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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要最近的研究强调了 DNA 修复途径改变的重要性以及 PARP 的重要性 PARPi 抑制剂（PARPi）在卵巢癌（OC）中的应用 PARPi 治疗导致中位数延长。无进展生存期，主要针对 OCs 同源重组 (HR) 修复缺陷的患者。同样，抑制特定生长因子 (GF) 介导的信号传导也会导致 PARPi 敏感性增加尽管有这些观察结果，HR 熟练的 OC 细胞仍对 PARPis 和酪氨酸激酶抑制剂产生耐药性。由于 GF 配体表达的改变，个体生长因子 (GF) 仍然是一个主要问题在肿瘤微环境中产生，可能通过上调恶化对激酶抑制剂的反应检查冗余的生存途径是否可以针对多个 GF 介导的信号途径。同时，获得性耐药可能会被最小化，并且治疗癌症会更有效根除而不是靶向治疗，OC最终会产生耐药性。为此，我们鉴定了 PG545，一种高度硫酸化的小分子（Pixatimod、Zucero Therapeutics、澳大利亚布里斯班）报道了对晚期癌症患者的安全性（NCT02042781），并且在正如我们小组所证明的，多种肿瘤模型，包括卵巢癌、子宫内膜癌和胰腺癌重要的是，PG545 可以抑制和破坏乙酰肝素酶。由肝素结合生长因子 (HBGF)（例如 HB-EGF、FGF、VEGF 和 HGF）介导的信号传导。初步数据表明，PG545具有克服PARP耐药性OC中的PARP耐药性的潜力通过下调 RAD51 诱导 DNA 损伤和“BRCAness”细胞系并减少细胞核分泌型 DEK 的积累，通过与 RAD51 升高形成复合物，在 HR 修复中发挥重要作用 DEK 对 RAD51 稳定性或功能做出贡献的可能性本应用的目标是确定。使用 PDX 模型和患者来源的腹水观察 PG545 与 PARP 抑制剂在体内协同作用的功效细胞，并确认 OC 细胞中 PG545 下调 RAD51 的潜在机制反映了我们的初步体外数据，目前，HR-患者没有有效的治疗选择。迫切需要新的有效药物组合来治疗 PARPi 耐药的复发性卵巢癌。为了解决这一关键的临床挑战，本文提出的药物组合将解决这一缺陷。