Immune Checkpoint and Epigenetic Inhibition in Anaplastic Thyroid Cancers

• Applicant: Dr. Jacob Haase
• Subject Area: Hematology, Oncology ; General Genetics and Functional Genome Biology ; Endocrinology, Diabetology, Metabolism
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 500011875

The anaplastic thyroid carcinoma (ATC) is an almost invariably lethal cancer. Although rare (1-2 % of thyroid cancer cases), it accounts for up to 50 % of all thyroid cancer-related deaths. Progress on developing novel treatment options has been very slow for decades, thus conventional therapies remain largely palliative. Most recent clinical studies revealed immune checkpoint blockade (ICB) to be a highly promising alternative.ICB suppresses a cancer cells ability to evade immune surveillance. However, the underlying biology remains entirely unexplored for ATC, reported biomarkers fail to predict outcomes and the tumors can become insensitive to the treatment or do not respond at all. Accordingly, novel combinatorial therapies that improve the immune response are on the rise, but demand extensive and innovative research efforts. To date, the use of several treatment options combined with immunotherapy are being evaluated in clinical trials for several malignancies – many of which have shown to improve response rates, for instance by including the inhibition of the epigenetic modulator enhancer of zeste homolog 2 (EZH2).Active clinical trials will be the foundation for this project. The two broad objectives of this study are to: i) determine the biological consequences of the dual blockade of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in patient-derived ATC and blood samples for the first time on single cell-scale; and ii) evaluate rationale to further sensitize ATC for ICB by including EZH2.Me and my mentor Dr. Iñigo Landa will be joined by our collaboration partners Dr. Jochen Lorch and Dr. David Barbie. With those I am confident that I will significantly contribute to the development and investigation of ICB as a therapy approach for ATC and the improvement of response rates.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Hosts: Professorin Dr. Mariella Filbin; Professor Dr. Iñigo Landa, Ph.D.