First-line combination treatment with PARP and androgen receptor–signaling inhibitors in HRR-deficient mCRPC: Applying clinical study findings to clinical practice in the United States

Cancer Treatment Reviews, Год журнала: 2024, Номер 126, С. 102726 - 102726

Опубликована: Март 29, 2024

Introduction Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and develops from biochemically recurrent PC treated with androgen deprivation therapy (ADT) following definitive for localized PC, or metastatic castration-sensitive (mCSPC). In the mCSPC setting, treatment intensification of ADT plus receptor (AR)–signaling inhibitors (ARSIs), without chemotherapy, improves outcomes vs alone. Despite multiple phase 3 trials demonstrating a survival benefit in there high use monotherapy real-world clinical practice. Prior studies indicate that co-inhibition AR poly(ADP-ribose) polymerase (PARP) may result enhanced treating tumors regardless alterations DNA damage response genes involved either directly indirectly homologous recombination repair (HRR). Three recent evaluated combination PARP inhibitor (PARPi) an ARSI as first-line mCRPC: TALAPRO-2, talazoparib enzalutamide; PROpel, olaparib abiraterone acetate prednisone (AAP); MAGNITUDE, niraparib AAP. Results these have led to approval United States enzalutamide mCRPC any HRR alteration, both indicated AAP BRCA alterations. Summary Here, we review newly approved PARPi treatments within context landscape, provide overview practical considerations combinations practice, highlight importance testing, discuss benefits patients mCRPC.

Язык: Английский

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Combination of PARP Inhibitors and Androgen Receptor Pathway Inhibitors in Metastatic Castration-Resistant Prostate Cancer

Drugs, Год журнала: 2024, Номер 84(9), С. 1093 - 1109

Опубликована: Июль 26, 2024

Despite recent advances in the treatment of metastatic prostate cancer, progression to a castration-resistant state remains inevitable for most and prognosis is limited. Genetic testing homologous recombination repair pathway alterations recommended all patients with advanced cancer given that mutation present up 25% cases. Poly(ADP-ribose) polymerase (PARPis) are now approved use who have progressed on an androgen receptor inhibitor (ARPI) harbour germline or somatic mutation. Preclinical data support synergistic effect ARPI PARPi, various ARPI-PARPi combinations therefore been explored phase III clinical trials. heterogeneous findings, clear hierarchy benefit evident, harbouring BRCA deriving greatest magnitude benefit, followed by any The repair-proficient cohort less clear, questions remain about whether combination therapy should be offered without With ARPIs considered standard-of-care hormone-sensitive currently being earlier paradigm. purpose this review discuss rationale behind therapy, summarise results key trials, considerations future perspectives.

Язык: Английский

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Positioning Loss of PARP1 Activity as the Central Toxic Event in BRCA-Deficient Cancer

DNA repair, Год журнала: 2024, Номер 144, С. 103775 - 103775

Опубликована: Окт. 19, 2024

The mechanisms by which poly(ADP-ribose) polymerase 1 (PARP1) inhibitors (PARPi)s inflict replication stress and/or DNA damage are potentially numerous. PARPi toxicity could derive from loss of its catalytic activity physical trapping PARP1 onto that perturbs not only function in repair and replication, but also obstructs compensating pathways. combined disruption with either the hereditary breast ovarian cancer genes, BRCA1 or BRCA2 (BRCA), results synthetic lethality. This has driven development PARP as therapies for BRCA-mutant cancers. In this review, we focus on recent findings highlight activity, rather than PARPi-induced allosteric trapping, central to efficacy BRCA deficient cells. However, review PARP-trapping is an effective strategy other genetic deficiencies. Together, conclude mechanism-of-action unilateral; enhanced differentially killing depending context. Therefore, effectively targeting cells requires intricate understanding their key underlying vulnerabilities.

Язык: Английский

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Single-molecule analysis of PARP1-G-quadruplex interaction

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

The human genome contains numerous repetitive nucleotide sequences that display a propensity to fold into non-canonical DNA structures including G-quadruplexes (G4s). G4s have both positive and negative impacts on various aspects of nucleic acid metabolism replication, repair RNA transcription. Poly (ADP-ribose) polymerase (PARP1), an important anticancer drug target, has been recently shown bind subset G4s, undergo auto-PARylation. mechanism this interaction, however, is poorly understood. Utilizing Mass Photometry (MP) single-molecule total internal reflection fluorescence microscopy (smTIRFM), we demonstrate PARP1 dynamically interacts with 1:1 stoichiometry. Interaction single molecule nicked or containing G4 primer-template junction sufficient activate robust auto-PARylation resulting in the addition poly chains molecular weight several hundred kDa. Pharmacological PARP inhibitors EB-47, Olaparib Veliparib differently affect retention G4-containing compared DNA.

Язык: Английский

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Impact of a Cancer-Associated Mutation on Poly(ADP-ribose) Polymerase1 Inhibition

The Journal of Physical Chemistry B, Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

Poly(ADP-ribose) polymerase1 (PARP1) plays a vital role in DNA repair, and its inhibition cancer cells may cause cell apoptosis. In this study, we investigated the effects of PARP1 variant, V762A, which is strongly associated with several cancers humans, on by three FDA-approved inhibitors: niraparib, rucaparib, talazoparib. Specifically, compared mutant to that wild-type (WT) PARP1. Additionally, how mutation influences binding these inhibitors Our work suggests while exhibits only minor differences residual fluctuations, backbone deviations, residue motion correlations WT under niraparib rucaparib inhibitions, it shows significant distinct features when inhibited Among talazoparib uniquely lowers average fluctuations than including lower mutant's N- C-terminal residues catalytic domain, conserved H-Y-E traid residues, donor loop (D-loop) are important for catalysis more effectively other inhibitions. However, also significantly enhances destabilizing interactions between site HD domain WT. Further, among disrupts functional terminal regions mutant, otherwise present The do not affect PARP1's essential dynamics. Lastly, bind V762A WT, similar free energies them.

Язык: Английский

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