(From the July 2014 Issue of PediatricsOnline)
Studies of a viral therapy currently in clinical trials could improve the therapy’s effectiveness in treating medulloblastoma, the most common malignant brain tumor in children. The modified treatment uses an altered measles virus to kill cancer cells and inhibit growth of new blood vessels. If the newly engineered virus makes it into clinical care, it could one day reduce the need for toxic treatments, such as chemotherapy and radiation therapy.
The therapy uses a version of the measles virus loaded with two anti-angiogenic proteins and was more effective than the measles virus alone at preventing cancer growth in mouse models, according to a multi-institutional research effort led by scientists at Nationwide Children’s Hospital.
The two added proteins, endostatin and angiostatin, are native to the human body and fight the growth of cancer enhanced by angiogenesis — the formation of blood vessels and infrastructure that highly vascularized tumors, such as medulloblastoma, depend on for growth. Giving the body a “boost” by providing extra anti-angiogenic proteins in the right places helps cut off the tumor’s supply of growth factors, the researchers say.
“The virus itself is already very efficient at killing tumor cells, so the challenge we had was demonstrating that inhibition of angiogenesis significantly improved our therapy compared to viral treatment alone,” says Adam W. Studebaker, PhD, a researcher in the Center for Childhood Cancer and Blood Diseases in The Research Institute and senior author on the paper, published in BMC Cancer in March. “We wanted to find out whether a virus that included these potent anti-angiogenesis proteins would inhibit the tumor above and beyond what the virus itself did.”
The team found that the oncolytic measles virus injection engineered with the two proteins (called MV-E:A) was equally effective at killing cancer cells as the control measles virus injection, but MV-E:A further improved survival and reduced angiogenesis.
“Medulloblastoma is a very vascular tumor,” Dr. Studebaker says. “We think combining the anti-angiogenesis expression with the measles viral therapy will lead to better therapeutic potential of the virus.”
The measles virus used by Dr. Studebaker and his team is the same strain commonly used for vaccinations and is widely considered safe. It chooses its targets by searching for certain signals that happen to be expressed almost exclusively by cancer cells, so it preferentially infects and kills tumor cells, leaving normal cells unharmed. The measles virus also replicates easily and rapidly, allowing it to infect and kill neighboring tumor cells.
“Its ability to replicate and keep fighting tumor cells is critical,” says Dr. Studebaker. “The measles virus with embedded endostatin and angiostatin can provide a continual supply of angiogenesis inhibitors as long as it is actively replicating.”
This allows MV-E:A to overcome the barrier of short-term effectiveness of directly administering an injection of endostatin and angiostatin alone. Since the measles virus replicates to fight tumor cells as long as the cancer is present, MV-E:A can now also keep producing and expressing the two anti-angiogenic proteins added into its genetic code, providing a steady dose of angiogenesis inhibitors to the cancer.
Further work on measles viral therapy for medulloblastoma, including additional studies on the anti-angiogenesis protein expression of the virus, will continue under the leadership of Dr. Studebaker’s former colleague, Corey Raffel, MD, PhD, now at the University of California, San Francisco.
“My belief is that viral therapy in general is a very novel and effective means to target and treat pediatric brain tumors in an arena where most of the therapy children currently receive is detrimental or doesn’t work,” Dr. Studebaker says. “Very few people are currently pursuing viral therapy for brain tumors, but I think it is very feasible and has great potential for eventual clinical applications.”
Hutzen B, Bid HK, Houghton PJ, Pierson CR, Powell K, Bratasz A, Raffel C, Studebaker AW. Treatment of medulloblastoma with oncolytic measles viruses expressing the angiogenesis inhibitors endostatin and angiostatin. BMC Cancer. 19 Mar 2014, 14:206