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-11R? 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.
Scott Merville | EurekAlert!
Further reports about: > BMTP-11 > Bone Metastasis Targeting Peptide 11 > Cancer > IL-11R > IL-11Ra > bone metastasis > chemotherapy > human osteosarcoma > interleukin-11 receptor alpha > lung metastases > osteosarcoma > osteosarcoma cells > osteosarcoma treatments > primary malignant tumor > pulmonary metastases > synthetic biology > toxic side effects > tumor cells
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy