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
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.
We have also obtained approval from the ethics committees to enrol patients in a biopsy program to obtain the samples for Objective 3.
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.