Expanding the Chordoma Surfaceome

Surface antigens are an established class of therapeutic targets, and interest in identifying and targeting them with new modalities has grown substantially over the past decade. In addition to full-length cell surface proteins, an emerging class of targets comprises peptide–MHC (pMHC) complexes, which present intracellular proteins on the cell surface. Because these peptides can be highly tumor-specific, pMHC-targeted therapies have the potential to greatly expand the range of druggable cancer antigens. However, their application is constrained by HLA restriction. Conversely, conventional cell surface proteins are not limited by HLA, but expanding the repertoire of truly tumor-specific surface antigens has proven challenging because many are also expressed in normal tissues.

Chordomas are rare sarcomas that arise from remnants of the embryonic notochord. A defining molecular feature of these tumors is overexpression of the transcription factor TBXT (brachyury), which is essential for tumor maintenance. Although considerable effort has been devoted to developing small-molecule inhibitors of TBXT, the protein has proven difficult to drug directly. Because TBXT expression is largely restricted to chordoma (and an increasing number of other tumor types), targeting TBXT-derived peptides presented by MHC represents a promising alternative strategy. Success in this area could not only transform chordoma therapy but also establish a broader paradigm for targeting lineage-defining intracellular TBXT through pMHC-directed approaches in multiple cancers.

Beyond TBXT, however, chordomas have a low mutational burden, and progress in identifying additional tumor-specific surface antigens has lagged behind that of many other cancers. Traditional discovery approaches based primarily on RNA expression have yielded relatively few compelling candidates, highlighting the need for new technologies that interrogate the surfaceome more directly.

The Mark Foundation for Cancer Research and the Chordoma Foundation invite proposals that address these complementary challenges and accelerate the development of new strategies to target the chordoma surfaceome. We seek projects that advance the understanding and therapeutic targeting of TBXT pMHC, as well as additional tumor-specific surface antigens. Competitive proposals will generate broadly enabling datasets, tools, technologies, or mechanistic insights that facilitate the development of multiple therapeutic modalities. Areas of interest include basic and translational research and preclinical proof-of-concept studies that de-risk future therapeutic development.

Scientific Scope

Proposed projects should address one or more of the following:

Understanding and targeting TBXT pMHC

  • Characterizing the expression, cell surface density, and immunogenicity of MHC-presented TBXT peptides across chordoma and other TBXT-expressing tumors, including those presented on HLA-E.
  • Discovering, engineering, and optimizing TCRs, antibodies, or alternative binding scaffolds (e.g., miniproteins) targeting TBXT pMHC, while defining the determinants of effective target engagement and cross-reactivity to non-TBXT peptides.
  • Characterizing MHC downregulation and loss in chordoma and identifying strategies to selectively enhance MHC presentation of immunogenic TBXT antigens in chordoma.
  • Defining how the immunosuppressive chordoma tumor microenvironment limits the activity of surface-targeted therapies and identifying strategies to overcome these barriers and improve therapeutic efficacy.

Expanding the targetable chordoma surfaceome

  • Applying cutting-edge technologies to discover or validate druggable tumor-specific surface targets in chordoma, including pan-cancer targets. Priority will be given to approaches that move beyond RNA expression profiling, including identifying protein complexes, co-expressed targets, conformational epitopes, aberrantly surface-localized proteins, post-translational modifications, glycolipids, glycans, and other noncanonical surface targets.

De-risking surface targeting approaches

  • Developing widely shareable research tools and datasets to enable development of surface-targeted therapies.
  • Defining potential barriers or primary resistance mechanisms to surface-targeting therapies, particularly T-cell-based therapies, and strategies for overcoming them.

The following project types are out of scope:

  • Direct support for clinical trials.
  • Late-stage therapeutic development, including IND-enabling studies and large-scale discovery screening campaigns. (Focused, hypothesis-driven screening efforts are within scope but should not constitute the primary emphasis of the proposal.)

Eligibility Criteria

  • Applicants must be employed by a non-profit academic or research institution. Applications will be accepted from both U.S. and non-U.S. entities.
  • Researchers are limited to one application as principal investigator but may be co-investigators on other proposals without limitation.
  • Principal investigators must be independent researchers at their respective institutions.

Award Terms

  • Applicants may request up to $500,000 for a period of up to 24 months.
  • The budget and duration requested for the grant must match a realistic estimate of the cost and timeline for the proposed work
  • The budget limit includes both direct and indirect costs, with indirect costs not to exceed 10% of the direct costs
  • Co-investigators are permitted
  • Revenue sharing terms will apply

Key Dates

October 26, 2026: Applicant portal opens
December 10, 2026: Concept letters due by 5pm ET
End of January 2027: Applications invited
March 1, 2027: Applications due
June 1, 2027: Grant start date

Contact us at grants@themarkfoundation.org with any questions.