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Review
. 2024 Jun 12:16:17588359241255174.
doi: 10.1177/17588359241255174. eCollection 2024.

PARP inhibitors in non-ovarian gynecologic cancers

Italo Fernandes  1 , Rania Chehade  1 , Helen MacKay  2
Affiliations
Review

PARP inhibitors in non-ovarian gynecologic cancers

Italo Fernandes et al. Ther Adv Med Oncol. .

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have transformed the treatment of ovarian cancer, particularly benefiting patients whose tumors harbor genomic events that result in impaired homologous recombination (HR) repair. The use of PARPi over recent years has expanded to include subpopulations of patients with breast, pancreatic, and prostate cancers. Their potential to benefit patients with non-ovarian gynecologic cancers is being recognized. This review examines the underlying biological rationale for exploring PARPi in non-ovarian gynecologic cancers. We consider the clinical data and place this in the context of the current treatment landscape. We review the development of PARPi strategies for treating patients with endometrial, cervical, uterine leiomyosarcoma, and vulvar cancers. Furthermore, we discuss future directions and the importance of understanding HR deficiency in the context of each cancer type.

Keywords: PARP inhibitor; clinical trials; homologous recombination deficiency; novel therapies; predictive biomarker.

Plain language summary

PARP inhibitors in non-ovarian gynecologic cancers Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed the way ovarian cancer is treated, especially for patients whose tumors have specific genetic issues affecting their ability to repair DNA. Over time, PARPi are being used for certain groups of patients with breast, pancreatic, and prostate cancers. More recently, their potential to help people with other types of gynecologic cancers than ovarian have been studied. In this review, we explore the reasons behind looking into PARPi for these non-ovarian gynecologic cancers. We analyze the clinical data and compare it to the current treatment options available, focusing on endometrial, cervical, uterine leiomyosarcoma, and vulvar cancers. Additionally, we discuss about future directions and stress the importance of understanding the specific DNA repair context for each type of cancer. Especially, we discuss the tests that aims to define who may benefit from the drug, with focus on the homologous recombination deficiency.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.
PARP and DNA damage response. PARP-1 detects SSBs and transduces signals, initiating the synthesis of negatively charged PAR polymers on target proteins through binding to adjacent DNA. This process, known as PARylation, involves the cleavage of coenzyme NAD+ into nicotinamide and ADP-ribose. Consequently, large PAR polymers are produced, forming a multiprotein repair complex that includes enzymes like DNA ligase III, DNA polymerase pol B, and scaffolding proteins such as XRCC1. After ADP-ribosylation, PARP-1’s DNA affinity decreases, leading to its release. The repair PAR polymers undergo degradation facilitated by PARG. NAD, nicotinamide adenine dinucleotide; PAR, poly(ADP-ribose); PARG, poly(ADP-ribose) glycohydrolase; PARP-1, poly(ADP-ribose) polymerase-1; SSBs, single-strand breaks; XRCC1, X-ray repair cross-complementing 1.
Figure 2.
Figure 2.
The role of HPV infection in the pathogenesis of CC. HPV encoded E6 and E7 oncoproteins disrupt key tumor suppressor proteins like P53 and retinoblastoma, fostering cell proliferation and impeding apoptosis. This, coupled with genomic instability often tied to malfunctioning DNA damage response pathways, contributes to tumorigenesis. Notably, PARPis exhibit effectiveness in cancers with DNA damage response deficiencies, exemplified in BRCA-mutated gynecological cancers. A second hypothesis implicates chronic inflammation induced by HPV infection in CC pathogenesis. HPV-triggered inflammatory responses culminate in oxidative stress and DNA damage. This chronic inflammation also leads to E6 overexpression, elevating DNA damage levels, and consequently enhancing PARP-1 activity. Both mechanisms provide potential targets for PARPi. CC, cervical cancer; HPV, human papilloma virus; PARPi, poly(ADP-ribose) polymerase inhibitors.
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