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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.

项目总结/文摘