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

项目摘要 我们在治疗癌症的能力上取得了巨大的进步。然而，我们仍然缺乏能力来确定 患者将从治疗中获益最多。在头颈部鳞状细胞癌（HNSCC）中， 用放射和化学疗法治疗是基于肿瘤阶段和进展的解剖学评估。在 此外，在治疗完成后数周评价治疗反应。尽早确定 治疗抵抗将极大地减轻患有治疗抵抗性肿瘤的患者的疼痛和痛苦 否则他们会经历几周无效的治疗。三个研究团队互补 漫反射光谱学、拉曼光谱学和辐射生物学的专业知识已经联合起来， 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对放疗和化疗的反应。具体地，这种多模式光学感测方法 提供了肿瘤氧合和代谢的同时，实时测定， 在形成治疗抵抗方面的互补作用。漫反射和拉曼的集成 光谱模式的动机是我们的初步数据，从耐辐射和敏感 肿瘤异种移植物显示出显著更高的再氧合和升高的脂质和糖原含量， 抗辐射肿瘤本申请旨在大大推进这些初步发现， 放射和化疗反应的综合表征。目标1侧重于临床前 研究使用漫反射光谱调查短期和长期的复氧动力学 化疗和放射抵抗性和敏感性肿瘤对临床治疗方案的反应， 过程中，确定时间依赖的阈值，可以可靠地预测辐射阻力。在目标2中，我们 应用拉曼光谱技术研究放化疗后肿瘤代谢的动态变化 光谱，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水平。 决定因素最后，在目标3中，我们试图通过一个 在计划接受放化疗的HNSCC患者中进行的初步临床研究。确定 我们的方法在治疗前半期内识别耐药肿瘤的初始灵敏度 方案，我们将开发和采用多模态逆空间偏移拉曼和漫反射 与标准临床喉镜兼容光谱探针。圆满完成这些目标 将以前所未有的速度描绘与辐射和化学抗性相关的功能和分子变化。 时间尺度治疗后立即发生的放射生物学变化的知识不仅有助于 区分治疗应答者和非应答者，而且还确定了另外的时间点， 对治疗进行有意义的改变可以提高治疗反应率。

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.