Ph.D., chief executive officer with Raven Biotechnologies in San Francisco, said most companies working in this area can be divided in two categories: those developing platforms and technologies for cancer stem cell characterization and those developing new compounds that might target and kill the cells. CD44 and CD24 remain the "gold standards," he said, but other antigens are now also emerging. Getting companies to discuss them is an entirely different matter, however. As is often the case with early-stage research, the cancer stem cell arena is highly proprietary. A company called Oncomed Pharmaceuticals in Redwood City, Calif., recently signed a multiyear strategic alliance with GlaxoSmithKline worth $1.4 billion, tied to achieving "undisclosed milestones" in cancer stem cell R&D. Oncomed has an antibody in clinical development that targets cancer stem cells, but when asked how, the company's CEO, Paul Hastings, would reveal only that it affects a "cancer stem cell pathway with broad applicability across multiple solid tumors."
The fact that lapatinib is a small molecule makes it unusual among the various cancer stem cell compounds in development. By far, nearly all compounds under development are monoclonal antibodies, which are easier to develop. That's because antibodies attack targets on the cell surface, whereas small molecules penetrate into the cell interior, where biochemical processes are more complex and difficult to manage.
Still, antibodies pose some challenging safety concerns, Clarke said. The biggest worry is that they might also attack normal stem cells that replenish damaged tissues. "The main thing to ensure is that we eliminate the malignant cancer stem cells without affecting the normal stem cells," he said. "Whether we’ll be able to do this is the billion-dollar question that everyone wants to answer."
To date, lapatinib seems to have no major side effects, which reflects the drug's apparent ability to target cancer stem cells specifically, Chang said. Standard chemotherapy, on the other hand, targets rapidly dividing cells in general, including hair cells and the cells lining the stomach's inner surfaces. "Tykerb's really well tolerated—no hair loss, no infection, no nausea, just a bit of acne," she said. "When you consider what we saw here, I think we’re coming to a point where we might one day be able to do targeted therapy without having to poison the patient."
But Chang acknowledges that many questions about lapatinib's purported ability to kill cancer stem cells remain unanswered. Also, it's not clear if the drug will be useful for patients with other types of cancer beyond HER2-positive breast tumors, she said. And the mechanistic evidence for the drug's stem cell–killing effects is built almost entirely on changes in the CD44/CD24 expression profile, which needs to be bolstered by other defining features. "I wear two hats in my work," Chang said. "I wear my research hat, and that tells me that we need to do more to prove we’re targeting cancer stem cells. But I also wear a clinical hat, and that tells me that my patients do a lot better when they take this drug.... My clinical hat wins out. I don’t care how it works, as long as it does. But we’re going to continue doing the work to figure out how it's doing this."
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