PI3K Inhibitors Promising for Rare Bone Cancer Therapy


Genome analysis points to potential new treatments for patients with chordoma.

An existing drug class may be able to treat rare bone cancer of the skull and spine, according to a study published by Nature Communications.

The authors discovered that certain patients with chordoma have genetic mutations that can be targeted with PI3K inhibitors. These findings may call for clinical trials of PI3K inhibitors in patients with the rare cancer, according to the study authors.

The Chordoma Foundation reports that the cancer is diagnosed in 1 in 1 million people per year, meaning that just 300 Americans are diagnosed annually. Chordoma typically forms in the bones of the skull base and the spine and tends to grow slowly. It is thought that the tumors develop from persistent embryonic tissue. In up to 40% of patients, the disease metastasizes to other parts of the body, according to the foundation.

Since chordomas affect the brain stem, spinal cord, nerves, and arteries, treating the disease can be challenging. Currently, treatment options are limited to surgery and radiation, underscoring the need for additional options.

In the new study, the authors used whole genome sequencing and analyzed tumors from 104 patients with chordoma to better understand the biology of the disease.

The investigators discovered that 16% of tumor samples had PI3K signaling mutations, according to the study.

“By sequencing the tumours’ [sic] DNA, we get a much clearer view of the genetic changes that drive chordoma,” said co-first author Sam Behjati, PhD. “We have shown that a particular group of chordoma patients could be treated with PI3K inhibitors, based on their mutations. This would have been missed had we not done genomic sequencing of their tumours [sic].”

The authors report that PI3K inhibitors target these mutations and are currently approved to treat cancers such as breast, lung, and lymphoma. It has not been previously explored as a potential therapy for chordoma, according to the study.

“These findings represent a major step forward in understanding the underlying causes of chordoma, and provide hope that better treatments may soon be available for some patients,” said Josh Sommer, chordoma survivor and executive director of the Chordoma Foundation.

The brachyury gene—sometimes called the T gene—has been known to play a role in chordoma; however, the authors discovered that only 1 additional copy of the gene increases cancer risk, according to the study.

Additionally, the authors discovered the LYST gene, which is specific to chordoma and not involved in any other cancers. This finding suggests that additional research is needed to determine how LYST can increase cancer risk, according to the authors.

Overall, the results suggest that PI3K inhibitors may be an effective therapy for this type of cancer that is in need of new treatment options, the study concluded.

“This study provides a resource for chordoma research for years to come,” said co-lead author Adrienne Flanagan, MD, PhD. “In the future, we hope to target chordoma from three angles: trialling PI3K inhibitors in chordoma; developing a therapeutic approach to switching off the extra copy of the T gene and studying the function of LYST as a cancer gene and its role in the development of chordoma.”

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