Synergistic therapeutic targeting of PSMA expressing tumors

• Applicant: Professorin Katharina Lückerath, Ph.D.
• Subject Area: Reproductive Medicine, Urology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321353898

Prostate cancer (PCa) is the most common malignancy and the third most frequent cause of cancer related death in men. The 5-year survival rate for early, limited disease is almost 100%, but declines to 28% in case of metastatic spread. Prostate-specific membrane antigen (PSMA) is overexpressed by various tumors, including 90-100% of prostate cancers. Its physiological expression is highly restricted. Thus, PSMA is considered a reliable biomarker and an ideal target for cancer-specific imaging and therapy. Recent introduction of novel radiolabelled PSMA-ligands (68Ga-PSMA and 177Lu-PSMA) suitable for combined positron emission tomography/computed tomography (PET/CT) imaging and peptide receptor radionuclide therapy (PRRT) of PSMA-expressing tumors opens up new clinical treatment opportunities. However, targeted radionuclide therapy alone -beyond thyroid cancer- is only palliative and non-curative. The purpose of this project is to examine a potentially synergistic combination of the novel radiolabelled PSMA-theranostic with compounds addressing the DNA damage response pathway. The rational behind choosing this particular combination founds on the ability of ionizing radiation, such as delivered by 177Lu-PSMA, to induce DNA damage by eliciting DNA replication- and oxidative-stress. In the first step of the proposed study radionuclide therapy with 177Lu-PSMA will be established using a mouse model of prostate cancer. Therefore, different amounts of peptide and radioactivity will be tested to find the optimal dose of 177Lu-PSMA for the treatment of PSMA-expressing prostate cancer. The optimal dose will be defined as the amount of peptide/activity that results in maximal anti-tumor effect with least side effects (e.g. damage of unrelated organs). Based on that, radionuclide therapy with 177Lu-PSMA will be combined with a triplet of inhibitors against the protein-kinase ATR, ribonucleotide reductase and deoxycytidine kinase. Various methods will be used to determine the anti-tumor effects induced by either monotherapy vs. the synergistic approach: Next to diagnostic PET/CT imaging to assess the metabolic response (FDG-uptake) and the size (CT) of the tumor, these include analysis of tumor weight, the biodistribution of the therapeutic ligand (dosimetry; amount in tumor vs amount in other organs), the extent of DNA damage and replication stress induced (quantification of DNA double-strand and single-strand breaks), cell cycle kinetics, nucleotide metabolism, global proteomics and phospho-proteomics as well as progression free and overall survival. Together, the two subprojects aim to establish radionuclide therapy and synergistic combinations therewith as well as PET/CT techniques of improved efficacy for imaging and treatment of PSMA-expressing tumors. Findings will be submitted for publication in high-quality peer-reviewed scientific journals in the fields of nuclear medicine and oncology.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Johannes Czernin