Periodic Reporting for period 1 - AR-DDR (Co-targeting androgen receptor signalling and DNA damage repair for precision therapy in advanced prostate cancer) Reporting period: 2019-05-01 to 2021-04-30 Summary of the context and overall objectives of the project Prostate cancer is the 2nd most common cancer type in the western world, and the most prevalent in men. When the disease spreads to other organs, metastatic prostate cancer is an invariably lethal disease. Prostate cancer is addicted to androgen signalling; chemical castration, typically with LHRH agonists, induces dramatic cancer regression. However metastatic prostate cancer eventually finds a way to overcome the effect of castration, a condition known as castration-resistant prostate cancer (CRPC)1. Until now, all CRPC are treated as one disease, with drugs targeting the AR pathway and/or taxane-based chemotherapy. Recently, studies by the researcher and others have described the genomic landscape of CRPC and the DNA damage repair (DDR) pathway has been postulated as a suitable therapeutic target, as 20-25% CRPC harbour defects in genes involved in DDR genes. These data have paved the way for the development of precision medicine strategies in prostate cancer, tailoring the treatment for each individual patient according to the genomic make up of each tumor. In particular, PARP inhibitors, a family of drugs that target enzymes involved in the single strand DNA break repair, have been found to be effective in some men with prostate cancer harbouring these mutations. These drugs, which were previously approved in certain subtypes of breast and ovarian cancer, may represent the first precision treatment for prostate cancer.Several preclinical studies have identified a cross-regulation between the androgen receptor signalling pathway and the DDR pathway, leading to clinical trials targeting both pathways simultaneously. However, the exact mechanisms mediating this cross-talk are unclear.In this project, the researcher aims to further elucidate the mechanisms underlying AR-DDR cross-regulation, in order to design optimal combinatory therapy approaches. Moreover, the researcher will specifically focus in ATM mutations, one of the most common DDR defects in prostate cancer, as a model for identifying therapeutic vulnerabilities in these tumors.The overall objectives of the project are:• Obj1: To assess the impact of ATM mutations in DDR function, transcriptional regulation and sensitivity to different drugs targeting the DDR pathway, using prostate cancer models with different biological backgrounds. • Obj2: To explore potential tumour vulnerabilities based on the identification of overlapping functions for AR and DDR proteins. • Obj3: To study in patients biopsies how exposure to a drug targeting AR actually may result in modulating the effect of DDR proteins, creating new vulnerabilities and paving the way for combination therapies. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far During the first three months of the project, we have established the laboratory models for performing the experiments planned for Objective 1.We have also obtained approval from the ethics committees to enrol patients in a biopsy program to obtain the samples for Objective 3. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Advancing towards more precise care represents a major need in cancer care in general, and for prostate cancer in particular. We and others have previously identified a disease subset characterized by DNA repair defects, amounting up to 1 in 4 of patients with metastatic disease. Moreover, we and others also discovered that about half of these alterations are linked to a hereditary cancer predisposing mutation, which led to changes in clinical guidelines such as the NCCN recommendations, now advocating for universal germline sequencing for metastatic prostate cancer patients. These findings have been now confirmed in several follow-up studies. Overall, these previous data has been key to the design of PARP inhibitors development in prostate cancer, trying to validate the right target population based on genomics biomarkers. At present, PARP inhibitors are in development also in combination with AR-targeting drugs in clinical trials. However, the development of the AR-PARPi combination in clinical trials is being conducted without integrating predictive biomarkers, under the assumption that the magnitude of synergy would be similar in all patients, which is quite unlikely and definitely far from personalized medicine approaches. Hence, there is a risk that a potentially relevant synergistic effect in a subgroup of patients is averaged out by the general population.In this proposal, we aim to study genomic patterns associated to induction of a DDR-defective phenotype when starting an AR targeting agent, pursuing a biology-driven, precise development of drug combinations, and potentially discovering other synthetic vulnerabilities that arise after initiation of AR-directed drugs that can support the development of other combination approaches beyond PARP inhibitors. picture1.png
