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

项目总结 我们在治疗癌症的能力方面取得了很大进步。然而，我们仍然缺乏能力来确定 患者将从治疗中受益最多。在头颈部鳞状细胞癌(HNSCC)中，决定 放疗和化疗是基于对肿瘤分期和进展的解剖学评估。在……里面 此外，在治疗完成几周后评估治疗反应。及早确定 治疗抵抗将极大地减轻耐药肿瘤患者的痛苦和痛苦。 否则他们将接受数周无效的治疗。三个研究团队互为补充 漫反射光谱、拉曼光谱和辐射生物学方面的专业知识已经联手 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对放疗和化疗的反应。具体地说，这种多模式光学传感方法 提供对起关键作用的肿瘤氧合和代谢的同步、实时测定 在形成治疗耐药性方面的互补作用。漫反射与拉曼光谱的积分 光谱模式是由我们从抗辐射和敏感获得的初步数据推动的 移植瘤表现出显著更高的复氧率和升高的脂质和糖原含量 抗辐射肿瘤。本申请旨在显著推进这些初步调查结果 放射和化疗反应的综合特征。目标1专注于临床前阶段 用漫反射光谱技术研究黄曲霉毒素的短期和长期复氧动力学 对临床治疗方案作出反应的耐化疗和耐放射的肿瘤，以及在 过程中，确定可以可靠地预测辐射抗性的随时间变化的阈值。在目标2中，我们将 用拉曼光谱研究放化疗后肿瘤代谢的动态变化 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，在目标3中，我们试图通过一个 计划接受放化疗的HNSCC患者的试点临床研究。要确定 我们的方法在治疗的前半段内识别耐药肿瘤的初步敏感性 方案，我们将开发和使用多模逆空间偏移拉曼和漫反射 与标准临床喉镜兼容的光谱探头。圆满完成这些目标 将以前所未有的速度描绘与辐射和化疗耐药性相关的功能和分子变化 时间尺度。这种对治疗后立即发生的放射生物学变化的了解不仅有助于 区分治疗应答者和无应答者，但也要确定其他时间点 对治疗进行有意义的改变可以提高治疗应答率。

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.