Photo: Grantees Itai Yanai, PhD, Claudia Scholl, MD, and Mateusz Bujko, PhD
Investments in chordoma research are bearing fruit, with several therapies recently showing promise in clinical trials. However, our quest for more effective and personalized treatments for a greater number of chordoma patients remains urgent. To further this, we’re excited to share that we’ve awarded nine new grants to expert research teams in the US and Europe — deepening some of our partnerships with investigators at MD Anderson Cancer Center, NYU, and the German Cancer Research Center (DKFZ) with a proven track record in chordoma research, while also supporting talented scientists to bring their expertise to this field for the first time.
Totaling approximately $2 million, the projects take aim at three primary goals: better understanding the function of TBXT (also known as brachyury, the main Achilles’ heel of chordoma), identifying targets for therapeutic modalities that are directed to molecules on the cell surface, and uncovering aspects of chordoma biology that can point to new, more personalized treatment strategies. Together, these investments are set to generate important data with the potential to unlock new treatment options and pave the way for better care for chordoma patients.
Brachyury function in chordoma cells
Three complementary projects seek to better understand the behavior of TBXT (also called brachyury), which will be instrumental in guiding ongoing and future brachyury drug development:
Identifying how brachyury is turned on in chordoma. Brachyury is known to be universally expressed in chordoma, but the internal wiring that drives its expression is unknown. This $300K, two-year project led by Kadir Akdemir, PhD at MD Anderson Cancer Center aims to better understand how the configuration of DNA within tumor cells enables those cells to maintain expression of the TBXT gene, with the ultimate goal of shedding light on new ways to shut it off.
Studying how TBXT controls other genes. Much like an orchestra conductor, TBXT controls the expression of many other genes that support chordoma pathogenesis, but the molecular mechanics of how it does this remain poorly understood. With over $200K in support over two years, Sebastian Arnold, MD, and colleagues at Freiburg University will comprehensively study how TBXT exerts its influence on other genes which could lead to the identification of new therapeutic strategies.
Understanding which genes TBXT regulates. TBXT is known to control many other genes and cellular processes, but the full list has not yet been enumerated and variation between tumors remains unknown. With a $150K, one-year grant, Claudia Scholl, MD, of the German Cancer Research Center (DKFZ) and colleagues will use chemical biology tools to shut down brachyury in chordoma cells, allowing them to generate a detailed list of the genes and pathways regulated by TBXT and illuminate how cells adapt to TBXT suppression. By studying a panel of chordoma cell lines, the researchers aim to determine how different patients’ tumors might respond differently to emerging brachyury targeted therapies. And by determining the downstream genes through which brachyury acts, this project also has the potential to reveal additional therapeutic targets.
Surface target discovery
Several of the most promising emerging therapeutic modalities including antibody-drug conjugates (ADCs), radioligand therapies (RLTs), and cell therapies like CAR T cells work by focusing on markers found on the exterior of tumor cells. These markers can serve as beacons, allowing the therapies to target and deliver treatment directly to cancer cells without affecting normal cells, offering a more precise and potentially less toxic alternative to other drug therapy options. The following three grants aim to position chordoma patients to benefit from these new modalities:
Two new grants aimed at discovering chordoma surface targets. With a $300K, two-year grant, a team led by William Sellers, MD, Gad Getz, PhD, and Yuen-Yi (Moony) Tseng, PhD at the Broad Institute of MIT and Harvard will comprehensively characterize proteins on the surface of chordoma cells, seeking to discover single and paired proteins that could serve as targets for various immunotherapies and other next-generation cancer therapies. In parallel, with a $50K pilot grant, a team at the University of Pennsylvania led by Lin Zhang, MD, will apply a cutting-edge computational approach to identify surface proteins that could serve as attractive therapeutic targets.
Applying PC CAR T cell therapy to chordoma. A two-year, $300K project we’re supporting led by Matija Snuderl, MD and Mark Yarmarkovich, PhD at NYU, will explore how to apply a new immunotherapy approach called peptide-centric (PC) CAR T cell therapy to chordoma. The method involves engineering immune cells to target protein fragments, called peptides, displayed on the surface of cancer cells. We’re grateful to be able to co-fund this grant with the Cancer Research Institute, the world’s premier supporter of cancer immunotherapy research.
Other target and biomarker discovery projects
Finally, we’re funding several additional projects aimed at discovering new treatment strategies and biomarkers:
Understanding the role of cellular plasticity in treatment resistance. Itai Yanai, PhD, of NYU is a pioneer in the field of cancer cell plasticity — how cancer cells’ ability to transition between cell states may enable them to adapt to and resist treatments. Now, with a $325K, two-year grant, he and his team will apply their expertise and methods to chordoma with the goal of uncovering chordoma cell states, how chordoma cells transition between these states, and identifying ways to block these changes, potentially stopping their ability to resist therapies.
Building maps of the chordoma tumor microenvironment. In a $100K, one-year project we’re supporting, Shaan Raza, MD, Matei Banu, MD, and colleagues at MD Anderson Cancer Center will use matched tissue from newly diagnosed and locally recurrent skull base chordomas to build high-resolution maps of the chordoma tumor microenvironment before and after disease recurrence. They hope that comparing the cellular composition and metabolic programs of tumors at diagnosis and recurrence will identify features associated with disease recurrence, which may lead to new prognostic biomarkers to inform personalized disease management.
Investigating composition of chordoma tumors. With a $275K, two-year grant, a team led by Mateusz Bujko, PhD of the Maria Sklodowska-Curie National Research Institute of Oncology and Bartosz Wojtas, PhD of the Nencki Institute will use an array of advanced approaches to assess tumor heterogeneity at a single-cell resolution, which could lead to new understanding of how chordoma cells interact with the immune system, how they invade surrounding tissues adapt to their environment, and how these features might affect how different tumors respond to various therapies.
We’re deeply grateful to the many supporters whose generosity has made these investments possible, and to the research teams committed to partnering with us in our search for better chordoma therapies. We look forward to keeping you posted on our efforts to bring the next wave of treatments to chordoma patients, and encourage you to sign up for our newsletter for updates.