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Co-targeting androgen receptor signalling and DNA damage repair for precision therapy in advanced prostate cancer

Co-targeting androgen receptor signalling and DNA damage repair for precision therapy in advanced prostate cancer

Objective

Prostate cancer is the 2nd most common cancer in the western world. The advanced stage, metastatic castration-resistant prostate cancer (mCRPC), is a lethal disease. Understanding inter-patient genomic heterogeneity renders the opportunity to advance towards personalised patient care. Prostate cancer is a disease primarily driven by the androgen receptor (AR) pathway; however, the applicant prior work contributed to identifying 1) that up to 25% of mCRPC harbour defects in DNA damage repair (DDR) genes, and 2) that some of these mCPRC patients with DDR defects are sensitive to targeted treatment with PARP inhibitors. In the proposed research plan, we aim to exploit the cross-regulation between AR and DDR pathways to optimize precise therapeutic options for mCRPC patients. To achieve the objectives, the applicant will use models generated at the host through CRISRP/Cas9 to pursue functional studies and characterise how defects in ATM impact DDR function and sensitivity to inhibitors of PARP, ATR and DNA-PK. We hypothesize such sensitivity would be modulated by co-targeting of the AR pathway and by second events such as TP53 loss-of-function. ChIP-Seq assays will be pursued to identify genes co-regulated by the androgen receptor and PARP-1, to identify potential synthetic vulnerabilities. Then, mCRPC patient’s biopsies acquired in clinical practice from patients receiving AR-targeting therapies will be used to study how AR inhibition modulate transcriptional regulation of DDR pathways, to inform the optimal design of combination therapies. These data would be correlated with genomics and immunofluorescence tests of homologous recombination function, in order to refine patient stratification in the clinic. The proposed research will be conducted in parallel to a personalised training and career development plans, designed for the applicant to achieve a position of academic independence as physician-scientist before the end of the fellowship at the host institute.
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Coordinator

FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON

Address

Calle Nazaret 115-117
08035 Barcelona

Spain

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 172 932,48

Project information

Grant agreement ID: 837900

Status

Ongoing project

  • Start date

    1 May 2019

  • End date

    21 July 2021

Funded under:

H2020-EU.1.3.2.

  • Overall budget:

    € 172 932,48

  • EU contribution

    € 172 932,48

Coordinated by:

FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON

Spain