New review suggests approaches toward better, more personalized chordoma treatments

Dan Freed, PhD, at Chordoma Foundation Labs

New therapies are urgently needed when surgery and radiation are no longer appropriate options for the treatment of chordoma, which is often resistant to conventional chemotherapy. The Chordoma Foundation is taking a systematic approach to tackling this challenge, and in a new review article, we present some ideas for how the chordoma research community can efficiently identify more effective and personalized treatments.

“Chordoma research is at a turning point,” says Dan Freed, PhD, Head of Target Discovery and Translational Research, who authored the paper alongside our Executive Director Josh Sommer and Senior Research Associate Nindo Punturi. “We now have the critical pieces in place — a robust research community, resources like tumor samples and disease models, and capacities like our Drug Screening Program — needed to quickly advance our knowledge of how chordoma behaves, what its vulnerabilities are, and how to target them,” he says. The new review highlights several promising research avenues that can open the door to better therapies:

• A fuller, more meaningful picture of chordoma biology. Traditional genomic profiling has limited utility for this disease because fewer than about 15% of chordomas have actionable genomic mutations. Instead, an approach to understanding chordoma biology called “multi-omics” integrates layers of information including and beyond genes — like RNA and proteins — to create a comprehensive view of the biological systems fueling tumor growth. This could ultimately lead to a better understanding of the processes driving chordoma tumors, how tumors differ across individuals, and which patients are likely to benefit from different treatments. To this end, we’re currently supporting a portfolio of complementary multi-omics projects (e.g., at NYU Langone Health and theUniversity of Minnesota and German Cancer Research Center) and are poised to follow up on their findings through our Drug Screening Program.

• Immunotherapies. Immunotherapies have revolutionized treatments for certain cancer types, and several immunotherapy approaches may benefit chordoma patients, too. To understand how to deploy the best immunotherapies in the right situations, a better understanding of the chordoma immune landscape is needed, which some of our current grantees are pursuing.

• Combination therapies. Using multiple drugs in combination can work to synergistically increase the magnitude and duration of treatment response, and identifying effective therapeutic combinations may hold the key to promoting durable, long-term disease control. In addition to the strategies we’re currently pursuing through our Drug Repurposing Initiative, the new article suggests new strategies — like experiments called anchor screens, which can help us understand how therapy resistance occurs and identify drug combinations that could be effective against chordoma.
• Advancing brachyury drug discovery efforts. Brachyury, the main Achilles’ heel of chordoma, belongs to a class of proteins that have traditionally been considered “undruggable.” However, attempts to discover drugs against brachyury are progressing steadily. The new article suggests new potential avenues for interfering with brachyury’s function. (And if these efforts are successful, resulting drugs may be repurposed for more common cancers in which brachyury is implicated, like breast, lung, prostate, and colon cancers.)

We see a future where these efforts could intersect to match the right patients with the right treatments: for example, a patient undergoing surgery could have their tumor profiled to predict prognosis; if they’re at high risk for recurrence or metastasis, their doctors could nominate treatments most likely to work against their particular chordoma subtype should their tumor recur — a strategy that’s been demonstrated with success in breast cancer, for example.

“Some of the approaches we discuss in our review are well underway, and some we’re just starting to think about,” says Dr. Freed, “but we’re on the path to being able to treat chordoma in far more sophisticated and personalized ways.” He adds, “As the research community identifies promising therapeutic strategies, our capabilities within Chordoma Foundation Labs will enable new treatments to be marshaled toward the clinic more efficiently than ever.”

The article is part of a special issue of Frontiers in Oncology dedicated to advances against chordoma.