Cancer is a world public health problem with a high incidence of newly diagnosed cases. In 2020 in Europe, the crude incidence rate was 587 per 100 000, and the estimated number of deaths was 261 per 100 000. Genomic instability is one of the main factors that can drive tumorigenesis. It can be induced by mutations in DNA damage response (DDR) genes which can lead to a deficiency in DNA repair. Molecular profiles of 52 000 tumours across 21 different cancer lineages showed that 17,4% were mutated for Homologous Recombination (HR) DDR genes. The second most commonly found mutated HR gene was Breast Cancer 2 (BRCA2), which deficiency is linked to higher risk in developing breast, ovarian or prostate cancers (PCa). Specifically, in PCa, BRCA2 deficiency is associated with high-grade tumours and an increased number of metastases. Additionally, patients with such tumours more often present resistance to therapies, illustrating the need for tailored treatment strategies.
In the last few years, a novel and promising treatment modality for patients with advanced PCa has been developed: radioligand therapy (RLT). In contrast to the classic external beam radiotherapy, which uses a radiation source from outside the body, RLT is injected into the bloodstream and uses beta or alpha emitters linked to a vector targeting the tumour cells (see Figure 1). In PCa, the most used radionuclide for this therapy is lutetium-177, a beta-emitter linked to an inhibitor of prostate specific membrane antigen (PSMA), which is vastly overexpressed on PCa cells compared to healthy tissues. Recently, a phase III clinical trial showed an increased overall and progression-free survival with this therapy compared to standard care, leading to the approval of this RLT by the US Food and drug Administration (FDA) in 2022 for the treatment of metastatic castration-resistant PCa.
In contrast to the fast clinical implementation of RLT, very few studies report the potential impact of DDR deficiency on its effectivity. In comparison, it has already been demonstrated that DDR deficiency for various genes increases the responsiveness of tumours towards damage induced by external beam radiotherapy. This could imply that mutations in DDR genes could also cause sensitivity towards RLT, but so far only few studies have been published with conflicting reports. On one hand, patients showing good response to treatment with alpha emitter RLT present a higher frequency of DDR genes mutation. On the other hand, it was reported that patients resistant to RLT have shown to be more often mutated for those same genes. These retrospectives studies however include a very small number of patients, rendering it difficult to understand the actual role of DDR deficiencies in the response to RLT, thus highlighting the need for further research.
My aim is to identify the impact of BRCA2 deficiency on the RLT response in PCa, and assess its potential as a treatment response biomarker for this new therapeutic option. Relying on pre-existing evidence with external beam radiotherapy, it is to be expected that patients presenting PCa with BRCA2 deficiency would be specifically sensitive to RLT. An important part of the tumour response to treatment is the immune response. Interestingly, BRCA2 deficiency has been correlated to an exclusion of CD8 T cells outside the tumour compartment, an increase in pro-tumoural, regulatory CD4 T cells and tumoural PD-L1 expression, which also correlates with worse survival in PCa. To overcome this BRCA2-driven immune resistance, RLT could induce an inflammatory response by releasing Danger Associated Molecular Patterns (DAMPs) and providing new tumour epitopes to be recognised by the immune cells after tumour cell death induction. These signals (DAMPs and tumour epitope) are necessary for the activation of a proper anti-tumour immune response, which could synergise with the RLT. Very few studies have reported the impact of RLT on the immune response, but increase in immune cytokines and tumour infiltrating lymphocytes have been observed after RLT in other pre-clinical models.
At the scientific level, the main impact of this project is increased knowledge on the immune response and DDR mechanisms following RLT. Understanding the RLT radiobiologic effect on cells in vitro and in vivo is crucial to the improvement of therapy. DDR study will further our knowledge on cell response to different irradiation activities, and immune response study will allow to assess the RLT response as a whole. RLT is a promising therapy, but needs to be improved. By increasing the knowledge on BRCA2 mutated tumour response to RLT, I hope to consolidate RLT’s potential as a treatment for PCa and identify potential candidates for biomarker of good response, and combined therapies. Following this project, further research could be done, with other PCa models to confirm our results and a therapeutic study to assess the precise tumour growth and survival of mice following treatment. In this project, we will reproduce most observed BRCA2 deficiency by introducing a KO in the PCa cell lines, but further research could also focus on specific mutations found in patients.
In addition, BRCA2 is also found mutated in other cancers such as breast and ovarian cancer, as previously mentioned. Taking into account the clear lack of study on BRCA2 deficiency impact on RLT, this work could increase the awareness in the scientific community about the potential of RLT in the treatment of other BRCA2 mutated cancers.
