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

描述（由申请人提供）：我们先前的工作集中于“概念验证”实验，以建立泛PI-3激酶抑制剂在神经胶质瘤治疗的临床前模型中的临床效用，并评估PTEN调节神经胶质瘤进展的机制，包括血管生成的要素和PI-3激酶作用的下游药效学靶点。我们先前的实验涉及在胶质瘤模型中研究充分表征的泛PI-3激酶抑制剂LY 294002。由于多种原因（下文讨论），LY 294002化合物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PI-3激酶新型小分子抑制剂的临床前开发，该抑制剂是我们实验室（与Semafore制药公司合作）共同开发的，用于神经胶质瘤治疗。该抑制剂是LY 294002的血管RGDS靶向前药衍生物，称为SF 1126。下面，我们提出了我们的初步数据，支持我们的建议，以进一步评估这种靶向泛PI-3激酶抑制剂在恶性胶质瘤的临床前模型。假设：泛PI-3激酶抑制剂（SF 1126）将通过其对包括HIF 1a-VEGF信号传导轴在内的许多重要信号传导途径的控制来减弱裸鼠中恶性神经胶质瘤的生长。泛PI-3激酶抑制剂将在体内显示抗神经胶质瘤和抗血管生成活性。我们的目标是对SF 1126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SF 1126控制胶质瘤细胞中HIF 1a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。我们先前的资助提案CA 94233的主要目标是：“确定泛PI-3激酶抑制剂在神经胶质瘤治疗的临床前模型中的效用”。在此，我们提出了一种临床上可行的泛PI-3激酶抑制剂前药，SF 1126的发展，我们开始在临床前胶质瘤模型中仔细表征这种药物。总体目标是为神经胶质瘤患者的I期临床试验准备这种药物。公共卫生相关性：恶性神经胶质瘤的诊断预后很差，目前还没有治疗方法可以治愈这种类型的脑肿瘤。已知某些遗传变化会导致恶性脑肿瘤，这些改变已成为新药开发的目标。在这项提案中，我们开发了第一个PI-3激酶抑制剂之一，称为SF 1126进入人体临床试验。这一建议将为SF 1126应用于治疗人类恶性神经胶质瘤提供有用的信息，因此可能潜在地改善患有这种癌症的患者的生存率。

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.