PARP Inhibitors: A New Horizon for Patients with Prostate Cancer

Belenchón, I. Rivero; Rivero, Inés; Osmán, Ignacio; Sáez, Carmen; López, R. Medina

doi:10.3390/biomedicines10061416

Cited by 29 publications

(23 citation statements)

References 112 publications

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“…Talazoparib has a trapping efficiency nearly one hundred times more potent than that of niraparib, followed by olaparib and rucaparib [ 87 , 88 , 89 ]. While higher trapping efficiency may potentially be more effective, it has been associated with more toxicity [ 90 ].…”

Section: Resultsmentioning

confidence: 99%

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Advances in PARP Inhibitors for Prostate Cancer

Tisseverasinghe

Bahoric

Anidjar

et al. 2023

Cancers

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Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair. PARPi is a promising drug class that has gained significant traction in the last decade with good outcomes in different cancers. Several trials have sought to test its effectiveness in metastatic castration resistant prostate cancer (mCRPC). We conducted a comprehensive literature review to evaluate the current role of PARPi in this setting. To this effect, we conducted queries in the PubMed, Embase and Cochrane databases. We reviewed and compared all major contemporary publications on the topic. In particular, recent phase II and III studies have also demonstrated the benefits of olaparib, rucaparib, niraparib, talazoparib in CRPC. Drug effectiveness has been assessed through radiological progression or overall response. Given the notion of synthetic lethality and potential synergy with other oncological therapies, several trials are looking to integrate PARPi in combined therapies. There remains ongoing controversy on the need for genetic screening prior to treatment initiation as well as the optimal patient population, which would benefit most from PARPi. PARPi is an important asset in the oncological arsenal for mCRPC. New combinations with PARPi may improve outcomes in earlier phases of prostate cancer.

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Section: Resultsmentioning

confidence: 99%

“…ADT may induce the downregulation of these DDR genes, promoting increased cancer cell death [ 119 ]. Consequently, subsequent increased PARP activity can lead to tumor-cell survival and modulation of AR-axis activity [ 90 ], which in turn can be countered by PARP inhibition.…”

Section: Discussionmentioning

confidence: 99%

Advances in PARP Inhibitors for Prostate Cancer

Tisseverasinghe

Bahoric

Anidjar

et al. 2023

Cancers

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“…Multiple studies have conclusively demonstrated that genomic alterations in DNA damage repair (DDR) genes are prevalent in both primary and metastatic PCa tissue [36], leading to the clinical utilisation of PARP inhibitors (PARPi) in patients with DDR de ciencies [37]. However, the emergence of resistance mechanisms has been observed in patients receiving PARPi treatment [38].…”

Section: Pde4d7 Speci C Knockdown In Lncaps Is Associated With Expres...mentioning

confidence: 99%

Diminished PDE4D7 Expression is Associated with Treatment-Resistant, Lethal Prostate Cancer and Manifests with Impaired Androgen Response, Neuroendocrine Differentiation and Alterations in DNA Repair

Gulliver

Huss

Semjonow

et al. 2023

Preprint

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Androgen signalling remains the seminal therapeutic approach for management of advanced prostate cancer. However, most tumours eventually shift towards an aggressive phenotype, characterised by androgen-independence and treatment resistance. The cyclic adenosine monophosphate (cAMP) pathway plays a crucial role in regulating various cellular processes, with the phosphodiesterase PDE4D7 being a vital modulator of cAMP signalling in prostate cancer cells. Our study provides evidence that loss of PDE4D7 expression represents a pivotal switch driving the transition from an androgen-sensitive state to hormone unresponsiveness and neuroendocrine differentiation. Additionally, we demonstrate that PDE4D7 loss results affects DNA repair pathways, conferring resistance to poly ADP ribose polymerase (PARP) inhibitors. Reinstating PDE4D7 expression sensitises prostate cancer cells to anti-androgens, DNA damage response inhibitors, and cytotoxic therapies. These findings provide significant insight into the regulatory role of PDE4D7 in the development of lethal prostate cancer and the potential of its modulation as a novel therapeutic strategy.

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“…BRCA mutated tumor cells are 1000-fold more sensitive to PARP inhibitors than BRCA wild-type cells (15). Hence, the development of PARP inhibitors initially emphasized the population with BRCA1/2 gene mutation.…”

Section: Mechanism Of Action Of Parp Inhibitorsmentioning

confidence: 99%

Use of PARP inhibitors in prostate cancer: from specific to broader application

Zhang

et al. 2023

Front. Endocrinol.

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Prostate cancer (PC) is one of the major health issues of elderly men in the word. It is showed that there were approximately 1.414 million patients with PC in 2020 worldwide, with a high mortality rate in metastatic cases. In the present choices of treatment in PC, androgen deprivation therapy has long been as a backbone of them. But the clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) were not ideal because of their poor prognosis, more effective therapeutic approaches are still necessary to further improve this problem. Poly (ADP-ribose) polymerase (PARP) inhibitors lead to the single-strand DNA breaks and/or double-strand DNA breaks, and result in synthetic lethality in cancer cells with impaired homologous recombination genes. It is estimated that approximately 20~25% of patients with mCRPC have a somatic or germinal DNA damage repair gene mutation. Furthermore, in “BRCAness” cases, which has been used to describe as tumors that have not arisen from a germline BRCA1 or BRCA2 mutation, there were also a number of studies sought to extend these promising results of PARP inhibitors. It is worth noting that an interaction between androgen receptor signaling and synthetic lethality with PARP inhibitors has been proposed. In this review, we discussed the mechanism of action and clinical research of PARP inhibitors, which may benefit population from “specific” to the “all-comer” in patients with PC when combined with novel hormonal therapies.

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PARP Inhibitors: A New Horizon for Patients with Prostate Cancer

Cited by 29 publications

References 112 publications

Advances in PARP Inhibitors for Prostate Cancer

Advances in PARP Inhibitors for Prostate Cancer

Diminished PDE4D7 Expression is Associated with Treatment-Resistant, Lethal Prostate Cancer and Manifests with Impaired Androgen Response, Neuroendocrine Differentiation and Alterations in DNA Repair

Use of PARP inhibitors in prostate cancer: from specific to broader application

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