Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours.

ABSTRACT:

Purpose

PARP inhibitor resistance may be overcome by combinatorial strategies with agents that disrupt homologous recombination repair (HRR). Multiple HRR pathway components are HSP90 clients, so that HSP90 inhibition leads to abrogation of HRR and sensitisation to PARP inhibition. We performed in vivo preclinical studies of the HSP90 inhibitor onalespib with olaparib and conducted a Phase 1 combination study.

Patients and methods

Tolerability and efficacy studies were performed in patient-derived xenograft(PDX) models of ovarian cancer. Clinical safety, tolerability, steady-state pharmacokinetics and preliminary efficacy of olaparib and onalespib were evaluated using a standard 3 + 3 dose-escalation design.

Results

Olaparib/onalespib exhibited anti-tumour activity ag

SUBMITTER: Konstantinopoulos PA 

PROVIDER: S-EPMC8980096 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature