Patient Oriented Research Program in Neuro-oncology

以患者为中心的神经肿瘤学研究计划

• 批准号: 8731813
• 负责人: VINAY K PUDUVALLI
• 金额: $ 18.05万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-13 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731813
• 关键词: 19q; Aggressive course; Angiogenesis Inhibitors; Angiogenic Proteins; Apoptosis; Area; Basic Science; Biological Markers; Biological Process; Biology; Blood Volume; Brain Neoplasms; Bypass; Cancer Center; Cell Death; Cell Differentiation process; Cerebrovascular Circulation; Chromatin; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Critical Pathways; DNA; DNA Structure; Data; Development; Diffusion; Disease; Endothelial Cells; Epigenetic Process; Faculty; Fellowship Program; Funding; Gene Expression; Glioblastoma; Glioma; Goals; Grant; Growth Factor Inhibition; Histone Deacetylase Inhibitor; Human; Incidence; Investigation; Laboratories; Laboratory Research; Laboratory Study; MGMT gene; MRI Scans; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Measurement; Measures; Mentors; Mentorship; Mesenchymal; Methods; Methylation; Molecular; Morbidity - disease rate; Mutation; Neurologic; Neurology; Oncologist; Outcome; Pathway interactions; Patients; Perfusion; Physicians; Platelet-Derived Growth Factor; Prediction of Response to Therapy; Primary Brain Neoplasms; Principal Investigator; Process; Progression-Free Survivals; Randomized; Recurrence; Regulation; Relative (related person); Research; Research Personnel; Research Training; Resistance; Resistance development; Resources; Role; Route; Scientist; Serum; Structure; Testing; Therapeutic; Time; Tissues; Training; Translational Research; Translations; Treatment Failure; Treatment outcome; Tumor Biology; Vascular Endothelial Growth Factors; Vorinostat; angiogenesis; arm; base; bevacizumab; career; clinical care; conventional therapy; design; experience; humanized antibody; hypoxia inducible factor 1; improved; insight; interest; member; mortality; neuro-oncology; novel; novel strategies; novel therapeutics; oligodendroglioma; oncology; outcome forecast; overexpression; patient oriented; patient oriented research; pre-clinical; preclinical study; prevent; programs; promoter; research study; response; screening; translational study; treatment response; tumor

DESCRIPTION (provided by applicant): The treatment of primary brain tumors poses a particularly formidable challenge in the field of oncology given its aggressive course and resistance to conventional therapies. To effectively generate paradigm-shifting therapeutic approaches against brain tumors, a rapid translation of high impact laboratory research findings into well constructed clinical trials is needed. As a mid-career physician scientist and researcher, I have successfully conducted basic research in the laboratory providing insights into biology of brain tumors and seamlessly moved these ideas into clinical trials against brain tumors; This has been possible due to my training in basic research and experience in clinical care in both neurology and neuro-oncology, which allow me to specifically conduct patient-oriented research related to neurological malignancies. In addition, I have taken a proactive role in mentoring neuro-oncology fellows as the former director of Neuro-oncology fellowship program. My current role as director of Clinical Research provides me with the unique opportunity to combine patient oriented research with focused mentoring. The K24 grant will provide protected time and resources to expand my clinical research efforts into epigenetics of brain tumors, which has emerged as a new area of interest based on my laboratory studies. Epigenetics pertains to the changes in gene expression not due to change in the DNA but due to alterations of control mechanisms that regulate the structure and access to chromatin. In disease processes such as cancer, epigenetic changes can dramatically influence tumor biology, response to therapy and prediction of outcome; one such effect, MGMT promoter methylation, is already known to influence the outcome of glioblastoma (GBM), the most aggressive of primary brain tumors. Recently, bevacizumab, a humanized antibody that blocks vascular endothelial growth factor (VEGF) and prevents neoangiogenesis has shown efficacy against recurrent GBM and is approved for this indication. Although initially effective, tumors adapt to VEGF inhibition and bypass this blockade through several mechanisms leading to recurrence. Epigenetic factors leading to altered gene expression have been shown to reverse this resistance in preclinical studies by inhibiting the escape routes including non-VEGF molecular pathways such as overexpression of HIF1¿, PDGF and IGF as well as recruitment of circulating endothelial cells. The short term goal of this project is to conduct a clinical trial to test the hypothesis that vorinostat, which epigenetically changes DNA structure, can prevent the development of resistance to bevacizumab in patients with recurrent glioblastoma and significantly delay tumor recurrence and improve survival. This trial is unique in that a new statistical design based on Bayesian adaptive randomization methods will allow us to compare the combination of bevacizumab and vorinostat with bevacizumab alone in an efficient "pick the winner" design. The study is also designed to include DCE/DSC MR imaging to measure changes in perfusion and diffusion within the tumor as a noninvasive marker of treatment outcome. It also includes serum biomarker measurements to determine their association with outcome. The study will provide both new insights into overcoming resistance to antiangiogenic agents and test novel trial designs; it will also provide me with an excellent opportunity for mentorship of fellows and junior faculty in the conduct of trial design and rational targeting of gliomas. Mentoring fellows and junior faculty is one of my major goals under this grant and I will actively involve neuro-oncology fellows in the various projects involving epigenetic laboratory research and clinical trials; my efforts will also be specifically directed towards guidance of junior faculy in their own projects with a goal to move them to an independent academic path. The long term goal of this project is to develop a comprehensive strategy towards a Brain Tumor Epigenetics Program within the Brain Tumor Center that will support studies of epigenetic factors influencing tumor biology in various areas of research and training and consequently develop novel approaches to brain tumor therapy.

