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Overhauser Enhanced Magnetic Resonance Imaging (OMRI)

奥豪瑟增强磁共振成像 (OMRI)

基本信息

批准号：
10926023
负责人：
murali cherukuri
金额：
$ 106.46万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10926023
关键词：
Aftercare Androgen Receptor Androgens Bathing Binding Biochemical Brain imaging Carbon Cell Nucleus Cell Respiration Chemicals Citric Acid Cycle Communities Complex Contrast Media Data Dependence Drug Targeting Electron Transport Evaluation Future Goals Heat-Shock Proteins 70 Image Isotope Labeling Label Link Magnetic Resonance Imaging Magnetism Malignant Neoplasms Malignant neoplasm of prostate Measures Metabolic Metabolic Diseases Metabolic Pathway Metabolism Mitochondria Monitor Nature Nuclear Pharmaceutical Preparations Physiological Physiology Prostate Cancer therapy Protons Pyruvate Rationalization Relaxation Reporting Research Ribosomes Role Sampling Signal Transduction Sodium Chloride Source Techniques Terminal Disease Theophylline Time Tracer Translations Water aerobic glycolysis alpha ketoglutarate androgen deprivation therapy castration resistant prostate cancer catalyst chemical bond density deprivation detection limit in vivo inhibitor metabolic imaging molecular imaging novel therapeutics treatment effect treatment response tumor

项目摘要

Evaluation of JG-98, inhibitor of HSP70 by metabolic MRI: The androgen receptor is a key regulator of prostate cancer and the principal target of current prostate cancer therapies collectively termed androgen deprivation therapies. Insensitivity to these drugs is a hallmark of progression to a terminal disease state termed castration-resistant prostate cancer. Therefore, novel therapeutic options that slow progression of castration-resistant prostate cancer and combine effectively with existing agents are in urgent need. We show that JG-98, an allosteric inhibitor of HSP70, re-sensitizes castration-resistant prostate cancer to androgen deprivation drugs by targeting mitochondrial HSP70 (HSPA9) to suppress aerobic respiration. Rather than impacting androgen receptor stability as previously described, JG-98's primary effect is inhibition of mitochondrial translation, leading to disruption of electron transport chain activity as shown by 13C MRI using hyperpolarized 133C labeled pyruvate. Although functionally distinct from HSPA9 inhibition, direct inhibition of the electron transport chain with a complex I or II inhibitor creates a similar physiological state capable of re-sensitizing castration-resistant prostate cancer to androgen deprivation therapies. These data identify a significant role for HspA9 in mitochondrial ribosome function and highlight an actionable metabolic vulnerability of castration-resistant prostate cancer. a-Ketoglutarate is a key biomolecule involved in a number of metabolic pathways horizontal line most notably the TCA cycle. Abnormal alpha-ketoglutarate metabolism has also been linked with cancer. Here, isotopic labeling was employed to synthesize [1-(13)C,5-(12)C,D(4)]alpha-ketoglutarate with the future goal of utilizing its [1-(13)C]-hyperpolarized state for real-time metabolic imaging of alpha-ketoglutarate analytes and its downstream metabolites in vivo. The signal amplification by reversible exchange in shield enables alignment transfer to heteronuclei (SABRE-SHEATH) hyperpolarization technique was used to create 9.7% [1-(13)C] polarization in 1 minute in this isotopologue. The efficient (13)C hyperpolarization, which utilizes parahydrogen as the source of nuclear spin order, is also supported by favorable relaxation dynamics at 0.4 muT field (the optimal polarization transfer field): the exponential (13)C polarization buildup constant T(b) is 11.0 +/- 0.4 s whereas the (13)C polarization decay constant T(1) is 18.5 +/- 0.7 s. An even higher (13)C polarization value of 17.3% was achieved using natural-abundance alpha-ketoglutarate disodium salt, with overall similar relaxation dynamics at 0.4 muT field, indicating that substrate deuteration leads only to a slight increase ( approximately 1.2-fold) in the relaxation rates for (13)C nuclei separated by three chemical bonds. Instead, the gain in polarization (natural abundance versus [1-(13)C]-labeled) is rationalized through the smaller heat capacity of the "spin bath" comprising available (13)C spins that must be hyperpolarized by the same number of parahydrogen present in each sample, in line with previous (15)N SABRE-SHEATH studies. Remarkably, the C-2 carbon was not hyperpolarized in both alpha-ketoglutarate isotopologues studied; this observation is in sharp contrast with previously reported SABRE-SHEATH pyruvate studies, indicating that the catalyst-binding dynamics of C-2 in alpha-ketoglutarate differ from that in pyruvate. We also demonstrate that (13)C spectroscopic characterization of alpha-ketoglutarate and pyruvate analytes can be performed at natural (13)C abundance with an estimated detection limit of 80 micromolar concentration x *%P(13C). All in all, the fundamental studies reported here enable a wide range of research communities with a new hyperpolarized contrast agent potentially useful for metabolic imaging of brain function, cancer, and other metabolically challenging diseases

