Development of Clinical Strategies to Prevent GBM Recurrences After Radiotherapy

预防放疗后 GBM 复发的临床策略的制定

基本信息

批准号：
8850819
负责人：
JOHN MARTIN BROWN
金额：
$ 48.44万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850819
关键词：
AMD3100 Binding Biological Biological Models Blood Vessels Bone Marrow Brain Neoplasms CXCR4 Receptors CXCR4 gene Cells Cessation of life Clinic Clinical Clinical Research Cranial Irradiation Data Detection Development Dose Endothelial Cells Ethylnitrosourea Failure Glioblastoma Goals Head Human Hypoxia ITGAM gene Implant Irradiated tumor Laboratories Lead Malignant neoplasm of brain Marrow Mediating Modeling Mus Pathway interactions Patients Pharmaceutical Preparations Plasma Primary Neoplasm Process Radiation Radiation therapy Radiobiology Rattus Recurrence Research Personnel Site Skin graft Solid Neoplasm Source Stem cells Stromal Cell-Derived Factor 1 Techniques Testing Time Treatment Failure U251 Up-Regulation Work base cancer recurrence chemokine receptor cytokine improved inhibitor/antagonist instrument irradiation microCT monocyte mouse model novel pre-clinical prevent receptor research clinical testing response restoration tumor uptake vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Our overall goal is to improve the cure rates of glioblastoma multiforme (GBM) for which treatment failure leading to patient death is the result of inability to control the primary tumor by radiotherapy. To do this we plan to exploit the hypothesis that the failure to cure these tumors despite high dose radiotherapy is the result of regrowth of the tumor vasculature from circulating cells (a process known as "vasculogenesis") following the course of radiotherapy. Targeting both the local tumor and vasculogenesis, primarily mediated by CD11b+ myelomonocytes and circulating endothelial cells (ECs), is a novel paradigm and could lead to a major increase in the curability of tumors by radiotherapy. We will test three drugs that inhibit vasculogenesis pathway, in two GBM model systems: 1) AMD3100, a specific inhibitor of the interaction of stromal derived factor-1 (SDF-1) with its receptor CXCR4. This interaction is responsible for the retention of the CD11b+ myelomonocytes in tumors after irradiation, 2) CCX662, a specific inhibitor of the interaction of SDF-1 with its second receptor, CXCR7, which we believe is responsible for the recruitment of circulating ECs and their capture in the irradiated tumor, and 3) NOX-A12, a highly specific inhibitor of SDF-1 which we hypothesize will prevent both the CD11b+ monocytes and circulating ECs from colonizing the irradiated tumor. The two GBM models systems we will use are the intracranially implanted human U251 GBM in the mouse and the ENU-induced GBM in the rat. We will test all three drugs given for 3-4 weeks, and for longer, following either single or fractionated irradiation to each of these tumors models and will determine their efficacy in preventing the radiation increased influx of CD11b+ and ECs and on for their ability to prevent recurrences of the tumors following the modest radiation doses that we will use. We will also test in the mouse model the ability of our strategy to work with focal tumor irradiation rather than whole brain irradiation. Our project combines the expertise of three laboratories, that of Dr. Brown, an experimental investigator with expertise in tumor radiation biology, that of Dr. Recht, a neurooncologist who treats GBM patients and whose laboratory has expertise with initiation and detection of the ENU-induced rat GBM model and Dr. Graves who built the micro-CT based irradiator. The goal is to provide the needed information to allow clinical testing of this new strategy. )

