Racking the brain

Researchers at MD Anderson Cancer Center, two California biotechs lead effort to create new treatments for glioblastoma multiforme

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HOUSTON, Texas—Researchers at the nationally acclaimedUniversity of Texas MD Anderson Cancer Center and two California-basedbiotechnology companies, ImmunoCellular Therapeutics Ltd. (IMUC) and TocagenInc., have joined forces to create new treatments to fight an aggressive formof brain cancer known as glioblastoma multiforme.
This deadly form of cancer rose to public consciousness in2008, when U.S. Sen. Edward Kennedy, D-Mass., announced that he was diagnosedwith it. The disease ultimately killed him some 15 months later in August 2009.
No other brain cancer is as deadly nor spreads so quickly,but new therapies hold the promise of more than doubling life expectancy forthose who suffer from it, according to Frederick F. Lang Jr., a researcher andneurosurgery professor at the University of Texas. However, Lang and otherresearchers know that simply extending a patient's life to a few more monthsfalls far short of the ultimate medical goals, which are to destroy the tumor andrestore the cancer patient's quality of life. 
Lang says the latest treatments, based on using viruses andthe body's immune system to attack tumors, hold much promise.
"We haven't cured anyone, but there are signs we're headingin the right direction," said Lang in a June 6 press release.
Brain tumors differ from tumors that occur elsewhere in thebody, Lang says. They are highly variable, with more than 125 known kinds. Theyare hard to see because the majority are not encased, like those that occur inthe breast and some other organs. They are difficult to remove, because thetumors' long fingers, which reach from a central body to burrow deep into brainmatter, can't be easily distinguished from normal brain tissue. And malignantbrain tumors, especially the common glioblastoma, are highly resistant totreatment.
Delivery of a drug also is a problem because the tumor isusually enclosed in a tight quarter in the brain protected by the blood-brainbarrier, Lang says. Radiation therapy is tricky because of the risk treatmentposes to brain tissue caught in the X-ray beam.
N. Paul TonThat, executive director of the National BrainTumor Society, says the cancer not only grows quickly, but also causesheadaches and extreme nausea and disrupts memory, balance, speech and vision.No one knows the cause. About 620,000 people are living with brain tumors, andan estimated 10,000 are diagnosed annually with glioblastoma.
There are two key areas of research in this field, TonThatsays. One adapts common viruses so they can be used to attack the cancerdirectly; the other delivers powerful chemotherapy drugs precisely targeted todestroy the tumors.
Both Lang, at MD Anderson, and San Diego-based Tocagen areusing modified viruses to attack brain cancer, though in very different ways.
In Lang's therapy, the virus infects cancer cells andreplicates the cells until it has no room left. Known as Delta-24, thetreatment has proven successful in studies in the laboratory and in animals,and is now being tested in a small number of human patients in the first ofthree stages of clinical trials typically required for regulatory approval.
Tocagen's experimental medicine, also in first-stage humantesting, requires doctors to drill a hole in a patient's skull and inject thevirus. Once the virus is delivered, it replicates throughout the cancer andserves as a sticky landing pad for an antibiotic that's given as a pill. Thecombination of the virus and the pill then become a powerful chemotherapy.
IMUC has taken a different approach to combat brain cancer.Its method uses the body's own disease-shielding abilities to target stem cellsthat spur cancer growth. On June 2, the Woodland Hills, Calif.- based biotechtold the American Society of Oncology meeting in Chicago that 50 percent of 16patients on its drug, ICT-107, were alive after four years, compared with 12percent on standard treatment. The treatment spurs an attack against themalignancy by the immune system's killer T-cells. In this case, the companyadapted immune-system messaging cells, called dendritic cells, to sniff outdeveloping cancer. Dendritic cells work similarly to the way signals from humanskin advise the brain that a touched surface is hot or rough.
"We try to give dendritic cells the scent of a criminal'sclothes, so the immune system can go like a hound after the tumor and kill it,"says John Yu, IMUC's chairman and chief scientific officer.
Updated data from the 16 patients in the Phase I trial showsthat patients treated with ICT-107 reported overall survival of 50 percentafter four years and 38 percent of the trial patients are progression-free for48 to 66 months, according to IMUC.
While not all 16 of the patients in the Phase I trial havecrossed the five-year time point, three of the patients are disease-free forfive years, IMUC states.
In IMUC's follow-on Phase II trial of ICT-107, 213 patientsare enrolled, of which 100 patients have been either randomized (or treatedwith the product) or are waiting to complete radiation therapy prior totreatment. The company recently announced that its Phase II trial is ongoing at25 sites, with patients enrolled in leading medical centers such asMassachusetts General Cancer Center and the Dana Farber Cancer Institute. 
There will be no magic bullet to treat brain cancer, saysRaymond Sawaya, an MD Anderson professor and chair of the Department ofNeurosurgery. The answer will not come from one approach.
"We have to test and perfect many different avenues fortreatment, and hit the right combination of multiple drugs and therapies thatworks best for each individual patient," he says. 

MD Anderson study shows normal gene hinders breast cancer chemotherapy
HOUSTON—In a preclinical study led by MD Anderson, scientistsat the cancer center found that the presence of normal p53, a tumor suppressorgene, instead of a mutated version, makes breast cancer chemotherapy withdoxorubicin less effective.
According to MD Anderson, the research, which challenges theexisting paradigm, is another step closer to personalized cancer medicine forbreast cancer.
"It's really important to understand the genetic defects atumor cell has before we treat it," said lead author Dr. Guillermina Lozano,professor and chair of the Department of Genetics. "What we learned here is thecomplete opposite of what we expected. We thought tumors would respond betterto treatment if the p53 gene were normal. But the opposite was true, and for areally interesting reason."
Lozano said the research in mouse models showed thatnon-mutated p53 halted cell division, initiating a cell-aging process thatallowed cells to survive. These senescent cells produce factors that stimulateadjacent cells to grow, fueling the relapse. Mutant p53 cells do not arrest andproceed through the cell cycle into cell division with broken chromosomescaused by the chemotherapy.
In this study, doxorubicin-treated p53 mutant tumor cellsdid not stop cell proliferation, leading to abnormal mitoses and cell death,whereas tumors with normal p53 arrested, avoiding mitotic catastrophe.
"There are a lot of data out there on responses of women todoxorubicin and other drugs that break DNA," Lozano said. "The response rateswere mixed, and we never understood the difference. Now we understand that weneed to know the p53 status to predict a response."
This project was funded by grants from the National CancerInstitute and the National Institutes of Health, a Theodore N. Law Endowmentfor Scientific Achievement and a Dodie P. Hawn Fellowship in Cancer GeneticsResearch. The study was published June 11 in the journal Cancer Cell.

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