Kinase Activity in Recurring Primary Chordomas and Chondrosarcomas: Identification of Novel Pathways of Oncogenesis and Potential Drug Targets

 

Background: Chordomas and chondrosarcomas are tumors that occur in the skull base. The primary clinical treatment for these neoplasms is surgery, while the role of adjuvant therapy remains highly debated. Some reviews have concluded that chordomas are radiotherapy resistant. In addition, no pharmacotherapies have been approved by the FDA for chordomas or chondrosarcomas. Currently, 45% of chordomas and 56% of chondrosarcomas recur within five years of surgery. The high propensity for recurrence and lack of definitive adjuvant therapy necessitates additional basic science research to identify molecular anomalies associated with recurrent disease to allow clinicians to target specific markers with pharmacotherapy.

Methods: We pooled tumor lysates from patients based on clinical criteria into four groups: benign primary chordomas, primary chordomas that eventually recurred, benign primary chondrosarcomas, and primary chondrosarcomas that eventually recurred. All tumors were from the skull base. We then used a peptide labeling method, iTRAQ, to uniquely identify each tumor group. Phosphorylated peptides were isolated, and then quantified via mass spectroscopy to determine the active kinases.

Results: Six groups of phosphorylated peptides were associated with primary tumors which recurred. The specific kinases associated with primary chordomas that eventually recurred were FES and FER. The specific kinases associated with primary chondrosarcomas that eventually recurred were FES, FER, SRC family kinases, PKC, Rock, and MAPK signaling (JNK, ERK1, p38).

Conclusion: These data provide clinicians with a means to screen skull base chordomas and chondrosarcomas to help identify tumors which may have a propensity to recur. By identifying these tumors early, additional medical interventions can be used to prevent recurrence and improve patient outcome. Also, many of these kinases can be efficaciously inhibited by FDA approved drugs that have not yet been used in clinical trials specifically for chordomas and chondrosarcomas, and thus may advance the treatment options for patients with these diseases.