PG545 synergizes with PARP inhibitors in ovarian cancer to disrupt DNA repair through modulation of DEK-RAD51 axis

PG545 与卵巢癌中的 PARP 抑制剂协同作用，通过调节 DEK-RAD51 轴破坏 DNA 修复

• 批准号: 10426460
• 负责人: VIJI SHRIDHAR
• 金额: $ 18.58万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426460
• 关键词: Address; Advanced Malignant Neoplasm; Ascites; Australia; Cancer Patient; Cancer cell line; Cell Line; Cells; Characteristics; Chemoresistance; Clinical; Clinical Trials; Co-Immunoprecipitations; Colon Carcinoma; Complex; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DTR gene; Data; Down-Regulation; Drug Combinations; Endometrial Carcinoma; Fibroblast Growth Factor; Gene Expression; Genetic Transcription; Goals; Grant; Growth; Growth Factor; Heparan Sulfate Proteoglycan; Heparin Binding Growth Factor; Histology; Immunofluorescence Immunologic; In Vitro; Individual; Large Intestine Carcinoma; Letters; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Modeling; Mus; Nivolumab; Non-Small-Cell Lung Carcinoma; Nuclear; Oncoproteins; Ovarian; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase II Clinical Trials; Platinum; Play; Progression-Free Survivals; Recurrence; Reporting; Resistance; Resistance development; Role; Safety; Sampling; Signal Pathway; Signal Transduction; Site; Sulfate; Testing; Therapeutic; Tumor Burden; Tyrosine Kinase Inhibitor; Up-Regulation; Vascular Endothelial Growth Factors; Western Blotting; Xenograft Model; Xenograft procedure; base; brca gene; cancer cell; cohort; effective therapy; heparanase; homologous recombination; in vitro Model; in vivo; inhibitor; inhibitor therapy; kinase inhibitor; malignant breast neoplasm; melanoma; mutational status; novel; patient derived xenograft model; prevent; recombinational repair; reduce symptoms; repaired; response; small molecule; targeted agent; targeted treatment; three dimensional cell culture; treatment response; tumor; tumor microenvironment; tumor xenograft

PROJECT SUMMARY/ABSTRACT Recent studies have highlighted the importance of DNA repair pathway alterations and the significance of PARP inhibitors (PARPi) in ovarian cancer (OC). The use of PARPi therapy has resulted in extending the median progression-free survival, mainly for patients whose OCs are homologous recombination (HR) repair deficient. Likewise, inhibiting specific growth factor (GF)-mediated signaling has also led to increased PARPi sensitivity in HR proficient OC cells. Despite these observations, resistance to PARPis and tyrosine kinase inhibitors against individual growth factors (GFs) continues to be a major problem due to altered expression of GF ligands produced in the tumor microenvironment that may worsen responsiveness to kinase inhibitors by upregulating redundant survival pathways. Consequently, if multiple GF-mediated signaling pathways could be targeted simultaneously, the acquired resistance could potentially be minimized and treatment is more effective in cancer eradication than targeted therapy for which OCs eventually develop resistance. To this end, we have identified PG545, a highly sulfated small molecule (Pixatimod, Zucero Therapeutics, Brisbane, Australia) with reported safety in advanced cancer patients (NCT02042781) and significant effect in multiple tumor models, including ovarian, endometrial and pancreatic cancers, as demonstrated by our group and in colon, breast, and lung cancers by other groups. Importantly, PG545 inhibits heparanase and disrupts signaling mediated by heparin-binding growth factors (HBGFs) such as HB-EGF, FGF, VEGF and HGF. Our preliminary data have shown that PG545 has the potential to overcome PARP resistance in PARP resistant OC cell lines by inducing DNA damage and “BRCAness” by downregulating RAD51 and diminished the nuclear accumulation of the secreted DEK that plays a vital role in HR repair by forming complexes with RAD51 raising the possibility that DEK contributes to RAD51 stability, or function. The goal in this application is to determine the efficacy of PG545 to synergize with PARP inhibitors in vivo using PDX models and in patient derived ascites cells and also to confirm whether the underlying mechanism by which PG545 downregulates RAD51 in OC cells mirrors our in vitro preliminary data. Currently, there are no effective treatment options for patients with HR- proficient and PARPi-resistant recurrent ovarian cancer. New effective drug combinations are urgently needed to address this critical clinical challenge. The drug combination proposed here will address this deficiency.

项目摘要/摘要 最近的研究强调了DNA修复途径改变的重要性和PARP的重要性 卵巢癌（OC）的抑制剂（PARPI）。 PARPI疗法的使用导致中位数扩大 无进展生存期，主要用于OC的同源重组（HR）修复缺乏的患者。 同样，抑制特定生长因子（GF）介导的信号传导也导致PARPI敏感性提高 HR熟练的OC细胞。尽管有这些观察，但对parpis和酪氨酸激酶抑制剂的抗性 由于GF配体的表达改变，个人生长因子（GFS）仍然是一个主要问题 在肿瘤微环境中产生的，可能通过上调对激酶抑制剂的响应性恶化 冗余生存途径。因此，如果可以针对多个GF介导的信号通路 同样，获得的抗药性可能会最小化，并且治疗在癌症中更有效 消除与有时会产生抗性的目标疗法相比。 为此，我们确定了PG545，这是高度硫酸的小分子（Pixatimod，Zucero Therapeutics， 澳大利亚布里斯班，据报道了晚期癌症患者的安全性（NCT02042781），并在 如我们组所证明的多种肿瘤模型，包括卵巢，子宫内膜和胰腺癌 在结肠，乳腺癌和肺癌中，其他群体。重要的是，PG545抑制肝素酶并破坏 肝素结合生长因子（HBGF）介导的信号传导，例如HB-EGF，FGF，VEGF和HGF。我们的 初步数据表明，PG545有可能克服抗PARP OC中的PARP抗性 通过下调RAD51的诱导DNA损伤和“ BRCACENS”的细胞系并减少了核 通过形成rad51升高的复合物在HR修复中起着至关重要的作用，分泌的DEK积累 DEK有助于RAD51稳定性或功能。该应用程序的目标是确定 PG545使用PDX模型和患者衍生的腹水在体内与PARP抑制剂协同效率 细胞并确认PG545下调OC细胞中RAD51的基本机制是否是否存在 反映我们的体外初步数据。目前，HR-患者没有有效的治疗选择 熟练度和抗parpi的复发性卵巢癌。迫切需要新的有效药物组合 应对这一关键的临床挑战。这里提出的药物组合将解决此缺陷。