Worldwide, more than 1 million men are diagnosed with prostate cancer each year and more than 300 000 die of the disease. Current statistics from the Belgian Cancer Registry show 8366 new cases of prostate cancer in 2015. Prostate cancer is the most common cancer in Belgian men, and average age at diagnosis is 70 years.
Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. The potential of PSMA-targeted radionuclide therapy for advanced, castrate-resistant prostate cancer is being demonstrated by a growing number of reports detailing institutional experience with various agents and prospective clinical trials are in progress to further establish the safety and efficacy of this approach. Although extremely promising, PSMA-ligand therapy remains a non-curative treatment and, therefore, the prolongation in survival and amelioration of disease-related symptoms must be balanced against the direct toxicities of the treatment and their impact on quality of life. Of these, xerostomia, due to radiation injury of the salivary glands, is amongst the most common and debilitating, particularly for Ac225-PSMA. The nature of this dysfunction is incompletely understood and strategies for its prevention and treatment are still under evaluation.
In addition, radiation-resistance is an issue in current prostate cancer treatments. Following a prostate cancer diagnosis, approximately 50 percent of men will receive external beam radiation therapy. However, recurrence rates in these patients remain high (20-30%) and are associated with a limited chance of cure. Therefore, the development of potent radiosensitizers, agents that increase the sensitivity of malignant prostate cells to radiation, is urgently required. Also treatment modalities based on targeted radionuclide therapy may benefit from radiosensitizers for prostate cancer cells.
Characterization of the biological basis for therapeutic and cytotoxic responses is essential to guide the evaluation of current as well as novel therapeutic options for protstate tumor, including prevention strategies for salivary gland toxicity and radiosensitizing strategies. It may also provide a means to select patients most likely to benefit from these strategies.
This PhD project aims at a better understanding of (i) salivary gland toxicity after PSMA-targeted radionuclide therapy and (ii) the molecular mechanisms underlying prostate cancer cell radioresistance. As such, we aim to contribute to establish strategies for prostate cancer treatment optimization, increasing radiation therapy treatment response and mitigating the adverse effects of targeted radionuclide therapy on the salivary glands.
(i) Investigation of salivary gland toxicity after PSMA-targeted radionuclide therapy
(ii) Investigation of the molecular mechanisms underlying prostate cancer cell radioresistance
Techniques that will be applied are cell culture, ELISA, flow cytometry, western blot, RT-qPCR, colorimetric assays and fluorescence microscopy.