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Glioblastoma, the most common malignant tumor of the brain, is highly aggressive and usually becomes resistant to standard treatment over time. “That’s why it’s so important for patients to have access to new agents in clinical trials,” says Batchelor. Among the medical therapies under investigation for these tumors are drugs called angiogenesis inhibitors, which are believed to temporarily normalize leaky blood vessels supplying the tumor — allowing chemotherapy and radiation to work more effectively — and then to block tumor growth. One of the drugs that has been extensively studied in the Cancer Center, AZD2171, also known as cediranib, has shown promising activity in patients with glioblastoma when other therapies have failed. (See “Therapeutic Door Opens for Aggressive Brain Cancer”)
Imaging will also be used at regular intervals to measure therapeutic effects on the tumor. All of the half-dozen clinical trials of angiogenesis inhibitors now in development for brain tumors at the Cancer Center, says Batchelor, depend on the advanced imaging techniques of the Martinos Center.


Although neurosurgeon Martuza performs image-guided surgery, he is also known internationally for applying molecular techniques to problems that surgery cannot solve. Surgery cannot completely remove glioblastomas, for example, because malignant cells can infiltrate the normal tissue surrounding the tumor. So Martuza and his colleagues pioneered another approach called oncolytic viral therapy — a close cousin of gene therapy — in which viruses, such as the herpes simplex cold sore virus, are genetically engineered to become cancer-killing agents.
In typical gene therapy, scientists use viruses to insert a normal or altered gene into cells to replace a disease causing gene. Viruses are like uninvited guests that insinuate themselves into a cell’s environment. Researchers disable the virus so that it cannot cause infection and use it to slip the corrective gene inside the cell. Once there, the virus takes over the cell’s reproduction machinery, allowing the virus and its healthy gene to replicate.
Oncolytic viral therapy is a variation on this theme. Rather than engineering the virus to carry a corrective gene, scientists alter the virus to selectively replicate in cancer cells but not in normal cells, explains Martuza. Various manipulation strategies create viruses that stop the tumor from growing or kill its newly formed blood vessels. “We can engineer the herpes virus so that the cancer cell provides just what the cancer-killing virus needs to grow within the cancer but not within the normal tissue.”
An agent called G207 is one of the first clinical applications of herpes viruses to tumors of the brain. In a clinical trial in patients with recurrent malignant gliomas (which include glioblastoma), results were encouraging. “G207 was safe even at the highest doses, despite being injected directly into the brain,” says Martuza. “And in about one-third of patients, we saw tumor regression on MRI scans.”


In an effort to improve the efficacy of viral therapy in malignant gliomas, Curry, Martuza and colleagues are planning a new clinical trial combining G207 with temozolomide, an oral chemotherapy drug that works by damaging the DNA in tumor cells. “When the tumor tries to repair the DNA,” explains Martuza, “that process actually stimulates the altered virus to multiply and spread to other tumor cells, thus killing the tumor.”
He and his colleagues in the Department of Neurosurgery, Manish Aghi, MD, PhD, and Samuel Rabkin, PhD, recently demonstrated some striking results using this combination therapy in mouse models of glioblastoma. Treating with either temozolomide or G207 alone extended survival from about 34 days to 50 days. But treating first with temozolomide and then with G207 — like a one-two punch — resulted in a 100 percent cure rate. According to Martuza, combining the therapies is ten times as effective as either therapy alone. “At least in the preclinical model, this combination therapy looks very exciting, which is why we are bringing it into clinical trials.”
Others in the Pappas Center are combining therapies to boost the efficacy of chemotherapy and radiation. Loeffler, for example, is studying agents that will enhance the sensitivity of tumor cells, priming them to become more susceptible to radiation. Batchelor predicts that these and other combination therapies on the horizon offer the greatest hope for improving survival and quality of life in patients with malignant brain tumors. “We have already identified critical components of the tumor to target. Now we need to combine treatments to attack each of these components.” - Lonnie Christiansen
Advancing the Specialized Care of Individuals with Brain Tumors
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MGH Brain Tumor Center
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Patients & Families with questions about referrals, consultations or appointments may contact:
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Physicians with
questions may contact:
Tracy Batchelor, M.D.
Executive Director,
MGH Brain Tumor Center
Harvard Medical School
Mass General Hospital
MGH Cancer Center
NS @ MGHNS Diagnosis @ MGH
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