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Racking the brain
July 2012
by Lori Lesko  |  Email the author


HOUSTON, Texas— Researchers at the nationally acclaimed University of Texas MD Anderson Cancer Center and two California-based biotechnology companies, ImmunoCellular Therapeutics Ltd. (IMUC) and Tocagen Inc., have joined forces to create new treatments to fight an aggressive form of brain cancer known as glioblastoma multiforme.  
This deadly form of cancer rose to public consciousness in 2008, when U.S. Sen. Edward Kennedy, D-Mass., announced that he was diagnosed with 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 for those who suffer from it, according to Frederick F. Lang Jr., a researcher and neurosurgery professor at the University of Texas. However, Lang and other researchers know that simply extending a patient's life to a few more months falls far short of the ultimate medical goals, which are to destroy the tumor and restore the cancer patient's quality of life.
Lang says the latest treatments, based on using viruses and the body's immune system to attack tumors, hold much promise.  
"We haven't cured anyone, but there are signs we're heading in the right direction," said Lang in a June 6 press release.  
Brain tumors differ from tumors that occur elsewhere in the body, Lang says. They are highly variable, with more than 125 known kinds. They are hard to see because the majority are not encased, like those that occur in the breast and some other organs. They are difficult to remove, because the tumors' long fingers, which reach from a central body to burrow deep into brain matter, can't be easily distinguished from normal brain tissue. And malignant brain tumors, especially the common glioblastoma, are highly resistant to treatment.  
Delivery of a drug also is a problem because the tumor is usually enclosed in a tight quarter in the brain protected by the blood-brain barrier, Lang says. Radiation therapy is tricky because of the risk treatment poses to brain tissue caught in the X-ray beam. N. Paul TonThat, executive director of the National Brain Tumor Society, says the cancer not only grows quickly, but also causes headaches and extreme nausea and disrupts memory, balance, speech and vision. No one knows the cause. About 620,000 people are living with brain tumors, and an estimated 10,000 are diagnosed annually with glioblastoma.  
There are two key areas of research in this field, TonThat says. One adapts common viruses so they can be used to attack the cancer directly; the other delivers powerful chemotherapy drugs precisely targeted to destroy the tumors.  
Both Lang, at MD Anderson, and San Diego-based Tocagen are using modified viruses to attack brain cancer, though in very different ways.
In Lang's therapy, the virus infects cancer cells and replicates the cells until it has no room left. Known as Delta-24, the treatment 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 of three stages of clinical trials typically required for regulatory approval.
Tocagen's experimental medicine, also in first-stage human testing, requires doctors to drill a hole in a patient's skull and inject the virus. Once the virus is delivered, it replicates throughout the cancer and serves as a sticky landing pad for an antibiotic that's given as a pill. The combination 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 cells that spur cancer growth. On June 2, the Woodland Hills, Calif.- based biotech told the American Society of Oncology meeting in Chicago that 50 percent of 16 patients on its drug, ICT-107, were alive after four years, compared with 12 percent on standard treatment. The treatment spurs an attack against the malignancy by the immune system's killer T-cells. In this case, the company adapted immune-system messaging cells, called dendritic cells, to sniff out developing cancer. Dendritic cells work similarly to the way signals from human skin advise the brain that a touched surface is hot or rough.  
"We try to give dendritic cells the scent of a criminal's clothes, 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 shows that patients treated with ICT-107 reported overall survival of 50 percent after four years and 38 percent of the trial patients are progression-free for 48 to 66 months, according to IMUC.
While not all 16 of the patients in the Phase I trial have crossed the five-year time point, three of the patients are disease-free for five years, IMUC states.  
In IMUC's follow-on Phase II trial of ICT-107, 213 patients are enrolled, of which 100 patients have been either randomized (or treated with the product) or are waiting to complete radiation therapy prior to treatment. The company recently announced that its Phase II trial is ongoing at 25 sites, with patients enrolled in leading medical centers such as Massachusetts General Cancer Center and the Dana Farber Cancer Institute.
There will be no magic bullet to treat brain cancer, says Raymond Sawaya, an MD Anderson professor and chair of the Department of Neurosurgery. The answer will not come from one approach.   "We have to test and perfect many different avenues for treatment, and hit the right combination of multiple drugs and therapies that works 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, scientists at the cancer center found that the presence of normal p53, a tumor suppressor gene, instead of a mutated version, makes breast cancer chemotherapy with doxorubicin less effective.  
According to MD Anderson, the research, which challenges the existing paradigm, is another step closer to personalized cancer medicine for breast cancer.   "It's really important to understand the genetic defects a tumor 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 the complete opposite of what we expected. We thought tumors would respond better to treatment if the p53 gene were normal. But the opposite was true, and for a really interesting reason."
Lozano said the research in mouse models showed that non-mutated p53 halted cell division, initiating a cell-aging process that allowed cells to survive. These senescent cells produce factors that stimulate adjacent cells to grow, fueling the relapse. Mutant p53 cells do not arrest and proceed through the cell cycle into cell division with broken chromosomes caused by the chemotherapy.  
In this study, doxorubicin-treated p53 mutant tumor cells did 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 to doxorubicin and other drugs that break DNA," Lozano said. "The response rates were mixed, and we never understood the difference. Now we understand that we need to know the p53 status to predict a response."  
This project was funded by grants from the National Cancer Institute and the National Institutes of Health, a Theodore N. Law Endowment for Scientific Achievement and a Dodie P. Hawn Fellowship in Cancer Genetics Research. The study was published June 11 in the journal Cancer Cell.  
Code: E071222



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