Development of TRNT radiopharmaceuticals targeting Hsp90

Pancreatic cancer and advanced glioma are life threating diseases, currently untreatable and with high chance of recurrence or dissemination. There is a clear need for new treatment strategies. In this respect, targeted radionuclide therapy can offer solace. Heat shock protein 90 (Hsp90) has been widely investigated as a target in different cancers as it display characteristics which only occur in malignant cells (higher expression, increased affinity for inhibitors, forming of networks that do not occur in healthy conditions). Up to 18 small molecule inhibitors have advanced to the clinical stage. However, none of them advanced to clinical use, attributed to commonly observed adverse effects. These side effects arise from administration of pharmacological doses, which can be mostly precluded by administration of miniscule amounts of radioactively labeled vector molecules (TRNT). When the same vector molecule is labeled with a diagnostic radionuclide, patient selection, treatment efficiency determination and follow up can be achieved via a theranostic approach. The goal of this project is to develop and preclinically evaluate TRNT radiopharmaceuticals targeting Hsp90 in pancreatic cancer and advanced glioma. This project will be a collaboration with the Laboratory for Radiopharmaceutical Research at KU Leuven under supervision of Prof. Guy Bormans. A lab with expertise in PET imaging of Hsp90 in cancer and brain. Initial investigation will focus on development and expanding of the library of small molecule Hsp90 vectors, adapting them to incorporate radio metals which will be complemented by externally generated peptides and/or nanobodies/antibodies. Next these compounds will be radiolabeled with diagnostic (68Ga, Al18F) or therapeutic radionuclides (177Lu, 161Tb). The compounds will be thoroughly evaluated in vitro via autoradiography and cell binding/cell damage assays on relevant cell models. The effect of low dose Hsp90 inhibition will also be studied on these cell lines before and/or after exposure to external beam radiotherapy (EBRT) or TRNT. In the last phase, The most promising compounds will be evaluated in rodent tumor models. PK studies will be performed (biodistribution, metabolites, SPECT/PET imaging) and therapeutic efficiency studies will take place following a theranostic approach.