Researchers Identify Potential Therapeutic Target in Osteosarcoma
M. D. Anderson findings suggest a key role for interleukin-11 receptor alphaM. D. Anderson News 02/27/09
A receptor known to be active in bone metastases, but previously unexplored in primary bone tumors, is a potential therapeutic target in osteosarcoma, investigators from The University of Texas M. D. Anderson Cancer Center report in the March 1 issue of Cancer Research.
The researchers found that the protein - interleukin-11 receptor alpha (IL-11Ra) - is highly expressed in primary osteosarcoma and in lung metastases from these tumors. Their research suggests the possibility of delivering therapeutic agents directly to osteosarcoma cells by targeting the receptor with circulating particles that display a peptide mimic of the natural ligand that binds IL-11Ra.
Osteosarcoma is the most common primary malignant tumor of bone. "Existing treatment has not changed the prognosis for osteosarcoma for the last 20 to 30 years," said lead investigator Valerae O. Lewis, M.D., associate professor and chief of Orthopedic Oncology at M. D. Anderson. "About 30 percent of patients still relapse and die of their disease. New therapeutic strategies and agents are needed."
The effectiveness of the current chemotherapy regimens for osteosarcoma is limited by toxic side effects, including damage to the heart and nerves, kidney failure and hearing loss, Lewis noted. Identification of a target specific for osteosarcoma cells opens the door for the development of therapies that can shut down the tumor cells without inflicting the collateral damage caused by conventional osteosarcoma treatments.
IL-11Ra is a target in bone metastasis; far less is known about its attributes, if any, in primary tumors of bone. To address IL-11Ra as a potential molecular target in osteosarcoma, the authors confirmed the protein expression and localization of IL-11Ra in several mouse and human osteosarcoma cell lines.
In an orthotopic mouse model of human osteosarcoma, the investigators found that the IL-11Ra not only was markedly present in the primary osteosarcoma and in its metastases but was absent from normal bone marrow and lungs.
To evaluate the accessibility of IL-11Ra as a target, the researchers intravenously administered small, virus-like particles called phages equipped with a peptide that mimics IL-11, the receptor's natural ligand. After 24 hours in circulation, the ligand-directed particles were taken up in the tumors but showed little or no accumulation in several control organs.
"Connecting therapeutic agents to this ligand-directed system might result in improved, targeted drugs," said co-senior author Renata Pasqualini, Ph.D., Professor of Medicine and Cancer Biology in the David H. Koch Center at M. D. Anderson.
"It is conceptually unexpected that a receptor would be over-expressed not only in metastatic tumors to bone but also in primary bone tumors; this is quite important because human osteosarcoma is a malignant tumor with very few targets at the protein level," said co-senior author Wadih Arap, M.D, Ph.D., also Professor of Medicine and Cancer Biology in the David H. Koch Center.
Immunohistochemical staining analysis of IL-11Ra expression in primary and metastatic human osteosarcoma samples provided further evidence of the potential value of IL-11Ra as a therapeutic target. All primary human osteosarcoma samples exhibited moderate-to high-intensity staining of tumor cells. More than half of tumor blood vessels also showed moderate-to-high-intensity staining. All pulmonary metastases were positive for IL-11Ra expression, while normal, control lung tissue was negative.
"This indicates that therapeutic targeting of IL-11Ra may yield anti-tumor, anti-metastasis and anti-angiogenesis effects in osteosarcoma," Lewis said.
Phase I trial of IL-11R for bone metastasis
The U.S. Food and Drug Administration recently issued "safe to proceed" status for an M. D. Anderson-sponsored investigational new drug based on a cell-death-inducing therapy directed at IL-11R. The drug is defined as BMTP-11 (Bone Metastasis Targeting Peptide 11). The first clinical trial, in which BMTP-11 will be evaluated in prostate cancer patients, will soon be activated.
Lewis noted that the research group has initiated pre-clinical studies to measure potential anti-tumor effects of BMTP-11 in osteosarcoma models. If successful, such efforts may lead to a rapid evolution of BMTP-11 toward the management of osteosarcoma.
Research was funded by an M. D. Anderson Institutional Research Grant and a Robert Wood Johnson Foundation grant to Lewis and grants from the National Institutes of Health, the U.S. Department of Defense, the Gillson-Longenbaugh Foundation, and the Marcus Foundation, to Arap and Pasqualini.
Co-authors with Lewis, Arap and Pasqualini are Michael G. Ozawa, in the David H. Koch Center M. D. Anderson and an M.D./Ph.D. student in the Graduate School of Biomedical Sciences, operated jointly by The University of Texas Health Science Center at Houston and M. D. Anderson; Guiyang Wang, of the Department of Orthopedic Oncology; Michael T. Deavers, M.D. of M. D. Anderson's Department of Pathology; and Tamaki Shintani, D.D.S., Ph.D., of M. D. Anderson's Department of Radiation Oncology.