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

项目摘要 在子宫癌患者中，侵袭性组织学的预后较低。这可能是由于缺乏 鉴定子宫浆液性癌或高级别子宫内膜样肿瘤的特异性通路。我们 数据表明，AXL通路在子宫浆液性（USC）和3级类黄体中高度表达， 子宫内膜癌（G3 EEC）与较差的生存率相关。我们最近发现，高亲和力， AXL高选择性抑制剂AVB-500（现在称为batiraxcept）可以改善 USC和G3 EEC。此外，有数据表明，AXL表达与肿瘤的高度相关性。 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响应 对AXL抑制作用更好。此外，已发表的数据支持AXL调节VEGF-A，并且我们的临床前 数据支持抑制AXL可以改善对抗血管生成剂贝伐单抗的反应。我们 中心假设是用AVB-500抑制GAS 6/AXL将改善对标准治疗的反应 治疗我们将在三个具体目标中扩展以检验这一假设。 目的1：确定巴替西普与标准治疗紫杉醇联合治疗的安全性和耐受性， 复发性、侵袭性子宫内膜癌组织学类型（USC和G3 EEC）患者。 探索性目的2：确定与治疗反应相关的组织和血液标志物。 目的3：确定batiraxcept改善对标准治疗抗结核药物应答的机制。 血管生成贝伐单抗。 影响：Aim 1的临床试验数据将为未来的batiraxcept plus II期试验奠定基础 USC和G3 EEC患者中的紫杉醇。探索目标2的数据可能使我们能够开发一种代谢 可以预测对该药物组合的敏感性和/或提供对代谢的深入了解的生物标志物 对这种药物组合没有反应的肿瘤中涉及的过程。Aim 3的数据将提供 关键机制数据，以支持未来的临床试验相结合batiraxcept与贝伐单抗。从长远来看， 这项工作将使我们能够优化和个性化治疗的患者与侵略性子宫癌类型。 我们的团队有能力在临床和实验研究中检验我们的中心假设。

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.