MR Metabolic Imaging of Response to Targeted Therapies in GBM

描述(申请人提供)：拟议研究的目标是开发和机械验证MR可检测的代谢生物标记物，以评估多形性胶质母细胞瘤(GBM)对针对致癌信号通路的新疗法的分子反应，这些信号通路在此类病变中被激活。GBM患者的中位生存期不到18个月，新的治疗方法对于改善预后至关重要。一种有前景的治疗方法是靶向PI3K/AKT/mTOR通路，该通路在88%的GBM肿瘤中被激活。然而，这种新疗法的一个关键问题是，药物活性往往会导致肿瘤停滞，而目前的成像方法并不了解药物的作用。拟议的研究将使用以前未曾探索过的方法来解决这一未得到满足的需求。PI3K/AKT/mTOR信号调节丙酮酸向乳酸的转化以及磷胆碱(PC)的合成。我们假设，PC水平和超极化乳酸水平可以作为PI3K/AKT/mTOR信号的下游生物标志物，并提供抑制这一信号的药物靶标的代谢读数。PC水平可以通过1H MRS监测含总胆碱的代谢物(Tcho)来检测，超极化乳酸水平可以通过13C MRS监测超极化丙酮酸代谢来检测。在拟议的研究中，我们的策略是首先在肿瘤模型系统中使用非侵入性MR技术来监测Tcho和超极化乳酸的变化，并验证它们在检测新出现的PI3K/AKT/mTOR抑制剂的分子反应中的作用。在确认了这些参数在临床前环境中的生物学意义后，磁共振技术将应用于参与最先进临床试验的GBM患者。目的1.应用~(31)P、~(13)H和超极化~(13)C-MRS以及互补生物学方法，对不同遗传背景的人肾小管上皮细胞进行对照和PI3K/AKT/mTOR抑制剂处理，以验证PC、Tcho和超极化乳酸作为分子治疗反应的生物标志物。目的：应用~1H-MRSI、超极化~(13)C-MRSI和互补生物学方法对不同遗传背景的大鼠原位基底膜肿瘤进行对照和PI3K/AKT/mTOR抑制剂治疗，以验证Tcho和超极化乳酸作为体内分子治疗反应的生物标志物的作用。目的3.对接受常规放疗和替莫唑胺联合PI3K/AKT/mTOR抑制剂治疗的初诊GBM患者进行1HMRSI和超极化13C MRSI，以验证体内Tcho和乳酸作为治疗反应生物标志物的作用。这项拟议的研究将产生一种成像方法，可以提供药物传递和分子反应的信息。它将能够对肿瘤部位的药物作用进行纵向监测，并将提供一种工具来优化治疗方案，从而为GBM患者带来更个性化的护理和改善结果。

DESCRIPTION (provided by applicant): The goal of the proposed research is to develop and mechanistically validate MR-detectable metabolic biomarkers in order to evaluate the molecular response of glioblastoma multiforme (GBM) to novel therapies that target oncogenic signaling pathways, which are activated within such lesions. The median survival for GBM patients is less than eighteen months, and new therapies are essential to improve outcome. A promising therapeutic approach is to target the PI3K/AKT/mTOR pathway, which is activated in 88% of GBM tumors. However, a critical issue with such novel treatments is that drug activity often results in tumor stasis, and current imaging methods do not inform upon drug action. The proposed research will use a previously unexplored approach to address this unmet need. PI3K/AKT/mTOR signaling modulates the conversion of pyruvate into lactate as well as the synthesis of phosphocholine (PC). We hypothesize that levels of PC, detectable by monitoring total choline-containing metabolites (tCho) by 1H MRS, and levels of hyperpolarized lactate, detectable by monitoring hyperpolarized pyruvate metabolism using 13C MRS, can serve as linked downstream biomarkers of PI3K/AKT/mTOR signaling and provide a metabolic read-out of drug-target modulation by agents that inhibit this signaling. Our strategy in the proposed research is first to use non-invasive MR techniques in tumor model systems to monitor changes in tCho and hyperpolarized lactate and to validate their role in detecting molecular response to emerging PI3K/AKT/mTOR inhibitors. After confirming the biological significance of these parameters in a pre-clinical setting, MR techniques will be applied to patients with GBM who are participating in state of the art clinical trials. Aim 1. To apply 31P, 1H and hyperpolarized 13C MRS as well as complementary biological assays to control and PI3K/AKT/mTOR inhibitor-treated GBM cells with different genetic backgrounds in order to validate PC, tCho and hyperpolarized lactate as biomarkers of molecular response to therapy. Aim 2. To apply 1H MRSI, hyperpolarized 13C MRSI and complementary biological assays to control and PI3K/AKT/mTOR inhibitor-treated rat orthotopic GBM tumors with different genetic backgrounds in order to validate the role of tCho and hyperpolarized lactate as biomarkers of molecular response to therapy in vivo. Aim 3. To apply 1H MRSI and hyperpolarized 13C MRSI to patients with newly diagnosed GBM who are being treated with standard of care radiotherapy (RT) and temozolomide in combination with PI3K/AKT/mTOR inhibitors in order to validate the role of in vivo tCho and lactate as biomarkers of response to therapy. The proposed research will result in an imaging method that can inform on drug delivery and molecular response. It will enable longitudinal monitoring of drug action at the tumor site and will provide a tool to optimize therapeutic regimens, resulting in more personalized care and improved outcome for GBM patients.