Evaluation of Novel Dually Targeted Kinase Inhibitors for Therapy of Adult and Pediatric High-Grade Glioma

新型双靶向激酶抑制剂治疗成人和儿童高级别胶质瘤的评价

• 批准号: 10164961
• 负责人: Joya Chandra
• 金额: $ 33.57万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164961
• 关键词: 1-Phosphatidylinositol 3-Kinase; ABCG2 gene; Address; Adult; Adult Glioblastoma; Astrocytes; Back; Binding; Binding Sites; Biological Markers; Blood - brain barrier anatomy; Brain; Cell Line; Cells; Chemicals; Child; Childhood; Childhood Brain Neoplasm; Childhood Glioblastoma; Childhood Glioma; Clinical; Computer Models; Data; Development; Diagnosis; Diffuse intrinsic pontine glioma; Dose; Down-Regulation; Drug Combinations; Drug Interactions; Drug Kinetics; Drug resistance; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Evaluation; Exhibits; FRAP1 gene; Glioblastoma; Glioma; Human; In Vitro; Knowledge; Late Effects; Lead; Metabolic; Metabolism; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Mus; Mutation; Oncogenes; Oxidative Phosphorylation; P-Glycoprotein; PI3K/AKT; Pathway interactions; Patient-Focused Outcomes; Patients; Penetrance; Pharmacodynamics; Pharmacologic Substance; Phase; Phosphotransferases; Platelet-Derived Growth Factor Receptor; Property; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent tumor; Resistance; Risk; Series; Signal Pathway; Signal Transduction; Specificity; Structure; Survival Rate; Testing; Therapeutic; Therapeutic Index; Toxic effect; Ursidae Family; analog; base; biomarker identification; blood-brain barrier permeabilization; cancer cell; cancer type; clinically relevant; comparative efficacy; cytotoxic; cytotoxicity; design; drug action; early phase clinical trial; improved; in vitro activity; in vivo; in vivo Model; in vivo evaluation; inhibitor/antagonist; kinase inhibitor; metabolomics; nerve stem cell; novel; outcome forecast; pediatric patients; prognostic; response; response biomarker; single molecule; small molecule; small molecule inhibitor; success; targeted agent; therapeutic development; therapeutic target; treatment strategy; tumor; tumor metabolism

PROJECT SUMMARY High grade gliomas in both adults and children confer very poor prognosis, with median survival rates under two years post diagnosis. Amplification of epidermal growth factor receptor (EGFR) and platelet derived growth factor receptor (PDGFR), as well as mutations in the PI3K/AKT/mTOR pathway are frequent and can be targeted by kinase inhibitor based strategies. EGFR inhibition has been tested clinically, but responses have been limited. Inadequate target engagement, perhaps due to poor blood brain barrier penetrance, as well as downregulation or circumvention of the target in recurrent tumors, are amongst mechanisms cited for lack of efficacy of EGFR-targeted agents. Combination strategies using PI3K and MAPK inhibitors are promising, and can overcome acquired resistance to single agents in GBM. Advantages of using a single molecule to target multiple kinases include reduced risks of drug interactions, a single pharmacokinetic profile for optimization of dosing, and increased potential for overcoming drug resistance. Therefore, the development of therapeutics that target more than one kinase, identification of biomarkers of response and careful evaluation of BBB permeance are imperative to improving patient outcomes. Employing a computational modeling approach, we exploited the known binding modes of structurally related ATP binding site inhibitors of EGFR and PI3K to design small molecules that simultaneously inhibit both kinases in a selective manner. We hypothesize that this polypharmacology approach will provide better efficacy in vitro and in vivo compared to multi-drug combination strategies. Preliminary data generated in human glioblastoma and patient derived pediatric diffuse intrinsic pontine glioma (DIPG) lines shows potent cytotoxic effects of these dually targeted agents relative to targeting of EGFR alone or PI3K alone. Furthermore, we have identified unique metabolic features of the inhibitors, indicating suppression of both glycolytic pathways and oxidative phosphorylation, which is not seen with clinically relevant EGFR or PI3K inhibitors. We posit that this will lead to the development of metabolomics based biomarkers. In Year 1, in the R61 phase of this application, we will further optimize the pharmaceutical features of this chemical series of compounds to increase the likelihood of blood-brain barrier (BBB) penetrance. We have generated key preliminary data showing that MTX-241 possess critical attributes for BBB permeability. Therefore we will use in vivo models to test MTX-241, while simultaneously synthesizing and evaluating 15-20 structural analogs of MTX-241. The R33 phase of the proposal will be carried out in Years 2 and 3, whereupon we will focus on in vivo evaluation of the two most promising candidates identified using orthotopic models to address anti-tumor efficacy, blood brain barrier permeance, and biomarkers of drug action. These studies have been designed to support our hypothesis that a single inhibitor with dual specificity for EGFR and PI3K represents a rationale and promising treatment strategy for recurrent adult and pediatric HGG with high translational potential.

项目摘要 成人和儿童的高级神经瘤允许预后较差，中位生存率低于 诊断后两年。表皮生长因子受体（EGFR）和血小板衍生生长的扩增 因子受体（PDGFR）以及PI3K/AKT/MTOR途径中的突变频繁，可以是 由激酶抑制剂基于基于激酶的策略。 EGFR抑制已在临床上进行了测试，但反应已有 受到限制。目标参与不足，也许是由于血脑屏障的不良渗透性以及 反复肿瘤中靶标的下调或避免是由于缺乏的机制之一 EGFR靶向代理的功效。使用PI3K和MAPK抑制剂的组合策略是有希望的，并且 可以克服GBM中对单一药物的获得的抗性。使用单个分子靶向的优点 多种激酶包括降低药物相互作用的风险，一种用于优化的单一药代动力学特征 给药，并增加了克服耐药性的潜力。因此，治疗学的发展 该靶向多个激酶，对反应的生物标志物的识别以及对BBB的仔细评估 渗透对于改善患者预后至关重要。采用计算建模方法，我们 利用了EGFR和PI3K与结构相关的ATP结合位点抑制剂的已知结合模式 设计小分子以选择性方式同时抑制两个激酶。我们假设 与多药物相比 组合策略。人胶质母细胞瘤和患者衍生的小儿产生的初步数据 弥漫性内在庞然神经胶质瘤（DIPG）线显示了这些双向靶向药物的有效细胞毒性作用 相对于单独靶向EGFR或单独靶向PI3K。此外，我们已经确定了独特的代谢特征 抑制剂的抑制剂均抑制糖酵解途径和氧化磷酸化，这不是 可见具有临床相关的EGFR或PI3K抑制剂。我们认为这将导致 基于代谢组学的生物标志物。在第1年，在此应用程序的R61阶段，我们将进一步优化 该化学系列化合物的药物特征，以增加血脑屏障的可能性 （BBB）渗透率。我们已经生成了密钥初步数据，表明MTX-241具有关键属性 用于BBB渗透性。因此，我们将使用体内模型测试MTX-241，同时合成 并评估MTX-241的15-20个结构类似物。提案的R33阶段将在 第2和3年 使用原位模型来解决抗肿瘤功效，血脑屏障渗透和药物生物标志物 行动。这些研究旨在支持我们的假设，即具有双重特异性的单个抑制剂 对于EGFR和PI3K，代表了复发成人和小儿的理由和有希望的治疗策略 HGG具有很高的翻译潜力。