Research Topic: Determining 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: Understanding of how inhibitors like Noggin and s-Flt affect osteosarcoma cell growth and metastatic potential.
Patient Care Application of Results: 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, MD, faced a grave prognosis.
He had been diagnosed with osteosarcoma. Doctors surgically removed the tumors from his right leg and lungs, but unfortunately the cancer returned to his lungs, indicating that chemotherapy was ineffective. Dr. Weiss 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 Dr. Weiss’ 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 himself 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 osteosarcoma 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 osteosarcoma 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 osteosarcoma 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 osteosarcoma patients.
But one piece was still missing: Who would fund his research?
OREF provides the bridge
Dr. Weiss’ preliminary research showed that administering the cytokine antagonist Noggin will alter the viability and motility of osteosarcoma cells. But his data weren’t yet developed enough to win support 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.”
The bridge funding he received as an OREF/DePuy Orthopaedic Resident Educational Grant recipient allowed Dr. Weiss to continue his research while also building his practice and teaching residents.
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.”
As a result of his OREF-funded research, Dr. Weiss has been able to secure larger grants from the Sarcoma Foundation of America, and the National Cancer Institute.
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 see the value in it and support it.”