Orthopedic Oncology Research
Chondrosarcoma is the only primary bone cancer without an effective systemic treatment, resulting in a survival rate of only 10 to 25 percent. Unlike other forms of bone cancer such as osteosarcoma or Ewing’s sarcoma, chondrosarcoma is resistant to radiation and chemotherapy treatments. Surgery to remove the tumor is the only treatment, so the cancer has a poor prognosis, with most patients succumbing to lung metastases.
Richard Terek, MD, of the Lifespan Orthopedics Institute, has been working to find novel approaches to treat this devastating disease. With a $1.4 million, five-year research grant from the National Cancer Institute of the US National Institutes of Health to study bone cancer, the goal of his research project is to identify molecular targets for treatment of chondrosarcoma.
As a physician/scientist, Dr. Terek has worked on chondrosarcoma in the laboratory for over 20 years, having studied and analyzed these tumors for mutations in classic tumor suppressor genes, mechanisms of chemotherapy resistance, and regulation of metastatic pathways. As a surgeon, he performs limb-sparing surgeries to remove bone and soft tissue tumors and to then reconstruct the musculoskeletal system.
Primarily affecting adults, chondrosarcoma is composed of malignant cartilage cells. The research project seeks to determine how the processes of angiogenesis and metastasis are regulated in chondrosarcoma, with the goal of developing anti-angiogenic treatment strategies. Angiogenesis refers to the mechanisms by which tumors induce formation of the blood vessels necessary for tumor growth. Metastasis is the spread of tumor from the primary to a distant site, which for chondrosarcoma is most commonly the lungs.
The molecular mechanisms of metastasis in this tumor are unknown. There does not appear to be a single molecular genetic basis for these tumors, so there is no well-defined molecular target that can be exploited for diagnosis or treatment. Understanding the biology of the disease may allow for the development of targeted therapy so that tumor growth and metastasis can be inhibited.
Identifying Molecular Targets for Treatment
Dr. Terek’s current research focuses on microRNA-regulated metastatic pathways and nanotechnology as avenues for developing therapies and strategies to inhibit metastasis. Specifically, it focuses on modulating expression of specific microRNAs (cellular noncoding RNAs that regulate gene expression through interaction with messenger RNA) to inhibit tumor growth and metastasis.
Candidate microRNAs that were underexpressed or overexpressed in tumors were identified using microarray analysis to compare microRNA expression between primary chondrosarcoma tumors, chondrosarcoma cell lines cultured under hypoxic conditions, and normal cartilage. Building on prior work related to over-activity of C-X-C chemokine receptor type 4 (CXCR-4) in chondrosarcoma, microRNA 181a was found to be overexpressed and to enhance CXCR4 signaling by inhibiting RGS16 (regulator of G-protein signaling protein sixteen), which has an inhibitory effect on CXCR4 signaling.
Although we may have been taught in grade school to avoid use of double negatives, biology is rife with examples like this. By inhibiting an inhibitor, miR-181a enhances CXCR signaling, which in turn promotes expression of pro-angiogenic and pro-metastatic factors, thereby making miR-181a an oncomiR (a microRNA associated with cancer). The objective of the study is to further delineate how overexpression of miR-181a is linked to metastasis in chondrosarcoma, and determine its appropriateness as a therapeutic target.
To translate these findings to a clinical application, Dr. Terek collaborates with Qian Chen, PhD; Hongchuan Yu, PhD; and Yupeng Chen, PhD; (all are investigators in the Orthopedic Research Laboratory at Rhode Island Hospital) to utilize nanotechnology to deliver antagomirs, which are nucleotide sequences that inhibit miR-181a function, in a mouse chondrosarcoma model. The researchers hope their efforts result in the first biologically targeted therapy for chondrosarcoma.