Dr. Santiago Lozano-Calderon, 2019 recipient of SarcomaStrong research grant, and his team at Massachusetts General Hospital shed light on the genetics of extraskeletal osteosarcoma.

Sarcoma Strong interview with Dr. Lozano-Calderon by Gokul Kalyanasundaram, 2nd-year medical student at Albany Medical College

Learn more about Dr. Lozano-Calderon: https://www.massgeneral.org/doctors/19509/santiago-lozano-calderon

  1. How has the grant from Sarcoma Strong helped to advance your research?

In general, sarcomas are not common, and it is very difficult to start work on a specific sarcoma subtype because there are so few cases. Also, most agencies do not provide funding because there are not a lot of people suffering from sarcoma, so the funding may not have as much of an impact. My team is working on using a small particle of RNA that circulates in your body called microRNA to understand the genetics and characteristics of a rare sarcoma called extraskeletal osteosarcoma. Extraskeletal osteosarcoma is basically an osteosarcoma or a bone tumor that occurs in the soft tissues. Some people treat extraskeletal osteosarcoma as a soft tissue sarcoma meaning that patients receive radiation therapy and surgery. Other people treat extraskeletal osteosarcoma as an osteosarcoma of the bone, so patients receive chemotherapy and maybe radiation before surgery. Extraskeletal osteosarcoma is one of the rarest types of osteosarcoma, and since 1972, our department has only seen maybe 30 extraskeletal osteosarcomas. When I looked for funding for this project, the low incidence made it difficult. Therefore, the advantage of Sarcoma Strong is that pilot studies like this study can obtain funding. Then, the preliminary data can motivate other centers to either share their samples or collaborate on a larger study to come up with a better answer. 

  • What research studies led you to your current project?

Previously, we assessed the microRNA in patients that presented with pathologic fractures in osteosarcoma, and we were able to demonstrate that the markers in the patients with fractures were associated with a bad prognosis and decreased overall survival. We helped to clarify that when there is a fracture with osteosarcoma, the problem is not that the bone has broken and that the tumor is spreading all over the body. Instead, the problem is that the fracture itself is a manifestation of the aggressiveness of the tumor. This had been controversial, and our paper helped to clarify that.

  • What new questions remain unanswered in your research? What do you hope to find out in the next few years?

Currently, we are sequencing extraskeletal osteosarcomas along with conventional osteosarcomas and soft tissue sarcomas. Then, we will compare the extraskeletal osteosarcoma microRNA signatures to see if they are more similar to soft tissue sarcomas or osteosarcomas. This will help to determine the biology of these tumors. If we find that the extraskeletal osteosarcoma microRNA fingerprint is similar to the soft tissue sarcoma microRNA, we will advocate for treating extraskeletal osteosarcomas as a soft tissue sarcoma with preoperative radiation and then resection with negative margins. However, if we find that the extraskeletal osteosarcoma microRNA signature is similar to the osteosarcoma of bone microRNA, then this would be the basis for treating extraskeletal osteosarcoma patients with chemotherapy, radiation, and then surgery. Maybe some of the extraskeletal osteosarcomas are more similar to soft tissue sarcomas and others are more similar to bone osteosarcoma. Or maybe extraskeletal osteosarcoma is similar to only osteosarcoma, but some extraskeletal osteosarcomas have a microRNA signature that is characteristic of responding to chemotherapy and others have a microRNA signature that is characteristic of non-responders. After we identify important microRNAs, we will do further sequencing to identify mutated proteins that may be used to screen patients.

We recently participated in an international collaboration where clinical, demographic and treatment data were collected from patients diagnosed with extraskeletal osteosarcomas from several centers. Based on the clinical data, chemotherapy did not seem to help. However, a similar study was performed by several European centers and they found that chemotherapy provided benefit for patients. The clinical information is conflicting, but each paper may have some truth since some people may respond to chemotherapy while others do not. This microRNA analysis is a faster way to determine which extraskeletal osteosarcomas will respond to chemotherapy rather than enrolling many patients and waiting to see which patients respond and don’t respond to treatment. This is especially important because extraskeletal osteosarcomas are so rare.

  • How close are we to eventually applying this to patients? 

Our goal is to correlate the results that we get from the liquid biopsies from patients with the tumor characteristics, treatment response, and the oncological result after treatment. Hopefully, in five to eight years, patients will come for diagnosis, and in addition to getting a biopsy of the tumor itself, doctors will also get a liquid biopsy of their blood to identify circulating microRNA. The microRNA found in the circulation will hopefully help to guide management and determine which patients will respond to chemotherapy and radiation therapy. These individualized treatments will depend on each individual tumor and will replace current global treatments.

  • Can you talk more about how this current project will help your department receive NIH funding?

For NIH funding, we need to show that a new concept can solve a bigger problem. These microRNA experiments on osteosarcoma can eventually be applied to tumors other than osteosarcomas and this will help to individualize treatments for many types of cancer. To apply to the NIH, it is also important to show that we are capable of performing all of the necessary experiments correctly and efficiently. Ultimately, smaller publications and pilot studies will support our larger application to the NIH and make the argument that our department can really make progress on our basic science and clinical goals if the NIH chooses to fund us. 

  • How has the COVID-19 pandemic affected your research progress and goals?

The COVID-19 pandemic delayed the approval of the finances, so I was only able to receive the money from the grant 6 months after I was awarded the grant. Therefore, I had to ask for an extension to complete the project. Currently, I am still looking for samples and these have been difficult to retrieve during COVID-19 because the people that help to get the samples are non-essential workers. I’m hoping to get all of the samples by November so I can do the sequencing and run the analysis in December. 

  • Why are you interested in orthopedic oncology and sarcoma? What experiences brought you to become an orthopaedic oncologist?

I decided to become an orthopaedic oncologist during residency. Initially, I was planning to be a hand surgeon, but my mentor helped me to decide on orthopaedic oncology. I enjoy building a deep relationship with my patients and their family. It really keeps me grounded and makes me aware of our humanity. It makes me more grateful for things in my life because I see how easy it is to lose it. I also enjoy the breadth of orthopaedic knowledge necessary and the opportunity to collaborate with plastic, vascular, thoracic, and spine surgeons. 

  • Why should people donate to Sarcoma Strong?

Sarcoma Strong has a very high impact in the community by helping to get all of these ideas and projects out of the incubator. Sadly, the treatment of osteosarcoma has not changed significantly in the last 20-30 years. We improved survival 20-30 years ago when we started using chemotherapy and the survival rate went from 20% to around 70%. However, the advances in osteosarcoma since then have been very small because there is little funding for research. Pharmaceuticals are not interested because other tumors that are more common may represent a more viable investement from the financial stand point. Sarcoma Strong provides a platform for new studies, and these will lead to more advancement in the next 15-20 years.

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