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) 仍然是多种实体瘤化疗的金标准，包括 头颈鳞状细胞癌（HNSCC）的发展导致治疗失败率很高。 尽管经常使用 CDDP，但这种毒性相对较大的化疗后获得性耐药的发生率并不高。 肿瘤反应或获得性耐药发展的预测因素存在，治疗失败都是致命的。 鉴于对肿瘤反应和获得​​性耐药预测因子的迫切需求未得到满足，我们将重点放在 关于用微创成像（超极化磁）评估肿瘤反应的努力 磁共振成像；HP-MRI）以及患者循环肿瘤细胞（CTC）的生物变化检测 正在接受基于顺铂的治疗，我们已经证明 CDDP 和其他基因毒性药物会触发。 肿瘤细胞代谢的可测量波动可通过传统生化测定和HP-检测 [1-13C]-丙酮酸的 MRI 几种还原代谢途径中关键辅酶的回收将 遗传毒性应激对通过乳酸脱氢酶（LDH）从丙酮酸到乳酸的碳通量的影响。 先前表明，基因毒性剂会改变细胞内氧化还原状态，改变丙酮酸/乳酸代谢， 并以与抗肿瘤相关的方式抑制丙酮酸转化为乳酸的表观速率 (kPL) 与顺铂的获得相关的调控变化的基因组和转录组分析。 CTC 中的耐药性将加强顺铂敏感性和耐药性的基于成像的量化。 根据这些初步数据，我们追踪了顺铂中 Nrf-2 驱动的代谢重编程- 使用碳通量非侵入性成像组合（kPL-via HP- 为了评估这一前提，我们将使用特征良好的 HNSCC 临床前模型。 对顺铂敏感且具有耐药性的药物将在基线和 通过超极化成像和生化测定测量进行顺铂给药。 将通过体外和体内生化测定进行验证（目标 1）。 通过在诱导前后获取 HP-MRI 数据，研究 HNSCC 患者中与肿瘤 kPL 变化相关的情况 化疗（目标 2）将在 CTC 中进行生物学确认，以确定与化疗相关的生物标志物。 通过基因组和转录组分析确定顺铂耐药性将成功完成这项研究。 建立 HP-MRI 作为微创成像方法来表征肿瘤对顺铂的相对耐药性 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信息。 这项工作有可能改变临床决策的基础。 关于顺铂在 HNSCC 和相关呼吸消化道癌症中的使用，这是值得注意的第一步。 拟议的研究是一种精准肿瘤学方法，与 NIH 的部分使命相关： 涉及开发和应用有助于减轻人类疾病负担的基础知识。