Determination of functional and molecular biomarkers of treatment resistance with multimodal optical spectroscopy

用多模态光谱测定治疗耐药性的功能和分子生物标志物

• 批准号: 10672233
• 负责人: Narasimhan Rajaram
• 金额: $ 37.64万
• 依托单位: UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-13 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672233
• 关键词: Anatomy; Bioenergetics; Biological; Biological Process; Catabolism; Cell Line; Chemoresistance; Chemotherapy and/or radiation; Clinic; Clinical; Clinical Research; Clinical Treatment; Data; Databases; Development; Diffuse; Early identification; Endoscopes; Evaluation; Failure; Fatty Acids; Glucose; Glycogen; Glycolysis; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Hemoglobin; Human; Human Papillomavirus; Image; In complete remission; Kinetics; Knowledge; Laryngoscopes; Lipids; Malignant Neoplasms; Maps; Measurement; Metabolic; Metabolism; Methods; Microscopy; Modality; Modeling; Molecular; Monitor; Mus; Operative Surgical Procedures; Optics; Oxygen Consumption; Pain; Pathway interactions; Patients; Pentosephosphate Pathway; Play; Process; Publishing; Quality of life; Radiation; Radiation Dose Unit; Radiation Monitoring; Radiation therapy; Radiobiology; Raman Spectrum Analysis; Regimen; Research; Resistance; Role; Schedule; Shapes; Spectrum Analysis; Survival Rate; Testing; Therapeutic; Time; Translating; Translations; Treatment Failure; Treatment Protocols; Tumor Oxygenation; Tumor stage; Work; X-Ray Computed Tomography; chemoradiation; chemotherapy; clinical imaging; clinical practice; clinically relevant; design; diffuse reflectance spectroscopy; fractionated radiation; head and neck cancer patient; histological studies; improved; improved outcome; in vivo; in vivo monitoring; individual response; ineffective therapies; metabolome; metabolomics; molecular marker; multimodality; optimal treatments; personalized medicine; preclinical study; predictive marker; primary outcome; programs; radiation resistance; radiation response; radioresistant; responders and non-responders; response; side effect; therapy resistant; tool; treatment responders; treatment response; tumor; tumor metabolism; tumor microenvironment; tumor progression; tumor xenograft

PROJECT SUMMARY We have made great advances in our ability to treat cancer. However, we still lack the ability to determine which patients will benefit the most from treatment. In head and neck squamous cell carcinoma (HNSCC), the decision to treat with radiation and chemotherapy is based on anatomical evaluations of tumor stage and progression. In addition, treatment response is evaluated several weeks post-completion of therapy. An early determination of treatment resistance would greatly alleviate the pain and suffering for patients with treatment-resistant tumors who would otherwise undergo several weeks of ineffective therapy. Three research teams with complementary expertise in diffuse reflectance spectroscopy, Raman spectroscopy, and radiation biology have joined forces to develop a non-invasive, quantitative tool that can reveal key metabolic, functional and molecular changes in response to radiation and chemotherapy in HNSCC. Specifically, this multi-modal optical sensing approach affords simultaneous, real-time determination of tumor oxygenation and metabolism that play key complementary roles in shaping treatment resistance. The integration of diffuse reflectance and Raman spectroscopic modalities is motivated by our preliminary data acquired from radiation-resistant and sensitive tumor xenografts that shows significantly higher reoxygenation and elevated lipid and glycogen content in the radiation-resistant tumors. This application seeks to significantly advance these preliminary findings for comprehensive characterization of radiation and chemotherapeutic responses. Aim 1 is focused on pre-clinical studies using diffuse reflectance spectroscopy to investigate short-term and long-term reoxygenation kinetics of chemo and radiation-resistant and sensitive tumors in response to clinical treatment regimens and, in the process, identify time-dependent thresholds that can reliably predict radiation resistance. In Aim 2, we will investigate the dynamic changes in tumor metabolism after radiation and chemotherapy using Raman spectroscopy and correlate these findings with metabolomics to map the key spectral features to molecular determinants. Finally, in Aim 3, we seek to translate the consolidated panel of spectroscopic markers through a pilot clinical study in patients with HNSCC who are scheduled for chemoradiation therapy. To determine the initial sensitivity of our approach in identifying treatment-resistant tumors within the first half of the therapeutic regimen, we will develop and employ a multimodal inverse spatially offset Raman and diffuse reflectance spectroscopy probe that is compatible with a standard clinical laryngoscope. Successful completion of these aims will delineate functional and molecular changes associated with radiation and chemoresistance at unprecedented time scales. This knowledge of radiobiological changes occurring immediately after therapy will not only aid in differentiating treatment responders and non-responders but also identify additional time points at which meaningful changes to therapy could improve treatment response rates.