描述（由适用提供）：鉴于肿瘤学领域，对原发性脑肿瘤的治疗构成了特别巨大的挑战，鉴于其侵略性和对常规疗法的抵抗力。为了有效地针对脑肿瘤产生范式转移的治疗方法，需要将高影响力的实验室研究结果快速转化为结构良好的临床试验。作为一名职业生理学家和研究人员，我在实验室中成功进行了基础研究，从而提供了对脑肿瘤生物学的见解，并将这些思想无缝地转移到针对脑肿瘤的临床试验中。这是由于我在神经病学和神经肿瘤学方面的基础研究和临床护理方面的培训而进行的，这使我能够专门进行与神经肿瘤学有关的患者研究。此外，我在心理化神经肿瘤学方面发挥了积极作用，成为前神经肿瘤学奖学金计划的主任。 我目前担任临床研究主管的角色为我提供了将面向患者的研究与重点进行心理的独特机会。 K24赠款将提供受保护的时间和资源，以将我的临床研究工作扩展到脑肿瘤的表观遗传学上，根据我的实验室研究，这已成为一个新的感兴趣领域。表观遗传学与基因表达的变化有关，不是由于DNA的变化而导致的，而是由于调节结构和获取染色质的控制机制的改变。在癌症等疾病过程中，表观遗传变化会极大地影响肿瘤生物学，对治疗的反应和预测结果。一种这样的作用，即MGMT启动子甲基化，已经众所周知会影响胶质母细胞瘤（GBM）的结果，胶质母细胞瘤（GBM）是原发性脑肿瘤中最具侵略性的结果。最近，贝伐单抗是一种封闭血管内皮生长因子（VEGF）并防止新血管生成的人性化抗体显示出针对复发性GBM的有效性，并被批准用于此指示。尽管最初有效，但肿瘤适应VEGF抑制，并通过导致复发的几种机制绕过这种阻断。通过抑制包括非VEGF分子途径在内的逃生途径（例如HIF1 e，pDGF和IGF）以及循环内皮细胞的募集，导致基因表达改变的表观遗传因子在临床前研究中扭转了这种抵抗。 该项目的短期目标是进行临床试验，以检验以下假设，即表观遗传上改变DNA结构的伏诺替纳斯特可以防止复发性胶质母细胞瘤患者的抗贝伐单抗的耐药性发展，并显着延迟肿瘤复发并改善生存率。该试验的独特之处在于，基于贝叶斯自适应随机化方法的新统计设计将使我们能够在有效的“选择胜利者”设计中比较贝伐单抗和伏诺替托特与贝伐单抗的组合。该研究还旨在包括DCE/DSM MR成像，以测量肿瘤内灌注和扩散的变化，作为治疗结果的无创标志物。它还包括血清生物标志物测量值，以确定其与结果的关联。这项研究将既可以为克服对抗血管生成剂的抵抗力和测试新型试验设计提供新的见解。它还为我提供了一个很好的机会，可以在试验设计和合理的胶质瘤定位中进行研究员和初级教师的心态。 指导研究员和初级教师是我这笔赠款的主要目标之一，我将积极涉及神经肿瘤研究员参加涉及表观遗传实验室研究和临床试验的各种项目；我的努力还将专门用于在自己的项目中向初中的指导，目标是将他们转移到独立的学术道路上。 该项目的长期目标是针对脑肿瘤中心内的脑肿瘤表观遗传学计划制定一项综合策略，该计划将支持对表观遗传因素的研究影响研究和培训各个领域的肿瘤生物学，并因此开发了用于脑肿瘤疗法的新方法。