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: 10553686
• 负责人: VIJI SHRIDHAR
• 金额: $ 21.85万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553686
• 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; 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; Poly(ADP-ribose) Polymerase Inhibitor; 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; brca gene; cancer cell; cohort; effective therapy; efficacy evaluation; heparanase; homologous recombination; in vitro Model; in vivo; inhibitor therapy; kinase inhibitor; lung Carcinoma; malignant breast neoplasm; melanoma; mutational status; novel; patient derived xenograft model; prevent; recombinational repair; reduce symptoms; repaired; response; small molecule; synergism; 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.

项目总结/摘要 最近的研究强调了DNA修复途径改变的重要性和PARP的意义 抑制剂（PARPi）在卵巢癌（OC）中的作用。PARPi疗法的使用延长了 无进展生存期，主要用于OC同源重组（HR）修复缺陷的患者。 同样地，抑制特异性生长因子（GF）介导的信号传导也导致了PARPi敏感性的增加， HR精通OC细胞。尽管有这些观察结果，但对PARPis和酪氨酸激酶抑制剂的耐药性仍然存在。 由于GF配体表达的改变，单个生长因子（GF）仍然是一个主要问题 在肿瘤微环境中产生，可能会通过上调激酶抑制剂而恶化对激酶抑制剂的反应性 冗余的生存路径。因此，如果可以靶向多种GF介导的信号通路， 同时，获得性耐药性可能会被最小化，治疗癌症更有效。 根除比靶向治疗更有效，OC最终会产生耐药性。 为此，我们已经鉴定了PG 545，一种高度硫酸化的小分子（Pixatimod，Zucero Therapeutics， 布里斯班，澳大利亚），在晚期癌症患者中报告了安全性（NCT 02042781），在 多个肿瘤模型，包括卵巢癌、子宫内膜癌和胰腺癌，正如我们的小组所证明的那样， 以及结肠癌、乳腺癌和肺癌。重要的是，PG 545抑制乙酰肝素酶并破坏 由肝素结合生长因子（HBGF）如HB-EGF、FGF、VEGF和HGF介导的信号传导。我们 初步数据表明，PG 545具有克服PARP抗性OC中PARP抗性的潜力 细胞系通过诱导DNA损伤和“BRCAness”通过下调RAD 51和减少核 分泌的DEK的积累，通过与RAD 51形成复合物，在HR修复中起重要作用， DEK有助于RAD 51稳定性或功能的可能性。本应用程序的目标是确定 使用PDX模型和在患者来源的腹水中，PG 545与PARP抑制剂在体内协同作用的功效 细胞，并确认PG 545下调OC细胞中的RAD 51的潜在机制 与我们体外实验的初步数据吻合目前，对于HR患者没有有效的治疗选择- 熟练和PARPi耐药复发性卵巢癌。迫切需要新的有效药物组合 来应对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。