Research Topic: Determined the capacity for inhibitors, such as Noggin, a natural BMP inhibitor and s-Flt, a vascular endothelial growth factor (VEGF) inhibitor, to decrease the growth and metastatic potential of osteosarcoma cells.
Research Results: Found that Noggin and s-Flt affect osteosarcoma cell growth and metastatic potential on a dose-dependent basis, which led to additional research on osteosarcoma cell metastasis
Patient Care Application of Results: Potential therapies that prevent osteosarcoma metastasis and, therefore, improve survival rates for osteosarcoma patients
Simplified Patient Care Application of Results: Improved survival rates for osteosarcoma patients
From Patient to Practice
Firsthand experience and OREF funding fuel efforts to prevent osteosarcoma metastasis
In 1989, at the age of 15, Kurt R. Weiss faced a grave prognosis.
He had been diagnosed with osteosarcoma (OS). Doctors surgically removed the tumors from his right leg and lungs, but unfortunately the cancer returned to his lungs, indicating that chemotherapy was ineffective. Kurt had, at best, a 20 percent chance of surviving to adulthood.
Although his leg would eventually be amputated due to complications, an experimental form of chemotherapy saved Kurt’s life, and his experience motivated him to become an orthopaedic oncology clinician scientist. Dr. Weiss, who received a 2007 Orthopaedic Research and Education Foundation (OREF)/DePuy Orthopaedic Resident Educational Grant (now called the OREF/DePuy Resident Research Project Grant), said chemotherapy increased the survival rate for patients like him to about 65 percent. Unfortunately, little has changed in the three decades since he was diagnosed.
“To my mind, chemotherapy has gotten about as good as it’s going to get. We have to fight smarter, and do a better job of understanding the biology of these primary bone tumors and what molecular mechanisms they are using to spread to the lungs,” Dr. Weiss said. “I want to be an expert in understanding how that happens because once it’s understood, then, perhaps it can be stopped.”
With the help of OREF, Dr. Weiss is well on his way to uncovering a treatment strategy that can prevent the spread of a cancer that once threatened to take his life.
Assembling the puzzle pieces
Dr. Weiss believes his passion for research and patient care has come together like puzzle pieces. The first piece developed out of the admiration he felt for the doctors he met as a young patient. Other pieces built upon that first one, taking shape as he pursued his goal of becoming an orthopaedic surgeon and researcher.
Dr. Weiss was still an undergraduate when he learned about gene therapy under the tutelage of Mayo Clinic researcher Christopher H. Evans, PhD. Dr. Evans was the first to use gene therapy in orthopaedics, specifically to treat rheumatoid arthritis patients by altering the diseased cells to produce a protein that interrupts the inflammation and joint destruction caused by interleukin-1 and other cytokines.
“I became a believer in the potential of gene therapy to offer safe, biologically-directed treatment,” Dr. Weiss said. “I also learned from Dr. Evans that the translation of discoveries from the benchtop to the clinic is an attainable reality.
After his first year in medical school, Dr. Weiss had the unusual opportunity to work with the doctor who developed the experimental chemotherapy that saved his life—Eugenie S. Kleinerman, MD, at the University of Texas—and also to learn more about cytokines.
Next came a year with Lee Helman, MD, the chief of molecular oncology at the National Cancer Institute. Dr. Weiss witnessed the ability to discover which cells confer the strongest levels of metastatic potential. This was a critical lesson for Dr. Weiss’ focus on OS because virtually all patients die not from the original bone cancer, but from the pulmonary metastases which are often resistant to chemotherapy. Anything that decreases the spread of OS to the lungs, he now understood, would increase the number of survivors.
During his residency with the University of Pittsburgh’s Department of Orthopaedic Surgery, Dr. Weiss worked under Johnny Huard, PhD. As he studied stem cells, growth factors, and orthopaedic basic science, the puzzle pieces came together for Dr. Weiss. He began to ask questions: Do OS cells with different metastatic rates produce different amounts of growth factors? If so, is there a way to block these factors with specific natural inhibitors?
The picture was finally clear: Dr. Weiss hoped to provide biologically-intelligent, anti-metastatic therapy to improve the survival rate for OS patients. But one piece was still missing: Who would fund his research?
OREF provides the bridge
Dr. Weiss’ preliminary research showed that highly metastatic OS cells (K7M2) produce more Bone Morphogenetic Protein (BMP) and vascular endothelial growth factor (VEGF) than less metastatic OS cells (K12). Dr. Weiss wanted to know if naturally occurring antagonist proteins—Noggin and S-Flt— could be administered to inhibit the production of BMP and VEGF, respectively, therby reducing OS cells’ ability to metastasize. Preliminary research showed promise, but did not show what concentration would be most effective at inhibiting OS cell viability and motility, and Dr. Weiss’ data weren’t yet developed enough to win support for further study from large foundations or federal grants.
“You need that in-between funding that gets you from point A to point B.” he said. “That’s what OREF support did for me.”
Under the OREF/DePuy grant, Dr. Weiss studied the effects of dosing cells with Noggin and S-Flt in vitro. Dr. Weiss and his research team subjected K7M2 and K12 cells to different concentrations of Noggin to learn if there was an optimal dose that could be used to inhibit the motility of these cells. The researchers also treated cells with S-Flt to understand whether it would inhibit VEGF to prevent OS cell growth.
The study showed that Noggin could diminish cell production of BMP and reduce cell motility and that S-Flt could decrease production of VEGF and reduce cell viability, but only in a dose dependent fashion. More Noggin and S-Flt had to be added every 48 hours to continue the effect. Without additional dosing, OS cells would overcome the inhibitors. However, the work strengthened Dr. Weiss’ portfolio and helped him to successfully write grants for the National Institutes of Health National Cancer Institute and the Sarcoma Foundation of America.
With this funding, Dr. Wess had a new target in mind for inhibiting metastasis of OS cells.
Aldehyde hydrogenase (ALDH) is a group of enzymes that protect cells from oxidative stress as they move out of one one part of the body, into and through the blood stream and enter another part. A simple experiment in which Dr. Weiss collected and observed the cells from patients with primary (non-metastatic OS) versus the cells from patients with metastatic OS showed that there was a perfect correlation between ALDH and metastatic OS. ALDH protected the bone cancer cells, allowing them to move from the bone to the lungs.
Disulfiram, an ALDH inhibitor that has been approved for other applications may be the key to preventing osteosarcoma from metastasizing. Dr. Weiss and his research team are now studying ways to combine ALDH inhibitors like disulfiram with other chemotherapy to enhance results and believe they are close to a phase I clinical trial.
Receiving funding is difficult for everyone, Dr. Weiss said, but can be particularly challenging for surgeon scientists “because we’re competing with people who do science full-time and perhaps don’t have the demands on their time that an orthopaedic surgeon does. And OREF understands that.”
Dr. Weiss never forgets his remarkable transition from patient to caregiver, from a boy who almost became a statistic to a clinician researcher who strives to improve the statistics. He is grateful, not just to his mentors and to funders such as OREF, but to everyone who believes that research is essential to the continued improvement of orthopaedic care and treatment.
“We’re a hardworking profession, but we’re also a hard-thinking profession,” Dr. Weiss said. “I give all the thanks in the world for people who don’t do research, but who see the value in it and support it.”