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

用于神经胶质瘤治疗的血管靶向泛 PI-3 激酶抑制剂前药 SF1126

基本信息

批准号：
8067127
负责人：
DONALD DURDEN
金额：
$ 26.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8067127
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Affect Angiogenesis Inhibitors Applications Grants Attenuated Biological Markers Blood Vessels Brain Brain Neoplasms Cell Surface Receptors Cells Chemicals Clinical Clinical Trials Collaborations Cytokine Receptors Data Development Diagnosis Dose Double Minutes Drug Kinetics Elements Fibrinogen Glioblastoma Glioma Goals Growth Growth Factor Receptors Health Human Hypoxia Image Immunohistochemistry Integrins Intercept Laboratories MDM2 gene Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Methods Modeling Mus Mutation Nude Mice PTEN gene Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase I Clinical Trials Phosphatidylinositide 3-Kinase Inhibitor Phosphoric Monoester Hydrolases Physiologic pulse Positron-Emission Tomography Pre-Clinical Model Prodrugs Protein Isoforms Protein Tyrosine Kinase Proto-Oncogene Proteins c-akt Regulation Response Elements Schedule Signal Pathway Signal Transduction Stromal Neoplasm TEP1 gene Testing Therapeutic Transgenic Organisms Treatment Efficacy Vascular Endothelial Growth Factors Work Xenograft procedure angiogenesis cell growth chemokine chemokine receptor clinical application cytokine density drug candidate drug development expectation fluorodeoxyglucose hypoxia inducible factor 1 improved in vivo inhibitor/antagonist kinase inhibitor man migration mouse model novel outcome forecast pharmacodynamic model pre-clinical preclinical evaluation preclinical study promoter research study response small molecule stem tensin tumor

项目摘要

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.

描述（由申请人提供）：我们以前的工作集中在“概念证明”实验上，以在临床前模型中建立PAN PI-3激酶抑制剂的临床实用性，用于用于神经胶质瘤疗法，并评估PTEN调节神经胶质瘤进展的机制，包括血管生成和下游药物的靶标的元素，以实现Pharmagogeness和下游药物的靶标。我们以前的实验涉及对神经瘤模型中特征良好的PAN PI-3激酶抑制剂LY294002的研究。出于多个原因（下面讨论），LY294002化合物不是临床发育的可行药物。在我们的竞争性更新中，我们将重点关注当前的临床前开发PI-3激酶的新型小分子抑制剂，该酶在我们的实验室（与半段药物合作）用于神经胶质瘤疗法中共同开发。该抑制剂是一种靶向LY294002的前药衍生物的血管RGD，称为SF1126。下面我们介绍了我们的初步数据，该数据支持我们的建议，以进一步评估该靶向的PAN PI-3激酶抑制剂在恶性神经胶质瘤的临床前模型中。假设：PAN PI-3激酶抑制剂（SF1126）将通过对包括HIF1A-VEGF信号轴（HIF1A-VEGF信号轴）的许多重要信号通路的控制来衰减裸鼠中恶性神经胶质肿瘤的生长。 PAN PI-3激酶抑制剂将在体内表现出抗神经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，与PK和PD参数有关，肿瘤状态以及对血管生成和重要的下游生物标志物的影响。在修订的建议中，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。我们以前的赠款提案CA94233的主要目标是：“确定宾夕法尼亚宾夕法尼亚州治疗学模型中PAN PI-3激酶抑制剂的实用性”。本文中，我们介绍了临床上可行的PAN PI-3激酶抑制剂前药SF1126的开发，并在临床前神经胶质瘤模型中仔细表征了该药物的表征。总体目标是为神经胶质瘤患者的I期临床试验做好准备。公共卫生相关性：恶性神经胶质肿瘤的诊断带有令人沮丧的预后，目前没有可以治愈这种类型的脑肿瘤的疗法。已知某些遗传变化会引起恶性脑肿瘤，这些改变已成为新药开发的靶标。在此提案中，我们开发了最早的PI-3激酶抑制剂之一，称为SF1126进入人类临床试验。该提案将为SF1126在人类中的恶性神经胶质肿瘤治疗中的应用提供有用的信息，因此可能会改善这种形式的癌症患者的生存。