Aberrant Motor Regulation in Chordoma

One of the most challenging aspects of chordoma treatment is adequate control of primary disease. Recurrence is common, metastases occur in as many as 40% of treated patients, and survival has been estimated to be only 40% at 10 years. Chordoma has proven relatively insensitive in chemotherapeutic and radiation trials. High-dose fractionated radiotherapy has been shown to improve overall survival, but it is often limited due to highly radio-sensitive adjacent nervous structures.

Recent advances in targeted molecular therapeutics, however, offer promising new avenues by which novel treatments for chordoma could be developed. To better understand molecular mechanisms involved in the origin and perpetuity of chordoma after treatment, we are studying the canonical signaling pathways that have been shown to be involved in chordoma, including PI3K/AKT, PTEN, and mTOR signaling. In particular, mTOR signaling is an attractive target to study, given that tuberous sclerosis proteins tuberin and hamartin function to inhibit the mTOR pathway. Tuberous sclerosis is the only known genetic syndrome with an increased incidence of chordoma. We examined mTOR genes that act upon the tuberous sclerosis complex at the transcriptional and translational levels using quantitative real-time PCR, western immunoblot, and immunofluorescence.

In our western immunoblot analysis, we found elevated p70 S6K protein expression in two primary human chordoma samples. p70 S6K is a serine/threonine kinase that is activated through phosphorylation by mTOR complex 1 to regulate translation. p70 S6K plays an important role in G1 cell cycle progression and cell growth. Interestingly, p70 S6K is tightly suppressed in human embryonic stem cells, and increased levels of expression induce differentiation in these cells. We are currently examining the role of p70 S6K in the tumorigenesis of chordoma.

We are also examining other potential mechanisms of dysregulation of the mTOR complex 1. Several microRNAs have been predicted to be involved in p70S6K regulation. We performed a microRNA microarray on primary patient samples to examine microRNA expression levels in primary human chordoma samples. In particular, microRNA 539 was overexpressed in chordoma samples compared with normal levels of expression. In vitro studies of microRNA overexpression in chordoma cell lines are ongoing.