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: 8300649
• 负责人: VINAY K PUDUVALLI
• 金额: $ 16.37万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300649
• 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; Screening procedure; 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; 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; 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. PUBLIC HEALTH RELEVANCE: Primary brain tumors are among the worst in prognosis among human malignancies. Efficient development of novel therapies against primary malignant gliomas require rapid translation of results from promising laboratory studies to well designed clinical trials; this will allow rapid screening of new therapies in order to channel the most promising of these to large confirmatory trials. This Mid-Career Investigator grant will allow Dr. Puduvalli, the principal investigator of this project, to design and deploy novel therapeutic strategies that targets "epigenetics" of brain tumors, which is essential for regulation of the tumors biological processes and treatment response; in addition, it will allow Dr. Puduvalli to develop a new program in brain tumor epigenetics and provide opportunities for mentorship of neuro-oncology fellows and junior faculty.

描述（由申请人提供）：鉴于原发性脑肿瘤的侵袭性病程和对常规疗法的耐药性，原发性脑肿瘤的治疗在肿瘤学领域提出了特别艰巨的挑战。为了有效地产生针对脑肿瘤的范式转变治疗方法，需要将高影响力的实验室研究结果快速转化为精心构建的临床试验。作为一名职业生涯中期的医师科学家和研究员，我在实验室成功地进行了基础研究，提供了对脑肿瘤生物学的见解，并将这些想法无缝地转移到针对脑肿瘤的临床试验中；这得益于我在神经病学和神经肿瘤学方面的基础研究培训和临床护理经验，这使我能够专门进行与神经系统恶性肿瘤相关的以患者为导向的研究。此外，作为神经肿瘤学研究金项目的前主任，我在指导神经肿瘤学研究人员方面发挥了积极的作用。 我目前担任临床研究总监的角色为我提供了独特的机会，可以将以患者为导向的研究与重点指导结合起来。 K24 资助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，根据我的实验室研究，这已成为一个新的兴趣领域。表观遗传学涉及基因表达的变化，不是由于 DNA 的变化，而是由于调节结构和染色质通路的控制机制的改变。在癌症等疾病过程中，表观遗传变化可以极大地影响肿瘤生物学、治疗反应和结果预测；其中一种效应，即 MGMT 启动子甲基化，已知会影响胶质母细胞瘤 (GBM) 的结果，胶质母细胞瘤是最具侵袭性的原发性脑肿瘤。最近，贝伐珠单抗（bevacizumab），一种阻断血管内皮生长因子（VEGF）并防止新生血管生成的人源化抗体，已显示出对抗复发性 GBM 的功效，并被批准用于该适应症。尽管最初有效，但肿瘤会适应 VEGF 抑制，并通过几种导致复发的机制绕过这种封锁。临床前研究表明，导致基因表达改变的表观遗传因素可以通过抑制逃逸途径（包括非 VEGF 分子途径，如 HIF1、PDGF 和 IGF 的过度表达以及循环内皮细胞的募集）来逆转这种耐药性。 该项目的短期目标是进行一项临床试验，以检验伏立诺他（通过表观遗传改变DNA结构）可以预防复发性胶质母细胞瘤患者对贝伐珠单抗产生耐药性并显着延缓肿瘤复发并提高生存率的假设。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“选择获胜者”设计中将贝伐单抗和伏立诺他的组合与单独的贝伐单抗进行比较。该研究还旨在包括 DCE/DSC MR 成像，以测量肿瘤内灌注和扩散的变化，作为治疗结果的非侵入性标志物。它还包括血清生物标志物测量，以确定它们与结果的关联。该研究将为克服抗血管生成药物耐药性提供新见解，并测试新颖的试验设计；它还将为我提供一个极好的机会，指导研究员和初级教师进行神经胶质瘤的试验设计和合理靶向。 指导研究员和初级教师是我在这笔赠款下的主要目标之一，我将积极让神经肿瘤学研究员参与涉及表观遗传学实验室研究和临床试验的各种项目；我的努力还将专门针对初级教师自己的项目的指导，目标是使他们走上独立的学术道路。 该项目的长期目标是为脑肿瘤中心内的脑肿瘤表观遗传学计划制定全面的战略，该计划将支持在各个研究和培训领域影响肿瘤生物学的表观遗传因素的研究，从而开发脑肿瘤治疗的新方法。 公共卫生相关性：原发性脑肿瘤是人类恶性肿瘤中预后最差的一种。有效开发针对原发性恶性神经胶质瘤的新疗法需要将有前景的实验室研究结果快速转化为精心设计的临床试验；这将有助于快速筛选新疗法，以便将其中最有希望的疗法用于大型验证性试验。这项职业生涯中期研究员资助将使该项目的首席研究员 Puduvalli 博士能够设计和部署针对脑肿瘤“表观遗传学”的新型治疗策略，这对于调节肿瘤生物过程和治疗反应至关重要；此外，它将使 Puduvalli 博士能够开发脑肿瘤表观遗传学的新项目，并为神经肿瘤学研究员和初级教师提供指导机会。