Wirus Delta-24 inteligentną bombą na glejaka

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Wirus Delta-24 inteligentną bombą na glejaka

Postprzez moto_kate » Pt sie 15, 2008 10:05 am

http://www2.mdanderson.org/depts/oncolo ... -07-1.html

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Outsmarting Brain Cancer

by Dianne C. Witter

It’s been called a viral “smart bomb,” and with good reason. The name even has a military ring: Delta-24. Mission: eradicate glioblastomas while leaving critical nearby brain structures unscathed. The mission is even tougher than it sounds. Unlike most other solid tumors, glioblastomas are not shaped in a definitive lump; they spread into crevices within the brain, taking healthy tissue hostage as they go.

Delta-24 is a new-generation adenovirus therapy developed by researchers at The University of Texas M. D. Anderson Cancer Center. The virus targets the pathway of the retinoblastoma protein (pRb), a master regulator of cell growth that is deficient in many cancer cells. Researchers created a gene mutation in the virus that allows it to reproduce only in cells without pRb; thus, in normal cells, Delta-24 cannot replicate.

But when injected into tumor cells, the virus replicates exponentially until the cells burst, each releasing about 10,000 new copies of the virus. These copies spread out, attach to more cancer cells, and repeat the process. The virus moves, wavelike, throughout the tumor, infecting and killing cancer cells without affecting normal cells.

On the verge of important advances

Targeting tumors with a viral smart bomb is only one of the avenues showing promise. After several decades in which no new drugs were approved for the treatment of brain tumors and survival rates remained disappointingly low, there are now a variety of promising new medical treatments in the pipeline. They come close on the heels of the U.S. Food and Drug Administration’s approval in 2005 of the chemotherapy drug temozolomide for use in glioblastoma. Temozolomide, when used in addition to surgery and radiation, extends median overall survival by 2.5 months—and a few people in the early clinical trials of temozolomide are alive years beyond what was expected.

W. K. Alfred Yung, M.D., chair of the Department of Neuro-Oncology, believes temozolomide was the beginning of a positive trend in brain cancer treatment. “We are just now on the cusp of understanding much more about the molecular biology of this disease, which is leading us down some innovative and very promising avenues,” he said. “For example, in addition to the Delta-24 virus, we’re also looking at a peptide vaccine, antiangiogenesis agents, and epidermal growth factor receptor (EGFR) inhibitors, in addition to retooling existing chemotherapy drugs so they will cross the blood-brain barrier.”

Charles Conrad, M.D., associate professor in the Department of Neuro-Oncology, adds, “I think we’re going to see an explosion of new drugs for brain tumors within the next 3 to 5 years, and many of those are being developed at M. D. Anderson. We have a real optimism that advances are coming.” Nationwide, only 1% to 2% of glioblastoma patients survive long-term today. Dr. Conrad believes that within 5 or 10 years, that figure will have jumped to 20% or even 30%.

Sneak peek at projects under way

Researchers at M. D. Anderson designed a vaccine that alerts the immune system to the presence of epidermal growth factor receptor variant III (EGFRvIII), a protein found on gliomas that is believed to drive them to spread aggressively. The vaccine contains a synthesized piece of the protein and a stimulator to activate the immune system, inciting it to mount a response, attacking the EGFRvIII and the gliomas it’s attached to.

In a phase II clinical trial conducted at M. D. Anderson, glioblastoma patients whose brain tumors showed evidence of the protein on examination after surgical removal were eligible for the vaccine. Preliminary results suggest the vaccine is significantly increasing the expected life span of patients in the study; participants have had a median overall survival of at least 18 months. Researchers found that the treatment can potentially keep the disease at bay for a period of time in up to 50% of glioblastoma patients. However, there is evidence that the tumors may eventually circumvent the vaccine, so researchers plan to combine the vaccine with chemotherapy in the current study.

In other research, scientists are working to identify the genes and proteins associated with gliomas to identify or develop small-molecule drugs specifically targeted to these molecular pathways. Some of the more common genetic alterations in malignant brain tumors include the p53 tumor suppressor gene; EGFR genes that control cell growth; platelet-derived growth factor and vascular endothelial growth factor (VEGF) genes involved in cell growth and angiogenesis; and the PTEN (phosphatase and tensin homologue) tumor-suppressor gene.

A number of signal-transduction inhibitors are being tested for use in brain tumors based on these molecular signatures, including erlotinib, ZD 1839, and AEE788 (which are EGFR inhibitors) and rapamycin and RAD001 (which are mammalian target of rapamycin [mTOR] inhibitors). mTOR inhibitors regulate the way tumor cells respond to nutrients and growth factors and also control blood supply to the tumor through their effects on VEGF.

