Research Summary Research topic:
Studying the role that neuropilin-2 (NRP-2) plays in causing angiogenesis linked to osteosarcoma Research results:
The possibility of slowing or stopping the progression of osteosarcoma tumors by blocking NRP-2 Patient care application of results:
Expanding the understanding of the molecular mechanisms that allow osteosarcoma tumors to progress, which will make possible new pharmaceutical treatments that, combined with existing chemotherapy and surgical interventions, will result in better patient outcomes
Simplified patient care application:
Smaller and less invasive tumors, increased limb salvage and better quality of life for patients with osteosarcoma
Fighting with and for Adolescent Osteosarcoma Patients
OREF grant recipient is reducing the threat of bone cancer
Osteosarcoma is the most common kind of bone cancer in children. Found mostly in teenagers, these tumors have a very high propensity for local invasion and distant metastasis. Nearly 1,000 new cases are diagnosed in the U.S. every year.
Despite treatment protocols that include intensive chemotherapy and surgical resection, osteosarcoma still recurs in more than 30% of treated patients, most commonly in the lung. Unfortunately, patient outcomes have not significantly improved in the last two decades.
In 2006, Bang H. Hoang, MD, received an OREF Research Grant that supported his study of the role that Wnt inhibitors play in the development of osteosarcoma. A 2011 OREF Career Development Grant is now providing him funding to build on that promising work.
“Although osteosarcoma is very common among teenagers, it is rare compared to other cancers,” explained, Dr. Hoang, associate professor in the Department of Orthopaedic Surgery at the University of California, Irvine. “That makes it much more difficult to obtain research funding from organizations like the National Institutes of Health (NIH) and the National Cancer Institute, which focus on more common cancers. Meanwhile, orthopaedic tumor surgeons like me know all too well how important it is to these young patients to move research forward.”
Neuropilin-2 and Osteosarcoma Growth
The molecular mechanisms that contribute to osteosarcoma progression are not well understood. Before more effective therapies for osteosarcoma can be developed, knowledge of how cancer cells release signaling molecules that cause normal tissue to trigger angiogenesis and, therefore, tumor growth is needed.
The Wnt signaling pathway is a network of proteins that affects various physiological processes, including cell differentiation and the development of cancer. Studies suggest the Wnt pathway is an important factor in osteosarcoma progression and metastasis. Preliminary data from Dr. Hoang’s first OREF-funded study indicate that Wnt proteins regulate osteosarcoma production of a member of the neuropilin family called neuropilin-2 (NRP-2).
“Our data suggest that NRP-2 is up-regulated in several osteosarcoma cell lines and NRP-2 knockdown suppresses in vivo tumor production,” said Dr. Hoang. “Other researchers have shown that NRP-2 expression in cancer correlates with increased tumor vascularity and a poor prognosis.”
These results form the foundation for his current research project, “Targeting Neuropilin-2 for Osteosarcoma Growth and Metastasis.” Neuropilins are multifunctional receptors that induce angiogenesis and tumor progression by acting as co-receptors for vascular endothelial growth factor (VEGF). Dr. Hoang is exploring the role of NRP-2 in the angiogenesis of osteosarcoma using both in vitro and animal models.
“Our objective is to understand how NRP-2 contributes to the pathophysiology of the disease. We hope our study leads to therapeutic strategies that will prevent tumor progression and metastasis,” said Dr. Hoang.
The first step is proving that NRP-2 is a target of Wnt signaling in vitro, using molecular techniques to introduce the protein into cell cultures and then introduce the inhibitors of the protein. “If inhibitors don’t succeed in slowing tumor growth, we’ll try to knock down or block the protein using molecular techniques. What we learn will be applied in the next stage, the mouse model,” explained Dr. Hoang.
That phase of the study involves injecting human tumor cells into nude mice to induce tumor growth in the tibia. The tumors will spontaneously metastasize from the bone into the lung. “At the end of the experiments we will examine the lungs and the tumors to study the effects of blocking NRP-2,” added Dr. Hoang. “Hopefully we’ll find further positive results.”
If NRP-2 proves to have a significant role in tumor growth and metastasis, blocking this receptor with antibodies or chemical compounds may lead to clinical trials for a second-line therapy, supplemental to standard multimodality therapy consisting of chemotherapy and surgical resection.
Dr. Hoang hopes other researchers will build on his results, possibly to design antibodies that can block the protein from activating the receptor. “Another approach would be to design mimic compounds that bind to the protein and prevent it from activating the receptor,” he said. “This would require screening a long list of compounds, some of which may already be available on the shelf.”
With more basic science knowledge about how osteosarcoma develops, Dr. Hoang is hopeful that further research will help reduce tumor burden, improve limb salvage and reduce metastatic disease. “I am optimistic that we will soon see strategies that will ultimately improve overall survival rates as well as quality of life for everyone with osteosarcoma,” he said.
Inspired by patient determination
Asked what inspired him in his work as a clinician scientist, Dr. Hoang related a story of treating a high school student who had just earned a lacrosse scholarship. The patient had an undiagnosed mass on his knee. A biopsy determined it to be a high-grade osteosarcoma. The patient asked Dr. Hoang if, with all the treatment options on the horizon, he might be able to return to playing lacrosse. “I told him, ‘most likely not. You probably won’t be able to play at that level,’” Dr. Hoang recalls.
Following chemotherapy and surgery involving implantation of a large prosthesis, the patient continued to see Dr. Hoang for annual checkups through college. The patient never mentioned athletics, and Dr. Hoang didn’t ask.
Several years later, the patient and his parents came to a reunion at the hospital for patient families. “I learned that the patient had played lacrosse not only for his varsity team, but at the NCAA level, and then went back to his high school and coached kids on his old team,” Dr. Hoang reported. “Whenever anybody asked him, ‘Where did you get that long scar on your leg?’ he said it was a shark bite. That tells you how determined this patient was—and is—that nothing will hold him back.”
Being moved by patients such as the lacrosse player, Dr. Hoang said, is what drives him to conduct research. “For people who have these kinds of diseases, hope is probably the biggest drive. It’s everything to them. To be able to offer them hope is very satisfying to me.”
Getting this satisfaction, according to Dr. Hoang, was made possible in part by his OREF grants. “Osteosarcoma, is not very high on the NIH agenda. OREF is making a statement by supporting it—that it is important for musculoskeletal research and for the patients who have these diseases. I think the support from the OREF Career Development Grant is very important in moving this osteosarcoma research forward.
Mark Crawford is a contributing writer for OREF and can be reached at firstname.lastname@example.org