ESMO E-Learning: PARP Inhibition - basic science and clinical challenge

Learning Objectives

  • To understand a rationale from available preclinical data for a clinical development of PARP inhibitors 
  • To be familiar with current understanding of the mechanism of action of PARP inhibitors
  • To understand the current research and potential clinical Translation of PARP inhibitors for the anti-cancer therapy
Title Duration Content CME Points CME Test
PARP Inhibition - basic science and clinical challenge 36 min. 31 slides 1 Take Test
Helleday Thomas
Thomas Helleday
Read more

This E-learning module summarises the current understanding from available scientific data and clinical challenges related to PARP inhibition. Deeper understanding of DNA repair mechanisms and their potential value as therapeutic targets in oncology heralded the clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors. Although initially developed to exploit synthetic lethality in models of cancer associated with defective DNA repair, further understanding of PARP biology has resulted in these agents being exploited in cancer with selected chemotherapeutic agents.

The author, who is a top-notch PARP researcher, describes relevant data for pre-clinical development of PARP inhibitors and discusses the clinical testing of the various PARP inhibitors, either as mono- or combination therapy.

Homologous recombination repair defects are classically associated with BRCA1 and 2 Mutations that are associated with familial breast and ovarian cancer. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant cancers, and extend beyond these tumours if appropriate biomarkers can be developed to identify homologous recombination repair defects.

By explaining the basic mechanisms that led to BRCA deficient cells with PARP inhibitors, the author focuses on the clinical development of PARP inhibitors in BRCA 1/2 cancers. There are more than 80 phase I and II clinical trials with PARP inhibitors; in his presentation, Dr Helleday focuses on PARP inhibitors for BRCA1/2 ovarian cancer, response to PARP inhibitors in triple-negative breast cancer as dictated by BRCA mutation, platinum resistant ovarian cancers and non-BRCA response to PARP inhibition, olaparib maintenance treatment in relapsed high-grade serous ovarian cancer, as well as on the fact that ovarian cancers often have silenced Fanconi anaemia pathway, rendering in homologous recombination defect.

The module further covers potential biomarkers for PARP inhibitor sensitivity in monotherapy and mechanisms of resistance to PARP inhibitors, while the following segment covers PARP inhibitors in combination therapy, including iniparib plus chemotherapy in metastatic triple-negative breast cancer. Possible reasons for study failure are described; including the discovery that iniparib is not a PARP inhibitor. The module also elaborates on rucaparib with temozolomide in patients with metastatic melanoma.

The module provides an overview on strategies using PARP inhibitors as anti-cancer agents, including current understanding of which combination will work in the clinic based on tumour characteristics and drug mechanism of action. The last part of the module features the current explanation of PARP inhibitors mechanism of action.

This E-learning module is an excellent CME opportunity for all those who wish to keep abreast of the latest advances in PARP inhibition and are interested in the potential future outlook for the treatment of challenging cancers.

Last update: 05 December 2013

The author has reported no conflicts of interest