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.

侵入性和增殖表型是重要的癌症标志，这些表型被区分 由于侵入性细胞会随着肿瘤的生长而导致分裂细胞的路径。胶质母细胞瘤多形 （GBM）治疗，特别是化学疗法，因为癌细胞侵入和增殖肿瘤以外 边界。但是，这两个表型都无法使用现有的成像方法跟踪。我们将开发1H/23NA MRSI技术可区分和跟踪这些表型，并具有主要的临床相关性。 与正常细胞相比，癌细胞具有独特的化学和电性能。间隙液 酸度和盐度对于细胞存活至关重要。许多细胞机制有助于调节必需的细胞 通过维持盐度环境中的氢离子（H+）和钠离子（Na+）的功能，该机构是盐水和 接近中性pH。我们和其他人的研究表明，间质和细胞内的酸度和盐度 癌症中的空间发生了变化，例如，氢交换器1（NHE1），有助于H+外排和Na+流入， 在GBM中被上调，并导致跨膜离子分布的改变。 GBM模型的研究揭示了一种酸性的间质性液，对于重塑间隙基质至关重要 癌细胞增殖并指导癌细胞侵袭。在人类衍生的GBM上的类似工作表明 间质Na+也发生了变化，但是这种变化支持去极化细胞膜 - 对癌细胞至关重要 增殖。这些新的结果表明，间质pH（PHO）和跨膜Na+的组合 梯度（？na+M）地图可以帮助产生具有侵入性和增殖表型的独立生物标志物。 虽然1H-MRI具有Gadolinium剂的1H-MRI跟踪肿瘤的大小，但我们和其他人表明，具有其他代理 Lanthanides可用于用1H-MRSI和23NA-MRSI映射的Pho映射。这些1h/23na 当前，地图是单独获取的，需要对单独的代理注射进行冗长的收购。到 探索pH失调和调节癌细胞侵袭的电解质失衡之间的关系 在肿瘤生长/治疗过程中，必须比较增生，phO和？na+m地图。 我们的目标是检验以侵入性细胞在肿瘤生长随着细胞的导致细胞的假设，并探索 他们的模式如何随治疗而变化。首先，我们将交织1H和23NA获取以实现快速pho 和？Na+M映射，并用单个代理输注。接下来，由PHO组合的增殖和侵入性图 在结节与侵入性患者衍生的异种移植物（PDXS）中，使用IHC和na+m地图将得到验证 ICP-MS。对于临床相关性，我们将测试NHE1抑制剂作为辅助化疗的潜力以改善 GBM结果。我们将将pho和？na+m地图与两种不同的疗法进行比较（即一线GBM标准 单独的护理化学疗法替莫唑胺与替莫唑胺 + cariporide）捕获了侵入性和 结节性和侵入性PDX中的增殖表型。