Interleaved 1H/23Na imaging for invasive and proliferative phenotypes of brain tumors

用于脑肿瘤侵袭性和增殖表型的交错 1H/23Na 成像

• 批准号: 10634269
• 负责人: Dewan Syed Fahmeed Hyder
• 金额: $ 57.29万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-08 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634269
• 关键词: Acidity; Adjuvant Chemotherapy; Adjuvant Therapy; Biological Markers; Brain Neoplasms; Cell Proliferation; Cell Survival; Cell membrane; Cell physiology; Cells; Chemotherapy and/or radiation; Clinical; Computer software; Data; Diagnosis; Diffuse; Electrolytes; Gadolinium; Glioblastoma; Goals; Histology; Human; Image; Imaging technology; Immune; Immunotherapy; Individual; Inductively Coupled Plasma Mass Spectrometry; Infusion procedures; Injections; Intercellular Fluid; Intracellular Space; Invaded; Ions; Lanthanoid Series Elements; Lead; Libraries; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Maps; Membrane; Modeling; Modification; NHE1; Normal Cell; Operative Surgical Procedures; Outcome; Patients; Pattern; Phenotype; Preclinical Drug Development; Prognosis; Proliferating; Protons; Recurrence; Research; Saline; Sampling; Scanning; Shapes; Sodium-Hydrogen Antiporter; System; Technology; Testing; Tissues; Up-Regulation; Work; cancer cell; cancer therapy; cariporide; chemical property; chemotherapy; clinically relevant; electrical property; imaging modality; improved; inhibitor; interstitial; magnetic resonance spectroscopic imaging; novel; patient derived xenograft model; preservation; public health relevance; radio frequency; single-cell RNA sequencing; sodium ion; spatiotemporal; spectroscopic imaging; standard of care; temozolomide; translational approach; tumor; tumor growth; tumor microenvironment

Invasive and proliferative phenotypes are vital cancer hallmarks, and these phenotypes are distinguished by the fact that invasive cells lead the path for dividing cells as the tumor grows. Glioblastoma multiforme (GBM) treatments, specifically chemotherapies, fail because cancer cells invade and proliferate beyond tumor boundaries. But neither phenotypes can be tracked with existing imaging methods. We will develop 1H/23Na MRSI technology to differentiate and track these phenotypes, and which will have major clinical relevance. Compared to normal cells, cancer cells possess unique chemical and electrical properties. Interstitial fluid's acidity and salinity are crucial for cell survival. Many cellular mechanisms help regulate essential cellular functions by maintaining hydrogen ions (H+) and sodium ions (Na+) in the interstitial milieu, which is saline and near neutral pH. Research from us, and others, reveal that acidity and salinity of interstitial and intracellular spaces are altered in cancer, e.g., sodium-hydrogen exchanger 1 (NHE1), which aids H+ efflux and Na+ influx, is upregulated in GBMs and contributes to altered transmembrane ion distributions. Research on GBM models reveals an acidic interstitial fluid, vital for reshaping the interstitial matrix for cancer cell proliferation and to guide cancer cell invasion. Similar work on human-derived GBMs shows that interstitial Na+ is also altered, but this change supports a depolarized cell membrane - vital for cancer cell proliferation. These novel results suggest that the combination of interstitial pH (pHo) and transmembrane Na+ gradient (?Na+m) maps can help generate independent biomarkers of invasive and proliferative phenotypes. While 1H-MRI with gadolinium agents tracks tumor size, we and others have shown that agents with other lanthanides can be used for pHo mapping with 1H-MRSI and ?Na+m mapping with 23Na-MRSI. These 1H/23Na maps are currently obtained individually, requiring lengthy acquisitions with separate agent injections. To explore the relationship between dysregulated pH and electrolyte imbalances regulating cancer cell invasion and proliferation, pHo and ?Na+m maps must be spatiotemporally compared during tumor growth/therapy. Our goal is to test the hypothesis that invasive cells lead dividing cells as the tumor grows, and explore how their patterns change with treatment. First, we will interleave 1H and 23Na acquisitions to enable rapid pHo and ?Na+m mapping with a single agent infusion. Next, proliferative and invasive maps from combination of pHo and ?Na+m maps will be validated in nodular vs. invasive patient -derived xenografts (PDXs) using IHC and ICP-MS. For clinical relevance, we will test potential of NHE1 inhibitor as an adjuvant chemotherapy to improve GBM outcome. We will compare pHo and ?Na+m maps with two different therapies (i.e., first-line GBM standard of care chemotherapy temozolomide alone vs. temozolomide + cariporide) to capture fates of invasive and proliferative phenotypes in nodular vs. invasive PDXs.

侵袭性和增殖性表型是重要的癌症标志，这些表型是有区别的 事实上，随着肿瘤的生长，侵袭性细胞引导细胞分裂。多形性胶质母细胞瘤 （GBM）治疗，特别是化疗，会失败，因为癌细胞侵入并增殖到肿瘤之外 边界。但现有的成像方法都无法追踪这两种表型。我们将开发1H/23Na MRSI 技术能够区分和追踪这些表型，这将具有重大的临床意义。 与正常细胞相比，癌细胞具有独特的化学和电学特性。间质液 酸度和盐度对于细胞的生存至关重要。许多细胞机制有助于调节重要的细胞 通过在间质环境中维持氢离子 (H+) 和钠离子 (Na+) 来发挥作用，该环境是盐水和 接近中性pH值。我们和其他人的研究表明，间质和细胞内的酸度和盐度 癌症中的空间发生改变，例如钠氢交换器 1 (NHE1)，它有助于 H+ 流出和 Na+ 流入， 在 GBM 中表达上调，并导致跨膜离子分布改变。 GBM 模型的研究揭示了酸性间质液，对于重塑间质基质至关重要 癌细胞增殖并引导癌细胞侵袭。对人类 GBM 的类似研究表明 间质 Na+ 也发生了改变，但这种变化支持去极化的细胞膜 - 对于癌细胞至关重要 增殖。这些新颖的结果表明间质 pH (pHo) 和跨膜 Na+ 的结合 梯度 (?Na+m) 图可以帮助生成侵袭和增殖表型的独立生物标志物。 虽然使用钆药物的 1H-MRI 可以追踪肿瘤大小，但我们和其他人已经证明，使用其他药物的药物 镧系元素可用于使用 1H-MRSI 进行 pHo 绘图，以及使用 23Na-MRSI 进行 ?Na+m 绘图。这些 1H/23Na 目前，地图是单独获取的，需要通过单独的试剂注射进行长时间的采集。到 探索 pH 失调与调节癌细胞侵袭的电解质失衡之间的关系 在肿瘤生长/治疗期间，必须对增殖、pHo 和 ?Na+m 图进行时空比较。 我们的目标是检验这样的假设：随着肿瘤的生长，侵袭性细胞导致细胞分裂，并探索 他们的模式如何随着治疗而改变。首先，我们将交叉采集 1H 和 23Na，以实现快速 pHo 和单剂输注的Na+m 绘图。接下来，pHo 组合的增殖和侵袭图 和 ?Na+m 图谱将使用 IHC 和方法在结节性与侵袭性患者来源的异种移植物 (PDX) 中进行验证 ICP-MS。为了临床相关性，我们将测试 NHE1 抑制剂作为辅助化疗的潜力，以改善 GBM 结果。我们将比较 pHo 和 ?Na+m 图与两种不同的疗法（即一线 GBM 标准 护理化疗单独替莫唑胺与替莫唑胺+卡立泊利），以捕捉侵袭性和 结节性 PDX 与侵袭性 PDX 的增殖表型。