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Embarking on a systematic search for better ways to treat chordoma

We are optimistic that these efforts will soon uncover new opportunities to attack chordoma.


We're excited to announce that we have embarked on a multi-year partnership with the Center for the Science of Therapeutics at the Broad Institute of Harvard and MIT to systematically uncover new therapeutic targets for chordoma—aspects of chordoma’s biology that could provide opportunities to more effectively treat the disease. Our largest investment yet in target discovery, this project employs some of the most powerful tools available to find new therapeutic possibilities within a one to three-year timeframe.

Led by renowned Harvard professor and founding member of the Broad Institute, Dr. Stuart Schreiber, this project will draw on a breadth of expertise from within the Broad (rhymes with “road”) as well as collaborators at Dana-Farber Cancer Institute and Baylor College of Medicine. With an initial investment of $500,000 from the Chordoma Foundation, the Broad team and their collaborators will employ three complementary approaches to discover new therapeutic targets:

  • Genome-wide CRISPR loss of function screen
    Using a powerful new laboratory technique called CRISPR (commonly referred to as “genome editing”), the Broad team will systematically inactivate every single gene, one at a time, within chordoma cells to see which genes chordoma depends on for growth and survival. The genes that are identified will be compared to results from a wide variety of other cell types to reveal genes that are critical for chordoma but not for all cells. A drug that inhibits one of these chordoma-specific dependency genes would strike a lethal blow to chordoma cells while leaving healthy cells unharmed.
  • Small molecule sensitivity screen
    The Broad Institute has developed a collection of small molecules (drug-like chemical compounds) that are known to precisely target important nodes in cellular circuits that often go awry in cancer. Chordoma cell lines will be treated with this set of small molecules to identify the cellular circuits of chordoma that are vulnerable to perturbation. Results will be compared to nearly 1,000 other cell lines to identify vulnerabilities in chordoma that are not found across the board in other cell types.
  • Super-enhancer analysis
    A recently discovered phenomenon, super-enhancers are places within the genome where cells deploy a disproportionately large amount of the cellular machinery used to express (turn-on) genes. Super-enhancers tend to lie next to genes that are absolutely critical to the identity and survival of a cell. The reasoning goes that such genes are so essential that the cell must devote a large amount of its resources to ensure they are always produced. In several other types of cancer in which super-enhancers have been explored, researchers have found that super-enhancers are almost always found at the site of genes known to be key drivers of those cancers. The association is so strong that the presence of a super-enhancer at a gene can be interpreted as a signal that the gene is likely important to the cell. Thus, the Broad team will look for super-enhancer sites across the entire genome of chordoma cells in order to identify new genes that chordoma depends on for survival.

Applying these technologies will provide unprecedented insights into the genes and cellular processes that chordoma depends on for survival. But the real power of this project comes from combining results from all three approaches; this could reveal key vulnerabilities in chordoma that would not be apparent through any one of them alone. What’s more, these experiments will build upon data that has been produced through the ongoing Chordoma Genome Project to paint a more complete picture of how alterations in the chordoma genome translate into vulnerabilities that could be targeted to treat the disease. For example, we already know that brachyury is a key driver of chordoma, but therapies do not yet exist that can directly inhibit this target in patients. The hope is that this project will reveal vulnerabilities created by chordoma’s dependence on brachyury that could be more easily targeted.

We are particularly enthusiastic about working with the Broad on this project both because of its nearly unparalleled scientific capabilities and its track record of using similar approaches to discover vulnerabilities in other cancer types. Most importantly, however, the Broad is a unique place that brings together extraordinarily talented scientists from Harvard, MIT, and affiliated hospitals who share a deep and unusual commitment to collaboration in their efforts to accelerate the understanding and treatment of disease. In that spirit, the Broad team has formed a constructive partnership with a team of leading chordoma researchers at Massachusetts General Hospital. Furthermore, data and materials generated by the Broad team will be made available through public repositories to enable other researchers to quickly build upon their work.

We are optimistic that their efforts will soon uncover new opportunities to attack chordoma. Depending on the targets that are identified, this could provide a fast path toward new treatment options for chordoma patients—either with an already-approved drug or a drug that is in clinical development.

This project is made possible by a generous contribution from the family of a chordoma survivor. The family wishes to invite others in the chordoma community to join with them in supporting research needed to find a cure. To learn more about opportunities to invest in research, contact Josh via email or (919) 809-6779 x 102.

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