Researchers at M. D. Anderson expect to open two clinical trials of unique P13K inhibitors, PX-866 and BEZ-235, in glioblastoma patients in 2008. The agents are expected to offer several advantages, including significantly reducing the dose-limiting toxicity common with P13K inhibitors. The agents will be tested in combination with existing small-molecule drugs such as erlotinib and sorafenib, with the expectation of blocking multiple pathways.

Glioblastomas are highly vascularized, and the vascular system is thought to have a key role in their progression—which has led investigators to look increasingly at using antiangiogenic agents. “The antiangiogenic drug bevacizumab is one of the most promising agents being studied right now,” said Dr. Yung. “We’ve seen very good early responses in studies combining it with the chemotherapeutics irinotecan or erlotinib.”

“Most chemotherapy drugs have not traditionally had success in brain tumors due to their inability to cross the blood-brain barrier, which actively pumps out cytotoxic drugs as fast as we put them in,” said Dr. Conrad. With an improved understanding of the biology of the blood-brain barrier, researchers have developed a way to retool existing chemotherapies so that they will penetrate this barrier. This could be achieved through modification of the chemical structure or using carrier peptides or antibodies. For instance, M. D. Anderson researchers re-engineered the chemotherapy agent doxorubicin to cross the blood-brain barrier. Phase I trials of the resulting agent, RTA744, have shown encouraging results—including one patient with complete resolution of his tumor. Another agent under development is 2-deoxy-d-glucose, which inhibits the glycolysis process that brain tumors depend on for energy.

And then there is the new generation virus, Delta-24. Researchers were excited by the degree of success they had when testing Delta-24 in mice. “The virus completely eradicated some glioblastomas, a response that had never been seen before,” said Juan Fueyo, M.D., associate professor in the Department of Neuro-Oncology, who developed the treatment in collaboration with his wife and colleague, Candelaria Gomez-Manzano, M.D., assistant professor in the Department of Neuro-Oncology. “We found only empty cavities and scar tissue where the tumors had been. Some of the mice were considered clinically cured of their brain tumors.”

It’s a big finding, albeit in very small subjects. Recently, the researchers found even more promising news about Delta-24. They showed that, in addition to killing tumor cells, the virus can target and eliminate the actual stem cells that initiate the growth of glioblastoma. “These cells are highly resistant to chemotherapy and radiation, and they fuel the re-growth of the tumors after surgery,” said Dr. Fueyo. “We have to be cautious about extrapolating the results from animal studies, but the tumors grown from these cells closely resemble human tumors, so we’re very optimistic and excited to begin clinical trials.”

Glioblastoma is the most common, and most deadly, of brain cancers. If the results seen in mice turn out to be indicative of the results in humans, Delta-24 may ultimately prove to be an important new therapy for human glioblastomas. The Brain and Spine Center at M. D. Anderson expects to begin enrolling patients in the first clinical trial of the new viral therapy this fall.

In this clinical trial, Delta-24 will be injected into brain tumors through a surgically implanted catheter. After 2 weeks, the tumors will be surgically removed and examined. In future studies, however, the virus may be delivered to the tumors via mesenchymal stem cells, which would effectively serve as a Trojan horse for the virus. Researchers at M. D. Anderson have discovered that these stem cells preferentially home in to tumors, even if a tumor exists in the unique environment of the brain. By concealing the virus inside the stem cells, it could be carried directly to the tumor without detection by the immune system and, once inside, destroy it.

Looking forward

Glioblastoma is a formidable foe, and researchers say the key to outwitting it won’t come from one drug or one treatment; it will take a variety of approaches and an arsenal of next-generation drugs and therapies. “We need to attack multiple pathways at one time to outsmart the cancer cells,” said Dr. Yung. “So, in addition to identifying new drugs, we need to test different treatments in combination to find the optimal approach.”

For now, though, Dr. Yung stresses that there are many more options available to brain tumor patients than in the past. “We now have a wide range of trials using different approaches and targeting different types and stages of the disease; there’s something for everyone,” he said. “There are many things we can do to increase a patient’s chance of survival and quality of life.

“Most importantly, we can offer more hope,” he said.

For more information, call the Brain and Spine Center at 1-877-632-6789 or visit www.mdanderson.org/care_centers/brainspinal.

Serdecznie pozdrawiam,

..:: Kate ::..
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