Leveraging Hyperpolarized MRI for Precision Oncology Approaches in Head and Neck Cancer

项目摘要/摘要 头颈部鳞状细胞癌(HNSCC)仍然是全球癌症死亡的主要原因。 基因毒性药物，包括放射治疗(RT)和顺铂(CDDP)，是损害细胞的治疗方法。 DNART和CDDP是目前治疗包括HNSCC在内的多个实体肿瘤的标准治疗方案。CDDP是 近年来HNSCC中最常用的化疗药物被证明优于新型靶向药物 大型随机试验。尽管如此，出现耐药性的患者仍有很高的治疗失败率。 在这种有毒的化疗之后。治疗失败都是致命的。然而，没有可靠的预测因素 存在获得性顺铂耐药或肿瘤反应。鉴于这一关键的未得到满足的需求，我们集中努力 用微创定量成像(超极化磁成像)评估肿瘤反应 磁共振成像；HP-MRI)，同时患者正在接受治疗。我们证明了CDDP和其他基因毒性 药物引发可通过[1-13C]-丙酮酸HP-MRI检测的肿瘤细胞代谢的可测量波动 实时(由常规生化分析确认)。基因毒性应激抑制表观应激率 丙酮酸通过乳酸脱氢酶(LDH)转化为乳酸(KPL) 肿瘤的有效性。因此，我们假设KPL的变化提供了对新陈代谢的独特见解 顺铂诱导的变化，可用于优化对HNSCC的治疗反应。 在目标1中，我们将描述HNSCC的基线HP-MRI参数，如KPL 并验证CDDP与相关的碳通量变化之间的关系。我们还将确定 HNSCC模型中代谢组学差异影响代谢成像生物标志物和 调节顺铂引起的明显变化。在目标2中，我们将整合来自目标1的剂量反应数据 建立基于代谢成像参数的顺铂疗效预测模型。我们将使用 根据HNSCC动物模型HP-MRI数据调整治疗剂量以最大化的简单算法 肿瘤生长延迟，并测试是否可以使用提示强烈反应的阈值来选择更多 多个方案并行测试时的有效治疗方案。在目标3中，我们将进行第一次- 人类对HNSCC患者顺铂治疗后HP-MRI改变检测碳流量变化的评估。我们 将代谢成像参数的变化与肿瘤的基线代谢表型相关，如 通过代谢分析和直接测量肿瘤乳酸脱氢酶来确定。成功完成这项工作 研究将建立HP-MRI作为一种非侵入性成像方式，能够预测治疗反应， 这将是迈向我们一直在寻求的精确肿瘤学方法的值得注意的第一步 半个世纪了。因此，拟议的研究与NIH任务中与开发有关的部分相关 以及应用有助于减轻人类疾病负担的基础知识，并直接解决 最近出版的“特别关注的通知：口腔病变的精确成像”(NOT-DE-21-010)。

PROJECT SUMMARY/ABSTRACT Head and neck squamous cell carcinoma (HNSCC) remains a leading cause of cancer deaths worldwide. Genotoxic agents, including radiation therapy (RT) and cisplatin (CDDP), are treatments that damage cellular DNA. RT and CDDP are the current standard of care in multiple solid tumors, including HNSCC. CDDP is the most commonly used chemotherapeutic agent in HNSCC proving superior to novel targeted agents in recent large randomized trials. Despite this, high rates of treatment failure persist in patients who develop resistance following this toxic chemotherapy. Treatment failure is uniformly fatal. However, no robust predictors of acquired cisplatin resistance or tumor response exist. Given this critical unmet need, we have focused our efforts on the assessment of tumor response using minimally invasive quantitative imaging (hyperpolarized magnetic resonance imaging; HP-MRI) while patients are undergoing therapy. We showed that CDDP and other genotoxic agents trigger measurable fluctuations in tumor cell metabolism detectable through HP-MRI with [1-13C]-pyruvate in real time (confirmed by conventional biochemical assays). Genotoxic stress suppresses the apparent rate of pyruvate conversion into lactate (kPL) via lactate dehydrogenase (LDH) in a manner that correlates with anti- tumor effectiveness. We therefore hypothesize that changes in kPL provide unique insight into metabolic changes induced by cisplatin that can be used to optimize response to therapy in HNSCC. In Aim 1, we will characterize baseline HP-MRI parameters such as kPL across the spectrum of HNSCC subtypes and validate the relationship between CDDP and associated shifts in carbon flux. We will also identify metabolomic differences in HNSCC models that affect baseline values of metabolic imaging biomarkers and modulate apparent changes induced by cisplatin. In Aim 2, we will integrate the dose-response data from Aim 1 to develop a predictive model of response to CDDP based on metabolic imaging parameters. We will use a simple algorithm to adjust therapeutic dose based on HP-MRI data in animal models of HNSCC to maximize tumor growth delay, and test whether thresholds suggestive of strong response can be used to select the more effective treatment regimen when multiple regimens are tested in parallel. In Aim 3, we will conduct a first-in- human evaluation of changes in HP-MRI to detect shifts in carbon flux following CDDP in HNSCC patients. We will correlate changes in metabolic imaging parameters with the baseline metabolic phenotype of tumors as determined from metabolomic analysis and direct measurements of tumor LDH. Successful completion of this study will establish HP-MRI as a non-invasive imaging modality able to predict response to treatment, which will be a noteworthy first step towards a precision oncology approach that we have been seeking for nearly half a century. Thus, the proposed research is relevant to the part of the NIH’s mission that pertains to developing and applying fundamental knowledge that will help to reduce the burdens of human illness and addresses directly the recently published “Notice of Special Interest: Precision Imaging of Oral Lesions” (NOT-DE-21-010).