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

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)中的抑制物(PARPI)PARPI疗法的使用导致了中位数的延长 无进展生存，主要针对OCS为同源重组(HR)修复缺陷的患者。 同样，抑制特定生长因子(GF)介导的信号转导也导致PARPI敏感性增加 人力资源熟练的OC细胞。尽管有这些观察，对PARPis和酪氨酸激酶抑制剂的耐药性 由于生长因子配体表达的改变，个体生长因子(GFS)仍然是一个主要问题 在肿瘤微环境中产生，可能通过上调表达而恶化对激酶抑制剂的反应性 多余的生存路径。因此，如果可以针对多个GF介导的信号通路 同时，获得性耐药性可能被最小化，治疗癌症更有效。 根除而不是靶向治疗，OCS最终会对其产生抗药性。 为此，我们确定了PG545，一种高度硫酸盐化的小分子(Pixatimod，Zucero Treeutics， 澳大利亚布里斯班)，报告对晚期癌症患者的安全性(NCT02042781)，并在 多种肿瘤模型，包括卵巢癌、子宫内膜癌和胰腺癌，正如我们小组所证明的那样 而在结肠癌、乳腺癌和肺癌中，其他组也是如此。重要的是，PG545抑制乙酰肝素酶并破坏 由肝素结合生长因子(HBGFs)介导的信号转导通路，如HB-EGF、FGFs、VEGF和HGF。我们的 初步数据表明，在PARP抗性OC中，PG545具有克服PARP抗性的潜力 通过诱导DNA损伤的细胞株和通过下调RAD51和减少核的BRCAness 分泌的DEK通过与RAD51形成复合体而在HR修复中发挥重要作用 DEK对RAD51稳定性或功能有贡献的可能性。此应用程序的目标是确定 在体内PDX模型和患者腹水中PG545与PARP抑制剂的协同作用 也是为了证实PG545下调OC细胞RAD51的潜在机制 反映了我们的体外初步数据。目前，对于HR患者，还没有有效的治疗选择。 熟练且耐PARPI的复发性卵巢癌。迫切需要新的有效药物组合 以应对这一关键的临床挑战。这里提出的药物组合将解决这一不足。

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.