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  • Paths of Progress Spring/Summer 2011

    Trail blazing: 'smart' drugs yield glimmers of promise in treating glioblastomas
    By Richard Saltus

    Pat MenocheGlioblastoma patients like Pat Menoche, an avid skier, are enjoying improved quality of life thanks to targeted drugs such as Avastin. 

    When January's blizzards had many people hunkered down, 61-year-old Pat Menoche of Little Compton, R.I., and her husband Dick headed up to Vermont for the first of two annual cross-country skiing trips.

    Not one to sit still, Pat Menoche is also an avid gardener, volunteers at a local theater company, and is involved in several community organizations. She also tries to exercise three times a week and attend daily Mass.

    This might not seem so unusual for an active baby boomer, but in Menoche's case it's pretty amazing: Five years ago, she was diagnosed with glioblastoma, an often fatal brain tumor.

    Under the care of Patrick Wen, MD, director of the Center for Neuro-Oncology at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC), Menoche has done well – handily beating the average survival statistics.

    "I'm more cautious and slowermoving than I used to be," admits Menoche, who receives her treatment at DF/BWCC. "And it takes me a little longer to process information." But by and large, with the help of her husband and friends, she's living the life to which she's accustomed.

    The median survival for glioblastoma patients has been inching upward in the past five to 10 years. The traditional treatment regimen of surgery, radiation, and chemotherapy has been tweaked and refined, and the drug Temodar, which clinical trials showed can extend median survival, is now routinely given to glioblastoma patients along with radiotherapy.

    In addition, Wen has placed Menoche on several experimental agents, and, most recently, the newly approved monoclonal antibody drug, Avastin, which shrinks tumors by cutting off their blood supply.

    Menoche's case is an example of new directions in glioblastoma treatment research. An increasingly deeper understanding of the tumors' inner workings has fueled a growing arsenal of experimental drugs that mount precise attacks on the lifelines – both inside and outside cancer cells – that glioblastomas need for growth.

    Scientists believe "cocktails" of highly specific drugs will be key to helping patients live longer.

    "There is definite hope that over the next few years, new cocktails of drugs will be available to target the key molecular pathways involved in these tumors and help patients live longer and better lives," says Wen, who specializes in the care of people with brain tumors and conducts clinical trials focused on molecularly targeted treatments – a field in which he says Dana-Farber is helping to lead.

    Wen and his Dana-Farber colleagues helped pioneer one of the new strategies – using Avastin to deprive glioblastomas of the additional blood supply they desperately need to grow. "These tumors are very vascular," he says, "so there has been a lot of interest in angiogenesis inhibitors" – drugs such as Avastin that block molecular signals the tumors send to recruit extra blood vessels.

    Under Wen's leadership, Dana- Farber researchers, together with colleagues at other institutions, carried out clinical trials revealing a modest but significant benefit for patients who received Avastin. This led to its approval for glioblastoma patients by the Food and Drug Administration in 2009. "The majority of patients have some shrinkage of their tumor," notes Wen. "And their quality of life is much better."

    Since being diagnosed with a glioblastoma in 2007, plastic surgeon Michael Thompson, 49, of Wayland, Mass., has fared well on another angiogenesis blocker, Zactima, allowing him to spend more time with his young children. Zactima kept Thompson's cancer in check for more than three and a half years – well past the average survival period. And, as with Avastin, the drug has less-harsh side effects than traditional therapies.

    Research Intensifies

    Patrick Wen and Jan DrappatzFrequent MRI scans enable neuro-oncologists Patrick Wen, MD, PhD, (left) and Jan Drappatz, MD, to monitor the effects of new drug treatments. 

     About 17,000 people in the United States are diagnosed annually with malignant gliomas, tumors that originate in cells called astrocytes that support and nourish the brain's billions of neurons. Gliomas are "primary" tumors – not metastatic colonies from cancers elsewhere in the body. Glioblastomas, also known as Stage IV gliomas, account for about half of all malignant gliomas.

    Until now, the mainstay of chemotherapy has been highly toxic drugs that poison cancer cells or damage their DNA to halt their growth. Glioblastomas are notorious for quickly becoming resistant to such drugs and morphing into even more-aggressive forms. Many scientists, using knowledge gained from the human genome project (see related story, The Genomics Decade), are now betting on a more pinpoint approach by using molecularly targeted agents precisely aimed at the abnormal DNA in tumor cells. Scientists are hopeful that tumors will be less likely to develop resistance to these "smart" drugs.

