Application of Hyperpolarized 13C Magnetic Resonance Imaging to Detect Target Inhibition of NF-kB Activation and Response in Primary CNS Lymphoma

项目摘要/摘要 该提案将应用一种创新的代谢成像方法，即超极化(HP)1-13-C MRI，以解决 核因子-kB在肿瘤中的激活。核因子-kB是一种关键的促进生存的转录调节因子，它推动了多种 恶性肿瘤，其中之一是原发性中枢神经系统淋巴瘤(PCNSL)，一种高度难治性的活化B细胞 (ABC)型大细胞淋巴瘤。ABC型大细胞淋巴瘤是与癌症相关的重要原因 全球范围内的死亡率。最近使用靶向药物阻断核因子-kB激活的试验显示，在 PCNSL和系统性ABC型淋巴瘤，但反应仅持续几个月，这表明替代方案 核因子-kB的激活途径被适应性地诱导来介导抗性。我们假设惠普1-13-C MRI可能在检测PCNSL的临床反应、确定预后和靶点抑制方面具有特殊的实用价值 也可用于确定持久抑制核因子-kB激活的有效组合策略。在……里面 此外，我们预计，这种方法可能会在识别预测疗效的生物标志物方面产生影响。 免疫疗法。我们的团队最近首次证明了HP 1-13-C磁共振成像的可行性 恶性胶质瘤患者。这些研究支持Hp 1-13-C MRI识别代谢产物的潜力 产生影响PCNSL体内代谢过程的非侵入性生物标志物，包括耐药途径， 与标准MRI相比，敏感度和特异度显著提高。我们招募了一位才华横溢的， 多学科团队开展这一高度转化的项目，通过以下方式解决PCNSL研究中的关键差距 追求以下具体目标： 1)测试假设，超极化(HP)[1-13-C]代谢磁共振成像的基因定义，患者- 所建立的PCNSL原位模型可以无创性地评估联合应用核因子-kB的反应深度 靶向药物以及提供耐药出现的早期生物标志物。 2)验证HP[1-13-C]代谢磁共振指标可以作为非侵入性生物标志物开发的假设 同基因、免疫活性PCNSL模型中核因子-kB的激活和免疫抑制。 3)进行HP 13C MRI的初步患者研究，以确定HP的可行性和方法 [1-13C]丙酮酸盐MRI作为一种实时、非侵入性成像工具，用于评估PCNSL的反应。 我们将把肿瘤中核因子-kB激活的遗传标志与HP 13C MRI上的乳酸和在肿瘤中的乳酸相关联 脑脊液及其与无进展生存的关系。这些研究将构成以下方面的基础 HP13C代谢成像在PCNSL和ABC型淋巴瘤研究中的整合 提高检测、预测、识别耐药性，促进精准医疗。我们期待着这些 研究将确定可持久阻断核因子-kB的新组合和药物时间表，以便在 诊所。这些研究也可能为实现肿瘤乳酸作为一种新的生物标志物提供理论基础。 免疫疗法试验。最终，我们的研究可能会刺激多中心试验，以评估Hp 13C MRI在PCNSL中的应用。

PROJECT SUMMARY/ABSTRACT This proposal will apply an innovative metabolic imaging approach, hyperpolarized (HP) 1-13-C MRI to address NF-kB activation in cancer. NF-kB is a key pro-survival transcriptional regulator that drives resistance in a variety of malignancies, one of which is primary CNS lymphoma (PCNSL) a highly refractory form of activated B-cell (ABC)-type large cell lymphoma. ABC-type large cell lymphomas are an important cause of cancer-related mortality worldwide. Recent trials using targeted agents that block NF-kB activation have shown activity in PCNSL and systemic ABC-type lymphoma, yet responses last only a few months, suggesting that alternative pathways of NF-kB activation are adaptively induced to mediate resistance. We hypothesize that HP 1-13-C MRI may have particular utility in detecting clinical response, defining prognosis and target inhibition in PCNSL and can also be applied to identify effective combinatorial strategies that durably suppress NF-kB activation. In addition, we envision that this approach may be impactful in identifying biomarkers that predict efficacy of immunotherapy. Our team recently demonstrated for the first time the feasibility of HP 1-13-C MRI to image malignant glioma in patients. These studies support the potential of HP 1-13-C MRI to identify metabolites that yield impactful non-invasive biomarkers of in vivo metabolic processes in PCNSL, including resistance pathways, with markedly improved sensitivity and specificity compared to standard MRI. We have recruited a talented, multidisciplinary team to pursue this highly translational project to address key gaps in PCNSL research through pursuit of the following specific Aims: 1) Test the hypothesis that hyperpolarized (HP) [1-13-C]-metabolic MR imaging of genetically-defined, patient- derived orthotopic models of PCNSL can non-invasively evaluate depth of response to combinations of NF-kB targeting agents as well as provide an early biomarker of the emergence of resistance. 2) Test the hypothesis that HP [1-13-C] metabolic MR metrics can be developed as non-invasive biomarkers of NF-kB-activation and immunosuppression in a syngeneic, immunocompetent model of PCNSL. 3) Perform the initial proof of principle patient studies of HP 13C MRI to determine feasibility and methods of HP [1-13C] pyruvate MRI as a real time, non-invasive imaging tool for response assessment in PCNSL. We will correlate genetic markers of NF-kB activation in tumors with lactate on HP 13C MRI and lactate in cerebrospinal fluid and their relationship to progression-free survival. These studies will constitute a basis for integration of HP13C metabolic imaging in the research of PCNSL, and of ABC-type lymphomas in general, to improve detection, prognostication, identify resistance, and facilitate precision medicine. We anticipate these studies will identify novel combinations and schedules of agents that durably block NF-kB, to be tested in the clinic. These studies may also provide a rationale for implementation of tumor lactate as a novel biomarker for immunotherapy trials. Ultimately our studies may stimulate multicenter trials to evaluate HP 13C MRI in PCNSL.