通过代谢 MRI 评估 HSP70 抑制剂 JG-98：雄激素受体是前列腺癌的关键调节因子，也是当前前列腺癌治疗统称为雄激素剥夺疗法的主要目标。对这些药物不敏感是进展为晚期疾病状态（称为去势抵抗性前列腺癌）的标志。因此，迫切需要减缓去势抵抗性前列腺癌进展并与现有药物有效结合的新治疗选择。我们发现，JG-98（一种 HSP70 的变构抑制剂）通过靶向线粒体 HSP70 (HSPA9) 抑制有氧呼吸，使去势抵抗性前列腺癌对雄激素剥夺药物重新敏感。 JG-98 的主要作用不是像之前描述的那样影响雄激素受体的稳定性，而是抑制线粒体翻译，从而导致电子传递链活性的破坏，如使用超极化 133C 标记丙酮酸盐的 13C MRI 所示。尽管在功能上与 HSPA9 抑制不同，但用复合物 I 或 II 抑制剂直接抑制电子传递链会产生类似的生理状态，能够使去势抵抗性前列腺癌对雄激素剥夺疗法重新敏感。这些数据确定了 HspA9 在线粒体核糖体功能中的重要作用，并强调了去势抵抗性前列腺癌的可操作代谢脆弱性。 α-酮戊二酸是参与许多水平代谢途径（尤其是 TCA 循环）的关键生物分子。 α-酮戊二酸代谢异常也与癌症有关。在这里，采用同位素标记合成[1-(13)C,5-(12)C,D(4)]α-酮戊二酸，未来的目标是利用其[1-(13)C]-超极化状态对α-酮戊二酸分析物及其下游代谢物进行体内实时代谢成像。通过屏蔽中的可逆交换进行信号放大，使对准转移到异核 (SABRE-SHEATH) 超极化技术用于在该同位素体中在 1 分钟内产生 9.7% [1-(13)C] 极化。利用仲氢作为核自旋序源的高效 (13)C 超极化也得到了 0.4 muT 场（最佳极化转移场）的有利弛豫动力学的支持：指数 (13)C 极化建立常数 T(b) 为 11.0 +/- 0.4 s，而 (13)C 极化衰减常数 T(1) 为 18.5 +/- 0.7 s。使用天然丰度的α-酮戊二酸二钠盐实现了更高的 17.3% 的 (13)C 极化值，在 0.4 muT 场下具有总体相似的弛豫动力学，表明底物氘化仅导致由三个化学键分隔的 (13)C 核的弛豫率略有增加（约 1.2 倍）。相反，极化增益（自然丰度与[1-(13)C]标记）通过“旋转浴”的较小热容合理化，该“旋转浴”包含可用的（13）C自旋，必须通过每个样品中存在的相同数量的仲氢进行超极化，这与之前的（15）N SABRE-SHEATH研究一致。值得注意的是，在所研究的两种 α-酮戊二酸同位素异数体中，C-2 碳并未超极化。这一观察结果与之前报道的 SABRE-SHEATH 丙酮酸研究形成鲜明对比，表明 α-酮戊二酸中 C-2 的催化剂结合动力学不同于丙酮酸中的催化剂结合动力学。我们还证明，α-酮戊二酸和丙酮酸分析物的 (13)C 光谱表征可以在天然 (13)C 丰度下进行，估计检测限为 80 微摩尔浓度 x *%P(13C)。总而言之，这里报告的基础研究使广泛的研究团体能够使用一种新的超极化造影剂，该造影剂可能可用于脑功能、癌症和其他代谢挑战性疾病的代谢成像