Photo: CF Labs researcher Nindo Punturi speaking at CTOS
Reflecting the growing significance of research progress in Chordoma Foundation (CF) Labs, our scientists recently presented results from three ongoing projects at the annual Connective Tissue Oncology Society (CTOS) meeting — the main international gathering of sarcoma doctors and researchers. These include:
An oral presentation about targeting replication stress to treat chordoma. Last year, our research team, working in collaboration with Greg Cote, MD, PhD at MGH and Lee Zou, PhD at Duke, found chordoma models to be exceptionally sensitive to drugs that target replication stress — a phenomenon that occurs when DNA in a cell is being copied, or replicated, and encounters a “stress” that can compromise this process and lethally damage tumor cells. As described at CTOS, CF Labs scientists tested a combination of two drugs: gemcitabine, a widely-used, low-cost cancer drug which can exacerbate replication stress, and an ATR inhibitor, which removes the ability of cancer cells to remedy replication stress. Our tests in preclinical models have revealed this combination to be highly synergistic. These results serve as proof of concept that drugs targeting replication stress may be a promising option for chordoma treatment. Our team is now conducting followup studies, including exploring additional drug combinations capable of targeting replication stress, with the aim of rapidly advancing this therapeutic concept into the clinic.
A poster about targeting EGFR to treat chordoma. EGFR inhibitors like afatinib and cetuximab are being evaluated in clinical trials, and recently reported results from the afatinib trial indicate that a subset of chordoma patients experience a significant clinical benefit from that drug. Our recent poster describes our scientists’ work to study the molecular factors that may predict which patients are most likely to benefit from these therapies. They found that afatinib works well in some chordoma models, while it is ineffective in others, and this differential response may be linked to an immunological pathway called interferon (IFN) signaling. IFN in turn may be triggered by DNA damage in chordoma cells. Ongoing studies aim to identify the molecular factor within the IFN pathway that promotes afatinib resistance, both to identify treatments capable of reversing resistance and biomarkers that could predict therapy response. We were honored that this poster won recognition as best in the Tumor Heterogeneity and Resistance category at the CTOS meeting.
A poster about new capabilities to enable TBXT (brachyury) drug discovery. Developing drugs targeting TBXT, a key vulnerability of chordoma, is among our top research priorities. Recently, we’ve developed crucial new capabilities in CF Labs — like the ability to produce the TBXT protein, several types of tests needed to evaluate TBXT-targeting compounds, and more — that will help enable drug development. Our CTOS poster summarizes rationale for drugging TBXT and highlights these new capabilities, which dramatically increase the feasibility for companies to pursue TBXT drug discovery, and greatly expand the range of approaches that can be brought to bear against this important target. We were proud that this poster won recognition as best in the Basic Science category at the CTOS meeting.
We’re grateful for the commitment and expertise of the research collaborators who contributed to these projects, and to our supporters for ensuring that our pipeline of promising therapeutic concepts continues to expand and advance toward the clinic. We look forward to keeping you posted on these projects’ continued progress.
CF Labs research associate Tyler Vincent discusses his CTOS poster