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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

基本信息

批准号：
10460566
负责人：
Magdalena Bieniasz
金额：
$ 20.02万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-02 至 2024-01-31
项目状态：
已结题

项目摘要

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.

项目概要卵巢癌仍然是全国所有妇科恶性肿瘤中最致命的。不幸的是，目前的卵巢癌症治疗导致 85% 以上的患者产生化疗耐药性和肿瘤快速复发。这这里概述的项目代表了治疗干预急需的新机会。我们之前的已发表和正在进行的工作，揭示了短型 Ron (sfRon)，全长 Ron 的截短亚型 (flRon)受体酪氨酸激酶，可以驱动卵巢癌的发生和进展。之前我们展示过 sfRon 优先通过 PI3K 通路发出信号，并且关键的 sfRon 效应器 S6K1 对于肿瘤促进作用。我们的初步研究结果揭示了 sfRon-S6K1 信号传导在诱导细胞周期的有丝分裂进展。这些数据导致药物筛选研究表明，sfRon 的抑制作用或 S6K1（分别为 BMS777608 或 AD80）使卵巢癌细胞特别容易发生有丝分裂驱动蛋白 Eg5 抑制剂 Ispinesib。我们假设同时采用协同联合疗法阻断 sfRon 或 S6K1 和有丝分裂驱动蛋白可能被证明是晚期晚期患者的有效精准治疗卵巢癌。为了检验这个假设，我们提出了两个具体目标：（1）我们将通过以下方式确定机制：其中 sfRon 促进细胞周期的有丝分裂进程。我们将测试 sfRon 和/或 S6K1 是否耗尽遗传和药理学方法的信号传导影响细胞增殖、细胞周期分布和有丝分裂关键有丝分裂调节因子（例如 Aurora B 和/或 Plk1）的进展或正常功能。进一步，我们假设 S6K1 的缺失会导致卵巢癌细胞的有丝分裂滑移，从而使它们对 Ispinesib 敏感。为了测试这一点，我们将比较 sfRon、S6K1 和有丝分裂驱动蛋白抑制剂作为单一疗法或联合用药的效果。组合并确定药物诱导的细胞命运，包括有丝分裂停滞、有丝分裂滑移和细胞死亡。 (2) 我们将确定阻断 sfRon-S6K1 信号传导和有丝分裂驱动蛋白的协同联合疗法是否会导致使用临床相关的患者来源的异种移植物（PDX）获得有效且持续的抗肿瘤功效。我们将使用未经化疗的 PDX 并确定 sfRon 协同途径的抑制是否会导致更多比标准化疗具有持续的抗肿瘤反应。在疾病复发的情况下，我们将使用我们的化疗耐药的 PDX 模型，并研究联合疗法是否是一种有效的治疗方案复发性卵巢肿瘤目前的治疗选择非常有限。该提案将扩大我们的了解 sfRon 和/或 S6K1 调节细胞周期有丝分裂进程的机制。它还将为为什么 sfRon-S6K1 抑制使卵巢癌细胞特别脆弱提供新的见解有丝分裂驱动蛋白抑制剂。从长远来看，该项目可以提供一种新的精准疗法，旨在实现即使对化疗耐药的卵巢肿瘤也具有临床意义和持续的抗肿瘤反应。