Targeting sfRon-S6K1 signaling and mitotic kinesin Eg5 in ovarian cancer: a novel synergistic treatment strategy

卵巢癌中靶向 sfRon-S6K1 信号传导和有丝分裂驱动蛋白 Eg5：一种新型协同治疗策略

• 批准号: 10304648
• 负责人: Magdalena Bieniasz
• 金额: $ 24.52万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-02 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304648
• 关键词: Affect; Antitumor Response; Cancer Burden; Cancer Patient; Cancer cell line; Carboplatin; Carcinogens; Cell Cycle; Cell Cycle Arrest; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cell Proliferation; Cells; Centromere; Chemoresistance; Clinical; Combined Modality Therapy; Communities; Data; Death Rate; Defect; Development; Drug Combinations; Drug Screening; Ensure; Failure; Genetic; Kinesin; Length; Ligand Binding Domain; Ligands; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Minority Groups; Mitosis; Mitotic; Modeling; Mus; Oklahoma; Operative Surgical Procedures; Ovarian; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Platinum; Precision therapeutics; Protein Isoforms; Publishing; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent disease; Recurrent tumor; Research; Research Personnel; Rural Community; Signal Transduction; Testing; Therapeutic Intervention; Time; Treatment Protocols; Underserved Population; Work; cancer cell; cancer therapy; chemotherapy; clinically relevant; combinatorial; cyclin B1; effective therapy; experimental study; extracellular; in vitro Model; inhibitor/antagonist; innovation; insight; knock-down; mortality; novel; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; patient derived xenograft model; pre-clinical; precision medicine; preclinical evaluation; receptor; recruit; standard care; taxane; therapeutic target; therapy design; treatment strategy; tumor

PROJECT SUMMARY Ovarian cancer remains the deadliest of all gynecologic malignancies nationwide. Unfortunately, current ovarian cancer treatment leads to chemoresistance and a rapid tumor recurrence in more than 85% of patients. The project outlined here represents a much needed new opportunity for therapeutic intervention. Our previous published and ongoing work, has revealed that short-form Ron (sfRon), a truncated isoform of the full-length Ron (flRon) receptor tyrosine kinase, can drive ovarian cancer development and progression. Previously, we showed that sfRon preferentially signals through the PI3K pathway, and that the key sfRon effector S6K1 is crucial for tumor promoting effects. Our preliminary findings revealed a novel function of sfRon-S6K1 signaling in inducing mitotic progression of the cell cycle. These data led to drug screening studies showing that the inhibition of sfRon or S6K1 (by BMS777608 or AD80, respectively) renders ovarian cancer cells particularly vulnerable to mitotic kinesin Eg5 inhibitor Ispinesib. We hypothesize that a synergistic combination therapy simultaneously blocking sfRon or S6K1 and mitotic kinesins could prove an effective precision treatment for advanced ovarian cancer. To test this hypothesis, we propose two specific aims: (1) We will determine the mechanism by which sfRon promotes the mitotic progression of cell cycle. We will test if depletion of sfRon and/or S6K1 signaling by genetic and pharmacological approaches affects cell proliferation, cell cycle distribution, and mitotic progression or proper function of critical mitotic regulators such as Aurora B and/or Plk1. Further, we hypothesize that the depletion of S6K1 contributes to mitotic slippage of ovarian cancer cells sensitizing them to Ispinesib. To test that, we will compare the effects of sfRon, S6K1, and mitotic kinesin inhibitors as monotherapy or in combination and determine the drug-induced cell fate including mitotic arrest, mitotic slippage, and cell death. (2) We will determine if synergistic combination therapy blocking sfRon-S6K1 signaling and mitotic kinesins leads to a potent and sustained antitumor efficacy using clinically relevant patient-derived xenografts (PDXs). We will use chemotherapy naïve PDXs and determine if the inhibition of sfRon synergistic pathways results in a more sustained anti-tumor response than standard chemotherapy. In recurrent disease setting, we will use our chemoresistant PDX models and investigate if the combination therapy is an effective treatment regimen for recurrent ovarian tumors that currently have very limited treatment options. This proposal will expand our understanding of the mechanism by which sfRon and/or S6K1 regulates the mitotic progression of cell cycle. It will also provide new insight into why sfRon-S6K1 inhibition renders ovarian cancer cells particularly vulnerable to mitotic kinesin inhibitors. In the long-term, this project could offer a new precision therapy designed to achieve a clinically meaningful and sustained anti-tumor response to even chemoresistant ovarian tumors.

项目总结