CORDIS
EU research results

CORDIS

English EN
Synthetic Lethal Phenotype Identification through Cancer Evolution Analysis

Synthetic Lethal Phenotype Identification through Cancer Evolution Analysis

Objective

Prostate cancer (PCA) is a genetically heterogeneous disease. Advances in targeted hormonal therapy (second generation anti-androgens) have led to more effective management of castration-resistant prostate cancer (CRPC). Despite these highly potent drugs, disease recurs with new genomic and epigenetic alterations. In this ERC proposal, I will leverage my expertise in cancer genomics and a new computational methodology to unravel the landscape of lethal PCA, with a focus on determining the Achilles’ heel of these aggressive tumours. In Aim 1, I will take advantage of DNA sequencing data from over 1000 patient-derived tumour samples and use highly innovative mathematical algorithms to create a detailed evolution chart for each tumour and identify driver events leading to CRPC. After nominating candidate drivers, we propose testing 10 using in vitro gain- and loss-of-function validations experiments (i.e., CRISPR/Cas9, shRNA, and Tet-On assays) in PCA cell lines using migration, invasion, and cell cycle as readouts. In Aim 2, I will focus on genomic events that occur in recalcitrant CRPC, positing that genetic alterations occurring prior or secondary to treatment harbour clues into resistance. In vitro validations will be performed on the top 10 biomarkers. In Aim 3, I will nominate synthetic lethality combinations by mining CRPC genomic data taken from Stand Up 2 Cancer CRPC clinical trials. I will prioritize mutually exclusive genomic alterations in genes for which approved drugs exist. The top 5-10 candidates will be validated in a prostate lineage-specific manner. In summary, this ERC proposal will leverage my many years of expertise in PCA genomics and emerging public and private CRPC datasets to uncover driver mutations that will enhance our understanding of recalcitrant CRPC. Successful completion of this study should lead to novel treatment approaches for CRPC and to a computational model that may transform our approach to evaluating other cancers.
Leaflet | Map data © OpenStreetMap contributors, Credit: EC-GISCO, © EuroGeographics for the administrative boundaries

Host institution

UNIVERSITA DEGLI STUDI DI TRENTO

Address

Via Calepina 14
38122 Trento

Italy

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 996 428

Beneficiaries (1)

Sort alphabetically

Sort by EU Contribution

Expand all

UNIVERSITA DEGLI STUDI DI TRENTO

Italy

EU Contribution

€ 1 996 428

Project information

Grant agreement ID: 648670

Status

Ongoing project

  • Start date

    1 October 2015

  • End date

    30 September 2020

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 996 428

  • EU contribution

    € 1 996 428

Hosted by:

UNIVERSITA DEGLI STUDI DI TRENTO

Italy