描述（由申请人提供）：我们的总体目标是提高多形胶质母细胞瘤（GBM）的治疗速率，导致患者死亡的治疗失败是由于无法通过放射疗法控制原发性肿瘤的结果。为此，我们计划利用这样的假设：尽管放疗过程中，肿瘤脉管系统的再生是肿瘤脉管系统（一种称为“血管生成”的过程）的结果。靶向局部肿瘤和血管生成，主要是由CD11b+脊髓细胞和循环内皮细胞（EC）介导的，这是一种新型范式，可能导致放疗肿瘤的可疗法可升高。我们将在两个GBM模型系统中测试三种抑制血管生成途径的药物：1）AMD3100，AMD3100是基质衍生因子-1（SDF-1）与其受体CXCR4相互作用的特定抑制剂。这种相互作用负责辐射后CD11b+骨髓成细胞在肿瘤中的保留，2）CCX662，CCX662是SDF-1相互作用的特定抑制剂，SDF-1与其第二受体CXCR7相互作用的抑制剂，我们认为，我们认为这是造成循环ECS及其在Innodiped tumor中的招募及其在notaimed Tumor中的招募，以及wee dyx-112，以及AD-3），A和3）A.112，a-3）a-a12，A。假设将防止CD11b+单核细胞和循环EC殖民辐照肿瘤。我们将使用的两个GBM模型系统是颅内植入的人U251 GBM在小鼠中和大鼠中的ENU诱导的GBM。我们将测试三种药物3-4周，并在对每个肿瘤模型中的单一或分数辐照后更长的时间进行测试，并将确定它们在防止CD11b+和ECS辐射增加的辐射增加的功效，并在适度的辐射剂量后防止肿瘤复发的能力。我们还将在小鼠模型中测试我们的策略处理局灶性肿瘤照射而不是整个大脑照射的能力。我们的项目结合了三个实验室的专业知识，即Brown博士是Brown博士，Brown博士是具有肿瘤辐射生物学专业知识的实验研究者，Recht博士是对治疗GBM患者的神经研究医生Recht博士的专业知识，其实验室的实验室具有启动和检测为ENU诱导的RAT GBM GBM模型的专业知识，并建立了基于Micro-ct CT的Irivation Irivation Irivatientriant。目的是提供所需的信息，以允许对这种新策略进行临床测试。）

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SDF-1 Blockade Enhances Anti-VEGF Therapy of Glioblastoma and Can Be Monitored by MRI.

DOI：
10.1016/j.neo.2016.11.010
发表时间：
2017-01
期刊：
NEOPLASIA
影响因子：
4.8
作者：
Deng, Lei;Stafford, Jason H.;Liu, Shie-Chau;Chernikova, Sophia B.;Merchant, Milton;Recht, Lawrence;Brown, J. Martin
通讯作者：
Brown, J. Martin

Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats.

DOI：
10.1038/bjc.2013.830
发表时间：
2014-03-04
期刊：
British journal of cancer
影响因子：
8.8
作者：
Walters MJ;Ebsworth K;Berahovich RD;Penfold ME;Liu SC;Al Omran R;Kioi M;Chernikova SB;Tseng D;Mulkearns-Hubert EE;Sinyuk M;Ransohoff RM;Lathia JD;Karamchandani J;Kohrt HE;Zhang P;Powers JP;Jaen JC;Schall TJ;Merchant M;Recht L;Brown JM
通讯作者：
Brown JM

Cell Death Identification in Anticancer Therapy-Letter.

抗癌治疗中的细胞死亡识别-信函。

DOI：
10.1158/0008-5472.can-15-0908
发表时间：
2015
期刊：
Cancer research
影响因子：
11.2
作者：
Brown,JMartin;Wouters,BradlyG;Kirsch,DavidG
通讯作者：
Kirsch,DavidG

The Promise of Targeting Macrophages in Cancer Therapy.

DOI：
10.1158/1078-0432.ccr-16-3122
发表时间：
2017-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Brown JM;Recht L;Strober S
通讯作者：
Strober S

Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations.

10 种药物-放射组合疗效的临床前数据：评估、担忧和建议。

DOI：
10.1016/j.tranon.2016.01.002
发表时间：
2016
期刊：
Translational oncology
影响因子：
5
作者：
Stone,HelenB;Bernhard,EricJ;Coleman,CNorman;Deye,James;Capala,Jacek;Mitchell,JamesB;Brown,JMartin
通讯作者：
Brown,JMartin