Unravelling radiobiological mechanisms of therapeutic and toxic responses of prostate cancer radionuclide therapy

Prostate cancer is the second most commonly diagnosed malignancy among men. At localized stage, survival is high, but upon progression to metastatic castration-resistant disease (mCRPC), the five year survival drops to 15%. Current treatment options, including chemotherapy and hormonal therapy, have limited effect. A newly emerged treatment option for this disease stage targets prostate specific membrane antigen (PSMA). In PSMA-targeted radionuclide therapy (TRT), a PSMA-targeting molecule is combined with a radionuclide, delivering ionizing radiation to the prostate cancer cells. This novel treatment option showed promising results in clinical trials, but toxicity related to the salivary glands was observed. Damage to these glands results in salivary gland hypofunction and xerostomia. As saliva holds important functions in speech, swallowing and protecting the oral cavity against bacterial infection, salivary gland toxicity is not only dangerous, but also severely impacts the quality of life of patients undergoing PSMA-TRT. Mechanisms underlying this toxicity remain elusive. Therefore, the aim of this research project was to study how the FDA-approved compound, [177Lu]Lu-PSMA-617, is retained in the salivary gland cells and what the resulting effects are after exposure. Non-specific retention mechanisms of [177Lu]Lu-PSMA-617 were investigated and described. Prostate cancer and salivary glands cells as well as mouse kidney and pig salivary gland cells were incubated with [177Lu]Lu-PSMA-617 and several glutamate receptor antagonists to investigate mechanisms of non-specific retention. We showed that monosodium glutamate, kynurenic acid and (RS)-MCPG decreased binding of [177Lu]Lu-PSMA to the salivary glands. Additionally, underlying radiobiological mechanisms of therapeutic and toxic responses to PSMA-TRT were identified. Prostate cancer and salivary gland cells were incubated with [177Lu]Lu-PSMA-617 and cell viability, DNA damage, apoptosis and mitochondrial membrane potential were investigated at several time points after treatment. We showed that treatment with [177Lu]Lu-PSMA-617 decreased cell viability, induced DNA damage and influenced mitochondrial mitochondrial membrane potential, while no induction of apoptosis was observed in both prostate cancer and salivary gland cells. Summarized, in this work more insights were gained in the mechanisms of cellular responses to PSMA-TRT and salivary gland uptake mechanisms, contributing to the research for safer use of PSMA-TRT in patients.