In two papers published in prestigious journals within the past two months, research teams from Harvard and University College London both found that the mTOR pathway was activated in the majority of chordomas; a significant finding that could potentially lead to new treatment options.

Dr. Vijaya Ramesh and colleagues at Harvard published Aberrant hyperactivation of akt and Mammalian target of rapamycin complex 1 signaling in sporadic chordomas in the journal Clinical Cancer Research, while Dr. Adrienne Flanagan and colleagues at University College London and the Royal National Orthopaedic Hospital Stanmore published Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway in the British Journal of Cancer. Taken together, these two papers add chordoma to the growing list of cancers in which the mTOR pathway is activated, and indicate that the mTOR pathway may be a promising therapeutic target for chordoma.

The mTOR pathway is comprised of several different cellular proteins that work together to transmit signals that stimulate cancer cells to grow. Activation of this pathway can promote the development and progression of cancer. Two drugs capable of inhibiting the mTOR pathway are already approved to treat advanced kidney cancer, and are in clinical trials for a number of other types of cancers. Plus, new and more potent mTOR pathway inhibitors are also in development. Therefore, these findings could mean new treatment options are on the way for chordoma patients.

At the First ICRW in May 2007 Dr. Ramesh presented preliminary data hinting that mTOR was activated in ten chordomas that she studied.  Dr. Ramesh had previously published a case report of two children with a genetic disease called Tuberous Sclerosis Complex (TSC) who also developed chordomas. TSC is caused by inactivation of genes that regulate mTOR, suggesting that the mTOR pathway may play a role in chordoma development. After reading this paper Simone prompted Dr. Ramesh to test this hypothesis on other chordomas. The only problem was that Dr. Ramesh didn’t have access to chordoma tissue. So Simone brokered a collaboration with leading chordoma pathologist, Dr. Andrew Rosenberg (coincidentally, located just a few blocks away at Massachusetts General Hospital), who agreed to provide the ten samples for her study.

Then eleven months later at the Second ICRW Dr. Ramesh, as well as Dr. Nadege Presneau from Dr. Flannagan’s lab and three other researchers presented complementary data independently confirming that the mTOR pathway was indeed active in most chordomas. As a result the mTOR pathway was identified by the group as a major focus for future research. See ICRW2008 summary

Springboarding on information presented at the international chordoma research workshops, researchers in Italy launched a small off-label trial using an mTOR inhibitor in combination with Gleevec. A publication reporting the results of this study is forthcoming very soon.

It’s too early to tell whether the mTOR pathway will be an Achilles heel for chordoma, but it certainly seems to provide a promising new target for oncologists to exploit as they wage war against this tenacious disease.

The Chordoma Foundation sincerely thanks Dr. Ramesh, Dr. Flanagan and all of their collaborators for the important contributions they have made to our knowledge of chordoma, and for sharing their data openly with colleagues at the International Chordoma Research Workshops. Congratulations on these noteworthy publications.