奥拉帕尼
PARP抑制剂
耐受性
医学
药代动力学
合成致死
癌症研究
卵巢癌
药理学
肿瘤科
内科学
不利影响
癌症
生物
聚ADP核糖聚合酶
DNA修复
基因
聚合酶
生物化学
作者
Panagiotis A. Konstantinopoulos,Su–Chun Cheng,Jeffrey G. Supko,Madeline Polak,Andrea E. Wahner-Hendrickson,S. Percy Ivy,Brittany Bowes,Hannah Sawyer,Patrice Basada,Martin Hayes,Jennifer Curtis,Neil S. Horowitz,Alexi A. Wright,Susana M. Campos,Elena Ivanova,Cloud P. Paweletz,Sangeetha Palakurthi,Joyce F. Liu,Alan D. D’Andrea,Prafulla C. Gokhale,Dipanjan Chowdhury,Ursula A. Matulonis,Geoffrey I. Shapiro
标识
DOI:10.1038/s41416-021-01664-8
摘要
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.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.Olaparib/onalespib exhibited anti-tumour activity against BRCA1-mutated PDX models with acquired PARPi resistance and PDX models with RB-pathway alterations(CDKN2A loss and CCNE1 overexpression). Phase 1 evaluation revealed that dose levels up to olaparib 300 mg/onalespib 40 mg and olaparib 200 mg/onalespib 80 mg were safe without dose-limiting toxicities. Coadministration of olaparib and onalespib did not appear to affect the steady-state pharmacokinetics of either agent. There were no objective responses, but disease stabilisation ≥24 weeks was observed in 7/22 (32%) evaluable patients including patients with BRCA-mutated ovarian cancers and acquired PARPi resistance and patients with tumours harbouring RB-pathway alterations.Combining onalespib and olaparib was feasible and demonstrated preliminary evidence of anti-tumour activity.
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