    Some of the glioblastoma abnormalities are caused by massive chromosome damage, others by mutated genes and proteins. The latter include mutant kinase molecules that act like growth switches stuck on fast-forward, allowing cancer cells to multiply endlessly. Certain genetic conditions increase the risk of developing glioblastomas, but the great majority are rooted in mistakes in the genetic code of normal brain cells caused by DNA-damaging toxic agents like radiation – or random "typos" in genes' coded instructions that occur when cells divide.

    Each brain tumor carries a distinct collection of genetic abnormalities that help determine the tumor's behavior, the patient's prognosis, and, potentially, which drugs or combinations will be most effective. "Once tumors can be more accurately classified by mutations, treatment regimens can be tailored to individual tumors," says Wen.

    At DF/BWCC, samples of each patient's glioblastoma removed in surgery are analyzed to determine which genes were altered. Keith Ligon, MD, of Dana-Farber's Center for Molecular Oncologic Pathology, oversees a database of the genetic patterns found in the tumors, and Wen coordinates clinical trials of drugs tailored to those patterns.

    Meanwhile, researchers here are in hot pursuit of additional genetic flaws in glioblastomas. In 2001, Ligon, then in the laboratory of Charles Stiles, PhD, of Dana- Farber's Division of Cancer Biology, isolated a protein called Olig-2 that plays a key role in the developing brain; in adulthood, Olig-2 is relatively dormant. It was later shown that Olig-2 is active in 90 percent of brain tumors, including glioblastomas, making it a good potential target for designer drugs.

    Recently, Stiles' group reported that they had uncovered a previously unknown function of Olig-2 that triggers the formation of tumors, as well as a potential new target for anti-tumor drugs. Working in collaboration with the Stiles group, scientists in the Pediatric Oncology laboratory of Loren Walensky, MD, PhD, are testing designer drugs to attack glioblastomas by targeting Olig-2. Other new leads are coming from The Cancer Genome Atlas (TCGA) project, which is surveying several types of cancer to map their genetic abnormalities.

    Dana-Farber's Lynda Chin, MD, and Matthew Meyerson, MD, PhD, co-authored a 2008 report on progress in mapping genetic abnormalities in glioblastoma cells. The survey turned up a large number of broken, missing, and overactive genes – some of them implicated in glioblastomas for the first time and thus providing potential new drug targets.

    Identifying the group of mutations that drive a patient's tumor will enable doctors to tailor treatments to that specific tumor.

    In 2007, Jayne Stommel, PhD, a post-doc in the laboratory of Ron DePinho, MD, director of Dana- Farber's Center for Applied Cancer Science, found that a tumor's aggressiveness is often fueled by not just one, but several broken and overactive tyrosine kinase growth switches. Blocking a single abnormal kinase will not work for long because "backup" kinases continue to spur the tumor. Thus, the scientists said, it is urgent that clinical trials be undertaken to test kinase inhibitor combinations to thwart glioblastomas.

    While some of the new targeted drugs given alone have shown promising activity in glioblastomas, Wen agrees that improving survival will require combining the agents to block several malignant pathways simultaneously. To the frustration of patients and doctors alike, the federal approval process mandates that new drugs be tested singly for safety and efficacy before they can be combined in clinical trials. "I wish we had much better treatments and could cure every patient now," says Wen.

    One thing is certain: There is no shortage of ideas for attacking glioblastomas, and many are being investigated by Wen and others at DF/BWCC. In addition to exploring the combination of angiogenesis inhibitors with targeted drugs, scientists are pursuing new areas of attack such as tumor stem cells, immunotherapy (cancer vaccines), gene therapy to make tumors more vulnerable to treatment, and the manipulation of tumor cells' metabolic processes.

    As the research and development continues, Pat Menoche is continuing to do what she always does – keeping busy. At a recent appointment with Debra LaFrankie, RN, OCN, a member of Menoche's care team, Pat's husband Dick observed that he was running out of pages in the small notebook in which he's documented every detail of her treatment since her diagnosis. "When I got this notebook, I thought it would be all I would need," he says. But given how well his wife has done, he says with a smile, "I'm going to have to get another one."

    Paths of Progress Spring/Summer 2011 Table of Contents 

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