Speaker: Joaquin Mateo, MD, PhD - Vall d'Hebron Institute of Oncology & Vall d'Hebron University Hospital - Barcelona
Organizer: IRB Barcelona
Date: Thursday 27 May 2021, 12:00h
Title: Precision medicine meets prostate cancer
Host: Manuel Serrano, PhD
Prostate cancer arises as a hormonally-driven disease, relying on activation of the androgen receptor (AR) by endogenous ligands (e.g. testosterone and dihydrotestosterone) for growth, and is initially responsive to androgen deprivation therapy (ADT). Emergence of resistance to ADT leads to castration-resistant prostate cancer (CRPC), where AR signaling remains the main driver of prostate cancer progression in most cases, and for which therapeutic options are limited, with a median overall survival around 3 years. In the last few years, tissue-based molecular and genomic biomarkers and imaging tools have been developed, rising hopes to improve patient outcome based on precision medicine strategies.
Prostate cancer is linked to genomic instability and, particularly, CRPC is enriched for germline and somatic alterations in double-strand break (DSB) repair genes, most commonly in those involved in homologous recombination repair (HRR) regulation. This recent finding triggered the development of Poly (ADP-ribose) polymerase (PARP) inhibitors as the first precision medicine drug class for prostate cancer using adaptive trial designs. With the approval of these drugs, genomic stratification is being implemented in clinical practice; there is however high inter-patient heterogeneity in PARP inhibitor responsiveness, so refinement of the predictive biomarker suite is needed to reach true personalized care. We propose a model based on integrating co-clinical laboratory trials and multi-modality clinical and genomics data to accelerate research in the field.
The response rate PARP inhibitors in ATM-mutated prostate cancer is limited; thus, we have been working with prostate cancer laboratory models lacking ATM function and studying tumor biopsies from CRPC patients with ATM mutations, demonstrating that the antitumor activity of PARP inhibitors as single agent does not depend on HRR suppression, is highly synergistic with ATR inhibition and that loss of ATM results in accumulation of DNA damage and genomic instability, probably also related to AR signaling.
On the other hand, the registration trials of PARP inhibitors have also identified an underserved patient population, those with infrequent mutations in DSB repair genes beyond BRCA1/2, ATM or CDK12, where their low prevalence difficult clinical qualification of those biomarkers using traditional clinical trial design. We are pursuing the development and clinical validation of functional and genomic-based signatures to reclassify this lethal disease based on predictive biomarkers for treatment selection for patients.
Open to predoctoral UPF students
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