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

项目2：抑制AXL以改善子宫内膜癌的治疗反应

• 批准号: 10711637
• 负责人: David G Mutch
• 金额: $ 40.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711637
• 关键词: Address; Affinity; Angiogenesis Inhibitors; Apoptosis; Binding; Biological Markers; Biopsy; Blood; Blood Vessels; Cancer Histology; Cancer Patient; Cell Survival; Cessation of life; Chemoresistance; Chimeric Proteins; Clinical Research; Clinical Trials; Data; Diagnosis; Disease; Dose; Drug Combinations; Drug Kinetics; Endometrial Carcinoma; Endometrial Neoplasms; Endometrioid Tumor; Equity; Foundations; Future; Genes; Glycolysis; Growth; Histology; Immunohistochemistry; In Vitro; Invaded; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Metabolic; Metabolism; Monoclonal Antibody Therapy; Names; Neoplasm Metastasis; Oklahoma; PI3K/AKT; Paclitaxel; Pathology; Pathway interactions; Patients; Pharmacodynamics; Phase; Phase 1/1b Clinical Trial; Phase Ib Trial; Phenotype; Platinum; Positioning Attribute; Prognosis; Proliferating; Publishing; Recurrence; Relapse; Resistance; Route; Safety; Sampling; Serous; Serum; Sterically Stabilized Liposome; Testing; Tissues; Translating; Tumor Burden; Universities; Uterine Cancer; Uterus; VEGFA gene; Vascular Endothelial Growth Factors; Washington; Woman; Work; active method; angiogenesis; axl receptor tyrosine kinase; bevacizumab; blood glucose regulation; cancer cell; cancer type; chemotherapy; clinical care; density; experimental study; improved; in vivo; inhibitor; insight; metabolomics; mouse model; neoplastic cell; new combination therapies; objective response rate; open label; participant enrollment; patient derived xenograft model; personalized medicine; phase II trial; pre-clinical; primary outcome; protein expression; recruit; response; secondary outcome; stable isotope; standard of care; targeted treatment; treatment response; tumor

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.

项目摘要 子宫癌患者侵略性组织学的预后很低。这可能是由于缺乏 特定于子宫浆液癌或高级子宫内膜类药物肿瘤的识别。我们的 数据表明，AXL途径在子宫浆液（USC）和3级子宫内膜类药物中高度表达 子宫内膜癌（G3 EEC）与生存率较差有关。我们最近表明，高亲和力， AXL的高度选择性抑制剂AVB-500（现称为Batiraxcept）可以改善对紫杉醇的反应 USC和G3 EEC。此外，还有开发数据，即AXL表达与高度相关 糖酵解表型，以及与糖酵解的这种相关性可能使我们能够确定哪些肿瘤可以反应 更好地抑制AXL。此外，已发布的数据支持AXL调节VEGF-A和我们的临床前 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。我们的 中心假设是用AVB-500抑制GAS6/AXL将改善对护理标准的反应 治疗。我们将在三个特定目标中扩展以检验这一假设。 目标1：确定将Batiraxcept与护理标准紫杉醇相结合的安全性和耐受性 具有复发性，侵略性子宫内膜癌组织学（USC和G3 EEC）的患者。 探索目的2：确定与治疗反应相关的组织和血液标记。 AIM 3：确定Batiraxcept改善对护理标准反应的反应的机制 血管生成贝伐单抗。 影响：AIM 1的临床试验数据将构成Batiraxcept Plus未来II期试验的基础 USC和G3 EEC患者的紫杉醇。来自探索性目标2的数据可能使我们能够开发代谢 可以预测对这种药物组合敏感和/或提供代谢的生物标志物 参与对这种药物组合无反应的肿瘤的过程。来自AIM 3的数据将提供 关键机械数据支持将来的临床试验与贝伐单抗相结合。从长远来看 这项工作将使我们能够优化和个性化侵袭性子宫癌类型患者的治疗方法。 我们的团队在临床和实验研究中测试我们的中心假设。