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.

项目概要 成人和儿童的高级别胶质瘤预后非常差，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 通路中的突变很常见，并且可以 基于激酶抑制剂的策略靶向。 EGFR 抑制已在临床上进行了测试，但反应尚不明确 受到限制。目标参与不足，可能是由于血脑屏障渗透性差以及 复发性肿瘤中靶标的下调或规避，是被引用的缺乏机制之一 EGFR靶向药物的疗效。使用 PI3K 和 MAPK 抑制剂的联合策略是有前途的，并且 可以克服 GBM 中对单一药物的获得性耐药性。使用单分子靶向的优点 多种激酶包括降低药物相互作用的风险，用于优化的单一药代动力学特征 剂量，并增加克服耐药性的潜力。因此，治疗学的发展 以多种激酶为目标，识别反应生物标志物并仔细评估 BBB 渗透性对于改善患者的治疗效果至关重要。采用计算建模方法，我们 利用 EGFR 和 PI3K 结构相关的 ATP 结合位点抑制剂的已知结合模式 设计以选择性方式同时抑制两种激酶的小分子。我们假设 与多种药物相比，这种多药理学方法将在体外和体内提供更好的疗效 组合策略。在人类胶质母细胞瘤和患者衍生的儿科中产生的初步数据 弥漫性内在脑桥神经胶质瘤 (DIPG) 系显示出这些双重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，我们还发现了独特的代谢特征 抑制剂，表明糖酵解途径和氧化磷酸化均受到抑制，这不是 与临床相关的 EGFR 或 PI3K 抑制剂一起出现。我们认为这将导致以下领域的发展： 基于代谢组学的生物标志物。第一年，在这个应用的R61阶段，我们会进一步优化 该化学系列化合物的药学特性增加了血脑屏障的可能性 (BBB) 外显率。我们已经生成了关键的初步数据，表明 MTX-241 具有关键属性 为 BBB 渗透性。因此我们将使用体内模型来测试MTX-241，同时合成 并评估 MTX-241 的 15-20 个结构类似物。该提案的R33阶段将在 第 2 年和第 3 年，我们将重点关注已确定的两个最有希望的候选药物的体内评估 使用原位模型来解决抗肿瘤功效、血脑屏障渗透性和药物生物标志物 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一抑制剂 EGFR 和 PI3K 代表了成人和儿童复发性治疗的基本原理和有前景的治疗策略 HGG 具有很高的转化潜力。