项目摘要 我们在治疗癌症的能力方面取得了长足的进步。但是，我们仍然缺乏确定哪个 患者将从治疗中受益最大。在头颈部鳞状细胞癌（HNSCC）中，该决定 通过放射线和化学疗法治疗是基于对肿瘤阶段和进展的解剖学评估。在 此外，对治疗后几周进行了几周的治疗反应。早期确定 治疗耐药性会大大减轻耐药性肿瘤患者的疼痛和痛苦 否则，他们将接受几周的无效治疗。三个与互补的研究团队 扩散反射光谱，拉曼光谱和辐射生物学方面的专业知识已与力量联合起来 开发一种非侵入性的定量工具，可以揭示关键的代谢，功能和分子变化 HNSCC中对放射和化学疗法的反应。具体而言，这种多模式光传感方法 提供肿瘤氧合和新陈代谢的同时实时确定键 互补的作用在塑造治疗抗性中。扩散反射和拉曼的整合 光谱方式是由我们从抗辐射和敏感的初步数据激励的 肿瘤异种移植物显示出明显更高的氧化和脂质和糖原含量升高的肿瘤异种移植物。 抗辐射肿瘤。该申请旨在显着提高这些初步发现 辐射和化学治疗反应的全面表征。 AIM 1专注于临床前 使用弥漫性反射率光谱研究研究短期和长期重氧动力学的研究 对临床治疗方案的反应以及在 过程，确定可以可靠地预测辐射抗性的时间依赖性阈值。在AIM 2中，我们将 研究辐射和化学疗法使用拉曼后肿瘤代谢的动态变化 光谱法并将这些发现与代谢组学相关联，以将关键光谱特征映射到分子 决定因素。最后，在AIM 3中，我们试图通过一个 针对计划进行化学放疗治疗的HNSCC患者的试点临床研究。确定 我们方法在治疗的上半年识别耐治疗肿瘤方面的初始敏感性 方案，我们将开发并采用多模式的逆空间抵消拉曼和扩散反射率 与标准临床喉镜兼容的光谱探针。这些目标成功完成 将描绘出与辐射和化学抗性相关的功能和分子变化 时间尺度。对治疗后立即发生的放射生物学变化的了解不仅有助于 区分治疗响应者和非反应者，但也确定了其他时间点 治疗的有意义的变化可以提高治疗反应率。

项目成果

Longitudinal monitoring of tumor response to immune checkpoint inhibitors using noninvasive diffuse reflectance spectroscopy.

使用无创漫反射光谱纵向监测肿瘤对免疫检查点抑制剂的反应。

• DOI: 10.1364/boe.426879
• 发表时间: 2021
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: Troncoso,JoelRodriguez;Diaz,PaolaMonterroso;Lee,DavidE;Quick,CharlesM;Rajaram,Narasimhan
• 通讯作者: Rajaram,Narasimhan

CellSNAP: A fast, accurate algorithm for 3D cell segmentation in quantitative phase imaging.

CellSNAP：一种快速、准确的算法，用于定量相位成像中的 3D 细胞分割。

• DOI: 10.1101/2023.07.24.550376
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Raj,Piyush;Paidi,Santosh;Conway,Lauren;Chatterjee,Arnab;Barman,Ishan
• 通讯作者: Barman,Ishan