VEGF/Neuropilin-2 Signaling and Radioresistance in Triple-Negative Breast Cancer

三阴性乳腺癌中的 VEGF/Neuropilin-2 信号转导和放射抗性

基本信息

批准号：
10678449
负责人：
Ayush Kumar
金额：
$ 3.49万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-28 至 2027-03-27
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678449
关键词：
Adjuvant Chemotherapy Antioxidants Binding Blocking Antibodies Breast Cancer Cell Breast Cancer Patient Breast-Conserving Surgery Cell Death Cell Survival Cells DNA Damage Data Effectiveness Extinction Failure Fellowship Gene Expression Profile Genes Genetic Transcription Goals Growth Homeostasis In complete remission Literature Mediating Metabolic Metabolic Pathway Molecular Nature Neoadjuvant Therapy Neuropilin-2 Nitric Oxide Nitric Oxide Synthase Nuclear Organoids Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Pathologic Pathway interactions Patients Phenotype Physicians Population Prognosis Property Radiation Radiation Tolerance Radiation therapy Reactive Inhibition Reactive Oxygen Species Recurrence Regulation Research Residual Neoplasm Resistance Role Scientist Signal Induction Signal Transduction Surgical Management Survival Rate Technology Testing Therapeutic Training Variant Vascular Endothelial Growth Factors Vascular Endothelium bench to bedside cancer stem cell cancer subtypes carcinogenesis clinically significant effectiveness evaluation improved in vivo Model insight irradiation knock-down malignant breast neoplasm molecular subtypes neoplastic cell novel novel therapeutic intervention patient derived xenograft model pre-clinical radiation resistance radioresistant receptor relapse patients relapse prevention resistance mechanism response self-renewal single-cell RNA sequencing stem cells targeted treatment therapeutic target therapy outcome therapy resistant traditional therapy treatment response treatment strategy triple-negative invasive breast carcinoma tumor tumor heterogeneity

项目摘要

PROJECT SUMMARY Triple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer with standard therapy involving neoadjuvant chemotherapy, surgical management, and radiation therapy. However, the high recurrence rate and low pathological complete response of TNBC suggest that radioresistance is a critical factor in the diminished therapeutic efficiency of the current treatment strategy. There is limited literature exploring the specific pathways responsible for radiation resistance in TNBC, but most data support the role of limiting reactive oxygen species (ROS) accumulation. Our lab has studied the role of Vascular Endothelia Growth Factor (VEGF) binding to Neuropilin-2 (NRP2) and initiating several cancer stem cell properties. Preliminary data indicate that radiation enriches for NRP2 expressing cells and using a function blocking antibody specific to VEGF/NRP2 with irradiation decreases cell viability compared to either treatment alone in a TNBC organoid. The central hypothesis of this proposal is that VEGF/NRP2 induces radioresistance by altering redox homeostasis and can be targeted for better therapeutic outcomes in TNBC. This proposal will seek to investigate a possible role of NRP2 regulating NOS2 transcription and its contribution to mitigating ROS accumulation. I will also use single-cell RNA sequencing technology to identify the subpopulations of TNBC that are radioresistant and whether they utilize the NRP2/NOS2 signaling axis. Another aspect of this proposal is to observe the effectiveness of a function blocking antibody of NRP2 with radiation using an in vivo model. I plan to identify if this approach reduces the radioresistant clones in TNBC. The completion of this proposal will heighten the understanding of radioresistance in TNBC and identify a novel molecular pathway responsible for this phenotype.

项目摘要三重阴性乳腺癌（TNBC）是一种具有侵略性的乳腺癌形式，具有标准疗法，涉及新辅助化疗，手术管理和放射疗法。但是，高复发率和 TNBC的低病理完全反应表明，放射线是降低的关键因素当前治疗策略的治疗效率。有限的文献探索了特定的途径负责TNBC的辐射抗性，但大多数数据支持限制活性氧的作用（ROS）积累。我们的实验室研究了血管内皮生长因子（VEGF）与 Neuropilin-2（NRP2）并启动了几种癌细胞特性。初步数据表明辐射富集表达细胞的NRP2，并使用特定于VEGF/NRP2的功能阻断抗体与TNBC类器官中的任何一种治疗相比，辐射可降低细胞活力。中央该提议的假设是VEGF/NRP2通过改变氧化还原稳态和可以针对TNBC中更好的治疗结果。该建议将寻求调查可能 NRP2调节NOS2转录的作用及其对减轻ROS积累的贡献。我也会使用单细胞RNA测序技术，以识别辐射耐药和的TNBC亚群他们是否使用NRP2/NOS2信号轴。该提议的另一个方面是观察使用体内模型使用辐射的NRP2的功能阻断抗体的有效性。我打算确定是否这种方法减少了TNBC中的辐射克隆。该提案的完成将加剧了解TNBC中的放射线并确定了负责这种表型的新型分子途径。