The National Cancer Institute has awarded City of Hope researchers a five-year, $1.2 million RO1 grant to investigate and develop a cancer treatment that targets a cellular pathway associated with diabetes complications that is also active in brain tumors.
|Badie, left, leads investigations aiming to deploy the immune system against brain tumors. (Photo ©2005 Philip Channing)|
Behnam Badie, M.D., chief of the Division of Neurosurgery and director of the Brain Tumor Program, is principal investigator on the grant, which supports research into turning the body’s own defenses against brain cancers like glioma. This work may have implications for the fight against other cancers, as well.
“Current treatment options for brain tumors can be limited due to the sensitive location of the cancer and the body’s natural protective barriers,” Badie said. “My research has focused on using the immune system to fight cancers, and one of the ways we are trying to do that is by investigating an inflammatory process most often associated with diabetes.”
The seeds of the research grew out of Badie’s lunch conversations with a colleague, Samuel Rahbar, M.D., Ph.D., distinguished professor in the Division of Diabetes, Endocrinology & Metabolism. The scientists were discussing harmful substances called advanced glycation end products (AGEs).
In people with diabetes, too much sugar circulates in the blood, and AGEs form when this excess sugar binds to molecules in the body.
AGEs can then activate what are called receptors for advanced glycation end products, or RAGE. Activating RAGE can kick off inflammation, part of the immune system’s response to infections, damage or injury. It is a natural process that can lead to healing, but chronic inflammation in patients with diabetes can lead to deadening of nerve sensation, vision loss and congestive heart failure.
Badie recognized similar biochemical activity in brain tumors and suspected that RAGE activation in brain tumors might also activate immune cells known as macrophages, which seek to attack and destroy damaged or faulty cells, like cancer cells.
But in gliomas the opposite was found. Brain tumors protected themselves by shutting down macrophages through RAGE activation. The research team suspects the cancer cells may do this through a protein called SB100B. Gliomas, as well as melanomas, express high levels of SB100B, a protein that interacts with RAGE.
Badie is collaborating with colleagues Rama Natarajan, Ph.D., National Office Products Industry Professor in Diabetes Research, Jana Portnow, M.D., assistant professor in the Department of Medical Oncology & Therapeutics Research, and Christine Brown, Ph.D., assistant research professor in the Department of Cancer Immunotherapeutics and Tumor Immunology, to stop glioma’s chemical blockade and restart RAGE activation of the macrophages.
“The grant will enable us to further our understanding of RAGE activation in gliomas and melanomas,” Badie said, “and help identify drug targets that can block RAGE and activate the immune response to the cancer cells.”
Researchers take an up-close look at tiny tubes
The U.S. government’s Nanotechnology Characterization Lab (NCL) will conduct studies on a nanoparticle developed by City of Hope for the treatment of brain tumors.
Current research is driven by Behnam Badie, M.D., chief of the Division of Neurosurgery, and Jacob Berlin, Ph.D., assistant professor in the Department of Molecular Medicine.
The scientists aim to reprogram immune cells called macrophages to attack glioma cells by using the minute molecules. Carbon nanotubes 100,000 times thinner than a human hair are used to carry a cargo molecule into the macrophages, at which point the cargo activates the cells to attack cancer cells.
Badie has demonstrated in previous testing that the nanoparticles can lead to eradication of brain tumors in laboratory models.
“NCL has chosen to support our research by performing concurrent studies that are about a year’s worth of work, helping us to develop this potential nanoparticle therapy quicker,” said Badie. “I believe this will be the first nanotube-based technology they will have tested.”
The NCL was established as a joint program of the National Cancer Institute, the U.S. Food and Drug Administration (FDA) and the National Institute of Standards and Technology to test nanoparticles intended for cancer therapy. The government laboratory is a premier facility for the evaluation of nanoparticles’ structure and safety that is necessary to proceed with FDA review.
For more information on the NCL, visit http://ncl.cancer.gov.