Vascular targeted pan PI-3 kinase inhibitor prodrug, SF1126 for glioma therapy

描述（由申请人提供）：我们之前的工作重点是“概念验证”实验，以建立pan PI-3激酶抑制剂在胶质瘤治疗的临床前模型中的临床效用，并评估PTEN调节胶质瘤进展的机制，包括血管生成的要素和PI-3激酶作用的下游药效学靶点。我们之前的实验涉及在胶质瘤模型中研究一种表征良好的pan PI-3激酶抑制剂LY294002。LY294002化合物，由于一些原因（下面讨论）不是临床开发的可行候选药物。在我们的竞争性更新中，我们将专注于我们目前正在进行的用于胶质瘤治疗的新型PI-3激酶小分子抑制剂的临床前开发（与Semafore制药公司合作）。该抑制剂是LY294002靶向血管RGDS的前药衍生物，命名为SF1126。下面我们提出了我们的初步数据，支持我们进一步评估这种靶向pan PI-3激酶抑制剂在恶性胶质瘤的临床前模型中的建议。假设：一种pan PI-3激酶抑制剂（SF1126）通过控制包括HIF1a-VEGF信号轴在内的一系列重要信号通路来减弱裸鼠恶性胶质肿瘤的生长。pan PI-3激酶抑制剂在体内显示抗胶质瘤和抗血管生成活性。我们的目标是对SF1126进行正式的PK-PD建模，包括PK和PD参数、肿瘤的PTEN状态以及对血管生成和重要下游生物标志物的影响。在修订后的提案中，我们将研究SF1126控制胶质瘤细胞中HIF1a信号传导的机制，这是其抗血管生成活性的潜在重要组成部分。我们之前的拨款提案CA94233的主要目标是：“确定pan PI-3激酶抑制剂在胶质瘤治疗的临床前模型中的效用”。在这里，我们提出了一种临床可行的pan PI-3激酶抑制剂前药SF1126的开发，我们开始在临床前胶质瘤模型中仔细表征这种药物。总体目标是为胶质瘤患者的I期临床试验准备这种药物。公共卫生相关性：恶性神经胶质肿瘤的诊断预后不佳，目前尚无治疗方法可以治愈这种类型的脑肿瘤。已知某些基因变化会导致恶性脑瘤，这些变化已成为新药开发的目标。在该提案中，我们开发了首批进入人体临床试验的PI-3激酶抑制剂之一，称为SF1126。这一建议将为SF1126在人类恶性神经胶质肿瘤治疗中的应用提供有用的信息，因此可能潜在地提高这类癌症患者的生存率。

DESCRIPTION (provided by applicant): Our previous work was focused on "proof of concept" experiments to establish the clinical utility of pan PI-3 kinase inhibitors in preclinical models for glioma therapeutics and to evaluate the mechanisms for PTEN's regulation of glioma progression including elements of angiogenesis and downstream pharmacodynamic targets for PI-3 kinase action. Our previous experiments involved the study of a well-characterized pan PI-3 kinase inhibitor, LY294002 in glioma models. The LY294002 compound, for a number reasons (discussed below) is not a viable drug candidate for clinical development. In our competitive renewal we will focus on our current ongoing preclinical development of a novel small molecule inhibitor of PI-3 kinase co-developed in our laboratory (in collaboration with Semafore pharmaceuticals) for glioma therapeutics. This inhibitor is a vascular RGDS targeted prodrug derivative of LY294002 and is termed SF1126. Below we present our preliminary data which supports our proposal to further evaluate this targeted pan PI-3 kinase inhibitor in preclinical models for malignant glioma. Hypothesis: A pan PI-3 kinase inhibitor (SF1126) will attenuate the growth of malignant glial tumors in nude mice via its control over a number of important signaling pathways including the HIF1a-VEGF signaling axis. A pan PI-3 kinase inhibitor will display anti-glioma and antiangiogenic activity in vivo. Our goal is to perform formal PK-PD modeling of SF1126 as relates to PK and PD parameters, PTEN status of tumor and effects on angiogenesis and important downstream biomarkers. In the revised proposal, we will investigate the mechanism by which SF1126 controls HIF1a signaling in glioma cells a potential important component of its antiangiogenic activity. The primary goal our previous grant proposal, CA94233 was to: "determine the utility of pan PI-3 kinase inhibitor in preclinical models for glioma therapeutics". Herein, we present the development of a clinically viable pan PI-3 kinase inhibitor prodrug, SF1126 and we embark on a careful characterization of this agent in preclinical glioma models. The overarching goal is to prepare this agent for a Phase I clinical trial in glioma patients. PUBLIC HEALTH RELEVANCE: The diagnosis of malignant glial tumors carries a dismal prognosis and there are no current therapies which can cure this type of brain tumor. Certain genetic changes are known to cause malignant brain tumors and these alterations have become targets for new drug development. In this proposal, we have developed one of the first PI-3 kinase inhibitors, termed SF1126 to enter human clinical trials. This proposal will provide useful information for the application of SF1126 to the treatment of malignant glial tumors in man and therefore may potentially improve survival of patients with this form of cancer.