"There is a tremendous need for advancement in the treatment of malignant brain tumors, which are the number one cancer killer of children under age 20 and a devastating diagnosis for adults as well," said Dr. John Laterra, M.D., Ph.D., research scientist at the Kennedy Krieger Institute and senior author of the study. "The results of this study bring us closer to developing an alternative treatment option for both adults and for pediatric patients, who are hardest hit by conventional therapies."
A team of researchers, led by Dr. Jin Kim of Galaxy Biotech, LLC in Mountain View, CA and Dr. John Laterra of the Kennedy Krieger Institute in Baltimore, MD, designed the study to evaluate the effectiveness of L2G7 in treating human gliomas implanted in mouse models. Results indicate that treatment with L2G7 completely inhibited the growth of the tumors when established under the skin of animals, while control mAb had only a minimal effect. Even more promising results were observed in mice with tumors implanted within the brain. In this setting, L2G7 not only induced tumor regression, but dramatically increased survival. Animals treated with the control all died within 41 days of starting the experiment. All mice treated with L2G7 survived through day 70, and 80% of the animals were alive at day 90, six weeks after stopping the L2G7 treatment.
L2G7 was developed by Dr. Kim's team to inhibit the activities of hepatocyte growth factor (HGF). HGF is known to be a promising target for cancer therapy by virtue of its multiple actions that promote cancer malignancy. HGF stimulates tumor cell division, tumor angiogenesis (blood vessel formation) and tumor cell resistance to toxic agents such as chemotherapy and radiation. In this study, brain tumor cells were injected both under the skin and within the brain to specifically evaluate anti-tumor responses within the central nervous system. The central nervous system is a location often protected from cancer therapies by the "blood-brain barrier," which could possibly limit the effects of mAb therapy on tumors situated within the brain. Treatment with L2G7 or a control mAb was given to both subsets of mice twice weekly.
In one experiment, the researchers delayed treatment of a subset of mice for 18 days to determine the effect of L2G7 on larger, more advanced tumors within the brain. At that time, the average tumor size was 26.7 mm3, but following only three doses of L2G7, tumors shrank to 11.7 mm3. Conversely, tumors treated with the control mAb grew 5-fold to 134.3 mm3 during the same period, with a mean volume 12 times larger than the L2G7-treated tumors.
"Monoclonal antibodies to growth factors or their receptors are playing an increasingly important role in cancer therapy," said Dr. Cary Queen, President of Galaxy Biotech. "Because of its specificity for HGF, L2G7 may prove to be particularly effective at halting tumor growth while minimizing side effects and harm to the surrounding healthy brain cells."
"Our company is committed to the clinical development of L2G7, and we hope to extend the current success of targeted antibody therapies in the treatment of breast, colon and lung cancer patients to the treatment of serious central nervous system malignancies such as gliomas."
In a related study (Lal et al., Clin Cancer Res. 11:4479-4486, 2005), Dr. Laterra's research team showed that targeting brain tumor HGF with gene therapy can substantially enhance the anti-tumor effects of radiation therapy, again emphasizing the important role HGF plays in brain tumors.
About Brain Tumors
Primary brain tumors originate in the brain. As the most common primary brain tumors, gliomas are the leading cancer killer of children under age 20, now surpassing acute lymphoblastic leukemia (ALL), and are the third leading cause of cancer death in young adults ages 20-39, according to the National Brain Tumor Foundation. Metastatic brain tumors (cancer that spreads from other parts of the body to the brain) occur at some point in 10-15% of persons with cancer. Each year, 190,000 people in the United States will be diagnosed with a primary or metastatic brain tumor. Because brain tumors are located at the control center for thought, emotion and movement, the effects of toxic modalities such as chemotherapy and radiation can be devastating, especially in young children. Surgery to remove malignant brain tumors is a complex and difficult procedure, and typically does not eliminate all of the cancer cells.
About the Kennedy Krieger Institute
Internationally recognized for improving the lives of children and adolescents with disorders and injuries of the brain and spinal cord, the Kennedy Krieger Institute in Baltimore, MD serves more than 12,000 children each year through inpatient and day treatment programs, outpatient clinics, home and community services and school-based programs. Kennedy Krieger provides a wide range of services for children with developmental concerns mild to severe, and is home to a team of investigators who are contributing to the understanding of how disorders develop and pioneering new interventions and earlier diagnosis. For more information on Kennedy Krieger Institute, visit www.kennedykrieger.org.
About Galaxy Biotech, LLC
A start-up company with laboratories in Mountain View, CA, Galaxy Biotech is developing humanized antibodies against growth factors and their receptors for the treatment of cancer. The company was founded by Dr. Jin Kim, who while a senior scientist at Genentech, Inc. developed the mouse mAb from which the approved drug Avastin® was made, and by Dr. Cary Queen, who previously co-founded PDL BioPharma, Inc. and developed fundamental technology for the humanization of antibodies.
Journal
Clinical Cancer Research