Research Summary Research topic:
Investigated the role of osteoclasts in promoting chondrosarcoma pathogenesis and whether inhibiting them would reduce metastasis and tumor growth in bone Research results:
Found that tumors cannot grow without osteoclasts and that inhibition of osteoclasts slows the growth of tumors in bone. Patient care application of results:
Pharmacological therapies that could slow the progress of chondrosarcoma Simplified patient care application
: Chondrosarcoma patients could have more options and live longer, with fewer fractures and less pain.
Chondrosarcoma: a black box turns grey
OREF grant recipient finds a way to slow tumor growth, buy time for surgical planning
Chondrosarcoma (CHS) is among the more dire diagnoses for patients, a black box for clinicians. That’s how orthopaedic surgeon Jesse E. Otero, MD, PhD, sees it—today. As a result of research Dr. Otero completed under a 2013 Orthopaedic Research and Education Foundation Resident Clinician Scientist Training Grant, new treatment options for CHS are possible.
“I couldn’t have done this work without the grant. OREF’s support was critical, and led to success. The study achieved excellent results and produced good pilot data for future research.” Dr. Otero said.
Perfect orchestration, interrupted
For now, CHS remains a devastating bone cancer. Locally aggressive and undeterred by current chemo and radiation therapies, CHS is usually treated with wide surgical excision. Even then, surgery often leads to local recurrence of the tumor, metastasis to the lungs and death.
“Bone is a dynamic organ system with many cellular and molecular components that are orchestrated perfectly in health,” Dr. Otero said. All that changes when CHS intervenes.
A case to build a practice
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.
Dr. Otero zeroed in on the micro-environmental factors contributing to the pathology of CHS—in particular, the osteoclast, the sole bone-resorbing cell.
“I noticed that everywhere there was tumor opposed to bone, there were tons of highly active osteoclasts,” Dr. Otero 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 determine what happens in the process of bone destruction to promote tumor growth and metastasis. It required delving into cellular and molecular biochemical processes and understanding the complex signaling mechanisms and hierarchies that cause osteoclasts to form and, with the help of transcription factors, differentiate.
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 pharmacological response to CHS that would brighten prospects for patients.
Building on colleagues’ 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, 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 research. Second, that study also yielded slurries of tumor cells, although they had at that point been frozen for some 10 years.
Dr. Otero’s first 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 specific aims:
• Establish in vivo the relationship between CHS and bone turnover; and
• Determine whether osteoclasts contribute to CHS pathogenesis.
To address the first aim, 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. Behavior was gauged by osteoclast-specific gene expression and serum biomarkers associated with bone turnover. This part of the study looked at biochemical responses of osteoclast cells and their role in triggering bone metabolism or degradation of bone matrix.
For the second aim, Dr. Otero tested two inhibition models, one pharmacological, one genetic. Pharmacological inhibition was attempted using zoledronic acid, effective in inhibiting bone turnover and tumor growth in an osteosarcoma model and approved for human use for treating metastatic cancer to bone. The genetic inhibition model measured bone turnover and tumor growth in a strain of animal subjects that naturally lack osteoclasts compared with a control group with osteoclasts.
Dramatic findings, new opportunities
Although Dr. Otero was unable to eliminate CHS tumors in subject animals, he stopped 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. “It’s the first time in my research that something I’ve discovered has had immediate implications for patient care.”
Dr. Otero’s study has opened the door to developing a pharmacological 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. Additionally, there may be hope, using this strategy, for patients who have unresectable tumor such as in the spine, pelvis, and sacrum.
As Dr. Otero summed it up, “We are accustomed to thinking of chondrosarcoma as a black box rather than a dynamic system, with many components that are potential targets for therapy. Our study has revealed some of those targets.”
Dr. Otero said he was grateful the OREF grant gave him an opportunity to make a difference in patient care early in his career.
“Giving promising young clinician investigators a chance to start their research career is OREF’s biggest strength,” Dr. Otero said. “I know of a lot of investigators who are very successful—funded by the National of Institutes of Health—who started with OREF grants and that’s really exciting”