Project 2: Inhibiting AXL to Improve Treatment Response in Endometrial Cancer

项目总结 子宫癌患者侵袭性组织学预后较差。这很可能是因为缺乏 识别特定于子宫浆液性癌或高级别子宫内膜样瘤的通路。我们的 研究表明，Axl通路在子宫浆膜(USC)和3级子宫内膜样变中高度表达 子宫内膜癌(G3EEC)与较差的存活率有关。我们最近已经证明，高亲和力， 高选择性的Axl抑制剂AVB-500(现在称为batiraxcept)可以改善对紫杉醇的反应。 南加州大学和G3欧洲共同体。此外，有不断发展的数据表明，axl的表达与 糖酵解表型，这种与糖酵解的相关性可能使我们能够确定哪些肿瘤可以反应 最好是抑制AXL。此外，已发表的数据支持Axl调节血管内皮生长因子-A，以及我们的临床前 数据支持，抑制Axl可以改善对抗血管生成药物贝伐单抗的反应。我们的 中心假设是用AVB-500抑制Gas6/Ax1将改善对标准护理的反应 治疗。我们将在三个具体目标上扩展以检验这一假设。 目的1：确定巴替拉西普与标准护理紫杉醇联合应用的安全性和耐受性 具有复发、侵袭性子宫内膜癌组织学(USC和G3 EEC)的患者。 探索性目标2：确定与治疗反应相关的组织和血液标记物。 目的3：确定batiraxcept改善对照护标准的抗癌反应的机制 血管生成贝伐单抗。 影响：AIM 1的临床试验数据将构成未来batiraxcept plus第二阶段试验的基础 紫杉醇在USC和G3期食管癌患者中的应用。来自探索性目标2的数据可能允许我们开发一种新陈代谢 生物标志物，可以预测对这种药物组合的敏感性和/或提供对代谢的洞察 参与对这种药物组合不起作用的肿瘤的过程。来自AIM 3的数据将提供 关键的机制数据，以支持未来的临床试验结合batiraxcept和贝伐单抗。从长远来看， 这项工作将使我们能够优化和个性化治疗侵袭性子宫癌类型的患者。 我们的团队处于有利地位，可以在临床和实验研究中测试我们的中心假设。

PROJECT SUMMARY The prognosis for the aggressive histologies in uterine cancer patients is low. This is likely due to lack of identification of pathways specific to uterine serous cancer or high-grade endometrioid tumors specifically. Our data suggest that the AXL pathway is highly expressed in uterine serous (USC) and grade 3 endometrioid endometrial cancer (G3 EEC) is associated with worse survival. We have recently shown that high-affinity, highly-selective inhibitor of AXL, AVB-500 (now known as batiraxcept), can improve response to paclitaxel in USC and G3 EEC. Additionally, there is developing data that AXL expression is correlated with the highly glycolytic phenotype, and this correlation with glycolysis may allow us to determine which tumors can respond better to AXL inhibition. Furthermore, published data supports that AXL regulates VEGF-A, and our preclinical data supports that inhibition of AXL can improve response to the anti-angiogenic agent, bevacizumab. Our central hypothesis is that inhibiting GAS6/AXL with AVB-500 will improve response to standard of care treatment. We will expand to test this hypothesis in three specific aims. Aim 1: Determine the safety and tolerability of combining batiraxcept with standard-of-care paclitaxel in patients with recurrent, aggressive endometrial cancer histologies (USC and G3 EEC). Exploratory Aim 2: Identify tissue and blood markers that correlate with response to treatment. Aim 3: Determine the mechanisms by which batiraxcept improves response to the standard-of-care anti- angiogenic bevacizumab. Impact: The clinical trial data from Aim 1 will form the foundation of a future Phase II trial of batiraxcept plus paclitaxel in USC and G3 EEC patients. The data from Exploratory Aim 2 may allow us to develop a metabolic biomarker that can predict sensitivity to this drug combination and/or provide insight into the metabolic processes involved in tumors that do not respond to this drug combination. The data from Aim 3 will provide key mechanistic data to support a future clinical trial combining batiraxcept with bevacizumab. In the long term, this work will allow us to optimize and personalize treatment for patients with aggressive uterine cancer types. Our team is well-positioned to test our central hypothesis in clinical and experimental studies.