PhD defence C.D. (Circe) van der Heide

Below is a brief summary of the dissertation:

Biomarker‑guided radionuclide theranostics enables personalized cancer treatment, yet current clinical applications mainly target SSTR2 and PSMA, limiting eligibility to a small subset of patients. Fibroblast activation protein (FAP), expressed on cancer‑associated fibroblasts in the tumor microenvironment of most solid tumors, has therefore emerged as a promising pan‑cancer target. This thesis explores the (radio)biology of FAP‑directed theranostics and key determinants of therapeutic success.

The first part focuses on improving FAP‑targeted radionuclide therapy (FAP‑TRT). A new small‑molecule scaffold, eFAP, demonstrated high FAP affinity and rapid tumor accumulation, although without improved retention compared to existing tracers. The therapeutic peptide FAP‑2286, labeled with ^177Lu or ^161Tb, was evaluated in a clinically relevant pancreatic cancer model. Both tracers showed similar biological behavior, but no clear therapeutic response was observed, aside from a modest survival benefit in a tandem‑therapy regimen.

The second part examines preclinical models commonly used in FAP‑TRT research. Significant model‑dependent differences in FAP expression and tracer behavior were identified. To better mimic clinical conditions, a 2D co‑culture system combining FAP‑positive fibroblasts with FAP‑negative cancer cells was developed, enabling realistic assessment of CAF–tumor interactions and cross‑fire effects using bioluminescent readouts.

The third part investigates the influence of the tumor microenvironment, including CAF‑induced epithelial‑mesenchymal transition (EMT), on TRT response. EMT altered radiosensitivity across multiple triple‑negative breast cancer cell lines, underscoring the importance of TME‑driven biology in optimizing FAP‑TRT strategies.