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（由申请人提供）：原发性脑肿瘤的治疗在肿瘤学领域提出了一个特别艰巨的挑战，因为它具有侵袭性和对传统疗法的耐药性。为了有效地产生针对脑肿瘤的范式转换治疗方法，需要将高影响力的实验室研究成果快速转化为构建良好的临床试验。作为一名职业生涯中期的内科科学家和研究人员，我已经成功地在实验室进行了基础研究，提供了对脑肿瘤生物学的见解，并无缝地将这些想法应用于脑肿瘤的临床试验；这是由于我在神经学和神经肿瘤学方面的基础研究训练和临床护理经验，这使我能够专门开展与神经恶性肿瘤相关的以患者为导向的研究。此外，作为神经肿瘤学奖学金项目的前主任，我还积极指导神经肿瘤学研究员。