The PARP1 Inhibitor AZD5305 Impairs Ovarian Adenocarcinoma Progression and Visceral Metastases in Patient-derived Xenografts Alone and in Combination with Carboplatin

Article

作者: Formenti, Laura ; Dellavedova, Giulia ; Staniszewska, Anna D. ; Albertella, Mark R. ; Leo, Elisabetta ; Bani, Maria Rosa ; Ghilardi, Carmen ; Decio, Alessandra ; Wilson, Joanne ; Giavazzi, Raffaella

PARP inhibitors (PARPi) have changed the management of patients with ovarian cancer and their effectiveness has been demonstrated especially in homologous recombination repair–deficient tumors. These first-generation drugs target PARP1, but also PARP2 and other family members potentially responsible for adverse effects that limit their therapeutic potential and restrict their use in combination with chemotherapeutic agents.We investigated ovarian cancer patient-derived xenografts (OC-PDXs) to assess whether malignant progression could be impaired by a novel inhibitor selective for PARP1 (AZD5305) and to assess the potential of its combination with carboplatin (CPT), the standard-of-care for patients with ovarian cancer.In BRCA-mutated OC-PDXs, AZD5305 achieved greater tumor regressions and longer duration of response as well as a superior impairment of visceral metastasis and improved survival benefit compared with the first-generation dual PARP1/2 inhibitors.The combination of AZD5305 plus CPT was more efficacious than single agents. Subcutaneously growing tumors experienced regression that persisted after therapy stopped. Combination efficacy was greater against tumors that did not respond well to platinum, even at a dose at which AZD5305 monotherapy was ineffective. The combination therapy impaired metastatic dissemination and significantly prolonged the lifespan of mice bearing OC-PDXs in their abdomen. This combination benefit was evident even when CPT was used at suboptimal doses, and was superior to full-dose platinum treatment.These preclinical studies demonstrate that the PARP1-selective inhibitor AZD5305 retains and improves the therapeutic benefit of the first-generation PARPi, providing an opportunity to maximize benefits for this class of anticancer agents.Significance:Selective PARP1i AZD5305 can exceed the efficacy of first-generation PARPi, which target both PARP1 and PARP2, and potentiates the efficacy of CPT when given in combination. AZD5305 alone or in combination with platinum delayed visceral metastasis, ultimately extending the lifespan of OC-PDX–bearing mice. These preclinical models mimic the progression of the disease occurring in patients after debulking surgery, and are translationally relevant.

Frontiers in Pharmacology

Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305

Review

作者: Li, Zhengyu ; Zheng, Jingcao ; Min, Wenjiao

The family of poly (ADP-ribose) polymerases (PARPs) consists of 17 members, which have been demonstrated as having effects on a series of cellular processes, including DNA replication and repair. PARP inhibitors (PARPi) suppress DNA repair through “PARP trapping”, thus, constitute an important treatment option for cancer nowadays. In addition, PARP inhibition and homologous recombination repair (HRR) defects are synthetically lethal, giving a promising therapeutic for homologous recombination repair deficient (HRD) tumors including BRCA mutation. However, overlapping hematologic toxicity causes PARPi to fail in combination with some first-line chemotherapies. Furthermore, recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for antitumor activity in HRD cancer models. Currently approved PARPi have shown varying levels of selectivity for the entire 17-member PARP family, hence contribute to toxicity. Together, these findings above have provided the necessity and feasibility of developing next-generation PARPi with improved selectivity for PARP1, expanding significant clinical values and wide application prospects both in monotherapy and combination with other anticancer agents. In this review, we summery the latest research of current approved PARPi, discuss the current status and future promise of next-generation PARP1-selective inhibitor AZD5305, including its reported progress up to now and anticipated impact on clinical.

International Journal of Molecular Sciences

Leveraging PARP-1/2 to Target Distant Metastasis

Review

作者: Abdesselam, Djihane ; Croteau, Laurent ; Frederick, Mallory I. ; Clouvel, Anna ; Hassan, Saima

Poly (ADP-Ribose) Polymerase (PARP) inhibitors have changed the outcomes and therapeutic strategy for several cancer types. As a targeted therapeutic mainly for patients with BRCA1/2 mutations, PARP inhibitors have commonly been exploited for their capacity to prevent DNA repair. In this review, we discuss the multifaceted roles of PARP-1 and PARP-2 beyond DNA repair, including the impact of PARP-1 on chemokine signalling, immune modulation, and transcriptional regulation of gene expression, particularly in the contexts of angiogenesis and epithelial-to-mesenchymal transition (EMT). We evaluate the pre-clinical role of PARP inhibitors, either as single-agent or combination therapies, to block the metastatic process. Efficacy of PARP inhibitors was demonstrated via DNA repair-dependent and independent mechanisms, including DNA damage, cell migration, invasion, initial colonization at the metastatic site, osteoclastogenesis, and micrometastasis formation. Finally, we summarize the recent clinical advancements of PARP inhibitors in the prevention and progression of distant metastases, with a particular focus on specific metastatic sites and PARP-1 selective inhibitors. Overall, PARP inhibitors have demonstrated great potential in inhibiting the metastatic process, pointing the way for greater use in early cancer settings.

项与 Selective PARP1 inhibitor(Acerand Therapeutics) 相关的新闻（医药）

2024-09-25

·PipelineReview

Duke Street Bio Granted Approval by European Medicines Agency to Launch Next-Generation PARP1-Selective Inhibitor Trial

LONDON, UK I September 24, 2024 I Duke Street Bio Ltd, a precision medicine biotech developing next generation small molecule cancer therapies, is pleased to announce that the European Medicines Agency (EMA) has granted approval to commence a clinical trial for its highly-selective PARP1 inhibitor, DSB2455. This potentially best-in-class, potent, highly selective and CNS-penetrant agent targets cancers that harbour homologous recombination deficiencies (HRD) including BRCA mutations. The safety profile of first generation non-selective PARP1/2 inhibitors has restricted their application, particularly in combination with chemotherapy and radiotherapy. By selectively inhibiting PARP1, we believe that DSB2455 has the potential to achieve a significantly enhanced therapeutic index, representing a significant advancement in precision medicine cancer treatment. Preliminary data indicate a strong safety profile and compelling efficacy in preclinical studies, paving the way to open our trial in the clinic. Alan Wise, CEO of Duke Street Bio, commented, “The approval of the DSB2455 First-in-Human clinical trial by the EMA is a testament to the therapeutic potential of our innovative approach in the DDR space. Duke Street Bio’s mission is to improve patient outcomes and bring new hope to individuals battling cancer. We believe that DSB2455 has the potential for improved efficacy and tolerability versus first-generation PARP inhibitors in patient populations where there is still significant unmet medical need.” For more information about Duke Street Bio and our upcoming clinical trial, please visit www.dukestbio.com About Duke Street Bio: Duke Street Bio is at the forefront of developing therapies that reprogram tumour biology by targeting the underlying genetic and immune pathways that fuel tumour growth. We are dedicated to improving the lives of patients facing a cancer diagnosis through groundbreaking research and innovative treatments. SOURCE: Duke Street Bio

临床研究

100 项与 Selective PARP1 inhibitor(Acerand Therapeutics) 相关的药物交易

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