Chondrosarcoma (CHS) remains a devastating primary malignancy of the musculoskeletal system—a black box for clinicians. Locally aggressive and unresponsive to current chemotherapy and radiation therapies, CHS is usually treated with wide surgical excision. Even then, patients often experience local recurrence, metastasis to the lungs, and death. As a result of research Jesse E. Otero, MD, PhD, completed under a 2013 Orthopaedic Research and Education Foundation (OREF) Resident Clinician Scientist Training Grant, new treatment options for CHS are possible.

"The study achieved excellent results and produced good pilot data for future research," said Dr. Otero. "OREF's support was critical, and led to success."

Perfect orchestration, interrupted
Locally aggressive and undeterred by current chemotherapy and radiation therapies, CHS is usually treated with wide surgical excision; however, surgery often leads to local recurrence of the tumor, metastasis to the lungs, and death.

Dr. Otero first encountered CHS as a fourth-year medical student at Washington University during an elective rotation in surgical pathology, shortly after being matched to an orthopaedic surgery residency at the University of Iowa Carver College of Medicine.

"A remarkable specimen came into the lab: half a resected pelvis with a huge tumor. I took on the case," Dr. Otero recounted. "Learning the patient had CHS, and taking the specimen through decalcification and sectioning—it all seemed really brutal to me, especially since we know so much about cancer and have so many options for treatment."

The experience was formative for Dr. Otero. When his residency began and he was eligible for an OREF grant, he applied and obtained funding to study CHS further.

Osteoclasts key?
Dr. Otero zeroed in on the micro-environmental factors contributing to the pathology of CHS—in particular, osteoclast activity.

"I noticed that everywhere there was tumor apposed to bone, there were tons of highly active osteoclasts," he said. "I hypothesized that the osteoclasts were doing something to promote the tumor's pathogenesis."

Dr. Otero's study, which combined basic and translational research, was the first effort to examine how bone destruction, promote tumor growth, and metastasis relate to one another. The study required understanding the cellular and molecular biochemical processes and complex signaling mechanisms that promote osteoclast differentiation.

In the short term, Dr. Otero hoped to determine that inhibition of osteoclasts would reduce both CHS tumor growth in bone and metastasis. If successful, Dr. Otero theorized that further research would yield a pharmacologic response to CHS that would improve the prognosis.

Building on a colleague's work
Dr. Otero found a mentor and collaborator for his research in Jose A. Morcuende, MD, PhD, Marvin and Rose Lee Pomerantz Chair in Orthopaedic Surgery at the University of Iowa.

Thanks to a previous investigation directed by Dr. Morcuende, Dr. Otero was able to bring two important assets to his project. First, the earlier study had developed a proven rat model for CHS. Second, that study also yielded slurries of tumor cells, although they had at that point been frozen for 10 years.

Dr. Otero's initial step was to retrieve the tumor cells and test their efficacy. His attempt to subcutaneously grow tumors in test subjects from decades-old tumor cells succeeded.

Dr. Otero's study had two aims: establish, in vivo, the relationship between CHS and bone turnover, and determine whether osteoclasts contribute to CHS pathogenesis. Dr. Otero performed a series of three experiments in test subjects with and without bone tumors to detect osteoclasts and measure their behavior at the cellular level, and tested two inhibition models—one pharmacologic and one genetic.

Dramatic findings, new opportunities
Although Dr. Otero was unable to eliminate CHS tumors in subject animals, he did stop bone destruction.

"We found that inhibition of osteoclasts dramatically hampers the growth of the tumor in bone. The tumor cannot grow in the absence of osteoclasts," Dr. Otero said.

Dr. Otero's study has opened the door to developing a pharmacologic therapy capable of slowing the progress of CHS. If effective treatments emerge, surgeons will have more time to consider procedure options, and patients will live longer, possibly with fewer fractures and less pain. This strategy may also provide hope for patients who have unresectable tumors in the spine, pelvis, or sacrum.

Dr. Otero said he was grateful the OREF grant gave him an opportunity to make a difference in patient care early in his career.          

Sharon Johnson is a contributing writer for OREF. She can be reached at communications@oref.org