Quantification of cisplatin sensitivity and resistance using metabolic imaging and circulating tumor cell (CTC) biomarkers

使用代谢成像和循环肿瘤细胞 (CTC) 生物标志物量化顺铂敏感性和耐药性

• 批准号: 10707179
• 负责人: STEPHEN Y LAI
• 金额: $ 26.98万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707179
• 关键词: Aerodigestive Tract; Algorithms; Biochemical; Biological; Biological Assay; Biological Markers; Biological Models; Biopsy Specimen; Blood specimen; Carbon; Cell Line; Cells; Characteristics; Chemicals; Cisplatin; Clinical; Clinical Trials; Coenzymes; Coupled; Data; Detection; Development; Diagnostic Neoplasm Staging; Disease; Dose; Early Diagnosis; Effectiveness; Evaluation; Exposure to; Failure; Feedback; Genomics; Genotoxic Stress; Glycolysis; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Image; In Vitro; Knowledge; Lactate Dehydrogenase; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Measurable; Measurement; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mission; Modeling; Molecular; Mutagens; NADH; NADP; Neoadjuvant Therapy; Neoplasm Circulating Cells; Nicotinamide adenine dinucleotide; Non-Invasive Detection; Normal tissue morphology; Oxidation-Reduction; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Pyruvate; Recycling; Regimen; Research; Resistance; Solid Neoplasm; Spectrum Analysis; Systemic Therapy; Testing; Therapeutic; Time; Toxic effect; Treatment Failure; Tumor Biology; Tumor Burden; Tumor Markers; United States National Institutes of Health; Work; Xenograft procedure; biomarker identification; chemoradiation; chemotherapy; clinical decision-making; design; drug testing; effective therapy; imaging approach; in vitro Assay; in vivo; malignant oropharynx neoplasm; metabolic imaging; metabolic phenotype; minimally invasive; mortality; neoplastic cell; non-invasive imaging; novel; oxidation; phase 2 study; pre-clinical; precision oncology; prospective; real-time images; relative effectiveness; response; success; transcriptomics; treatment optimization; treatment response; tumor; tumor growth; tumor metabolism

PROJECT 3 SUMMARY Cisplatin (CDDP) remains the gold-standard for chemotherapeutic treatment for multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC). High rates of treatment failure result from the development of acquired resistance following this relatively toxic chemotherapy. Despite the frequent use of CDDP, no robust predictors of tumor response or development of acquired resistance exist. Treatment failure is uniformly fatal. Given the critical unmet need for predictors of tumor response and acquired resistance, we have focused our efforts on the assessment of tumor response with minimally invasive imaging (hyperpolarized magnetic resonance imaging; HP-MRI) and detection of biological shifts in circulating tumor cells (CTCs) while patients are undergoing cisplatin-based therapy. We have shown that CDDP and other genotoxic agents trigger measurable fluctuations in tumor cell metabolism detectable by both conventional biochemical assays and HP- MRI with [1-13C]-pyruvate. The recycling of key coenzymes in several reductive metabolic pathways links the effects of genotoxic stress to carbon flux from pyruvate into lactate via lactate dehydrogenase (LDH). We previously showed that genotoxic agents alter the intracellular redox state, shift pyruvate/lactate metabolism, and suppress the apparent rate of pyruvate conversion to lactate (kPL) in a manner that correlates with anti-tumor effectiveness. Genomic and transcriptomic analysis of regulatory shifts associated with the acquisition of cisplatin resistance in CTCs will re-enforce the imaging-based quantification of cisplatin sensitivity and resistance. Based on these preliminary data, we hypothesize that metabolic reprogramming driven by Nrf-2 in cisplatin- resistant HNSCC is detectable using a combination of non-invasive imaging of carbon flux (kPL- via HP- MRI) and scCTC analysis. To assess this premise, we will use well-characterized preclinical models of HNSCC that are sensitive and resistant to cisplatin. Alterations in glycolytic metabolism will be measured at baseline and following cisplatin administration through hyperpolarized imaging and biochemical assays. These measurements will be validated with biochemical assays in vitro and in vivo (Aim 1). We will also measure treatment response in HNSCC patients relative to alterations in tumor kPL by acquiring HP-MRI data prior to and following induction chemotherapy (Aim 2). Biological confirmation will be performed in CTCs to identify biomarkers associated with cisplatin resistance through genomic and transcriptomic analysis. Successful completion of this study will establish HP-MRI as a minimally invasive imaging approach to characterize relative tumor resistance to cisplatin and provide real-time feedback to optimize treatment. CTC biomarker analysis will provide critical biological support for the imaging findings. This work has the potential to change the basis for clinical decision-making regarding the use of cisplatin in HNSCC and related aerodigestive tract cancers. As a noteworthy first step towards a precision oncology approach, 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.

项目3摘要 顺铂（CDDP）仍然是用于多种实体瘤的化学治疗治疗的金标准，包括 头颈部鳞状细胞癌（HNSCC）。高治疗失败率来自开发 这种相对毒性的化学疗法后获得的耐药性。尽管经常使用CDDP，但没有强大的 存在肿瘤反应的预测因子或获得的抗性的发展。治疗失败是统一致命的。 鉴于对肿瘤反应和获得​​抗性的预测指标的关键需求，我们集中于我们的 通过微创成像（超极化磁）评估肿瘤反应的努力 共振成像； HP-MRI）和循环肿瘤细胞（CTC）中生物学转移的检测，而患者 正在接受基于顺铂的治疗。我们已经表明CDDP和其他遗传毒性触发 常规生化测定和HP-可检测到的肿瘤细胞代谢中可测量的波动 使用[1-13C] - 丙酮酸的MRI。在几种降低的代谢途径中，关键辅酶的回收与 遗传毒性应激对丙酮酸碳液的碳通量的影响，通过葡萄酸盐脱氢酶（LDH）的腐蚀作用。我们 先前表明的遗传毒性改变了细胞内氧化还原态，丙酮酸/乳酸代谢， 并以与抗肿瘤相关的方式抑制丙酮酸转化率的明显速率 效力。与顺铂获得有关的调节转移的基因组和转录组分析 CTC中的耐药性将重新强制基于成像的顺铂灵敏度和抗性的定量。基于 在这些初步数据上，我们假设NRF-2在顺铂 - 使用碳通量的非侵入性成像（通过HP- MRI）和SCCTC分析。为了评估这一前提，我们将使用HNSCC的特征临床前模型 对顺铂具有敏感性和抗性。糖酵解代谢的改变将在基线和 通过超极化成像和生化测定进行顺铂给药后。这些测量值 将通过体外和体内的生化测定进行验证（AIM 1）。我们还将测量治疗反应 在HNSCC患者中，相对于肿瘤KPL的改变，通过获取HP-MRI数据之前和之后的诱导 化学疗法（AIM 2）。生物学确认将在CTC中进行，以识别与 通过基因组和转录组分析的顺铂耐药性。这项研究成功完成将 将HP-MRI建立为一种微创成像方法，以表征对顺铂的相对肿瘤抗性 并提供实时反馈以优化治疗。 CTC生物标志物分析将提供关键的生物学 支持成像发现。这项工作有可能改变临床决策的基础 考虑到在HNSCC和相关的机动区域癌症中使用顺铂。作为一个值得注意的第一步 采用精确的肿瘤学方法，拟议的研究与NIH使命的一部分有关 与发展和应用基本知识有关，这将有助于减少人类疾病的伯纳斯。