Impact of BRCA2 deficiency one the DNA damage response and Immunogenicity of Prostate cancer after Radioligand therapy

Despite current advances in prostate cancer (PCa) treatment, 10 to 20% of PCa will evolve to a metastatic stage, where the overall survival is 14 months. Radioligand therapy (RLT) is a new, promising treatment consisting in the injection of a radiolabelled vector.

In PCa, this therapy targets Prostate Specific Membrane Antigen, which is overexpressed on PCa cells compared to other tissues.

RLT has been shown to increase the overall survival of patients in clinical trials, but in order to improve its efficiency and identify possible biomarkers for patient selection, tumour response mechanisms must be studied.Especially, some reports indicate that deficiency in DNA Damage Response (DDR) genes could be correlated to an increased sensitivity of tumour cells towards RLT.

In PCa, one of the most frequent deficient DDR gene is Breast cancer 2 (BRCA2), which is correlated with bad prognosis.

In addition, retrospective studies showed a potential link between BRCA2 deficiency and a modulation of the immune response, which also influences treatment response. Therefore BRCA2 deficiency could impact both the immune response and RLT outcome. In this project, I will investigate the impact of BRCA2deficiency on RLT response.

Both the tumour DDR and immunogenicity will be assessed, in order to view the treatment response as a whole. These studies will be conducted in vitro in murine and human PCa cell lines and in in vivo murine model.

Results of my project will show the impact of BRCA2 deficiency on RLT outcome and whether BRCA2 status could be used as a biomarker to predetermine potential good responders to RLT.

Besides contributing to the fundamental scientificadvancement on the effect of BRCA2 deficiency in RLT response, I also aim to raising the awareness of these principles in the scientific community and other stakeholders such as clinicians. This will open the way to development of potential biomarker of good response to this new treatment