Understanding How Ciliary Hedgehog Signaling Causes Medulloblastoma

了解睫状刺猬信号如何导致髓母细胞瘤

• 批准号: 10196981
• 负责人: David R Raleigh
• 金额: $ 17.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196981
• 关键词: Address; Adopted; Advisory Committees; Anabolism; Area; Award; Basic Science; Binding; Biochemistry; Biological Markers; Brain Neoplasms; Cancer Etiology; Cell Cycle; Cell Proliferation; Cells; Cellular biology; Child; Childhood; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Cilia; Clinical; Communities; Cytoplasmic Granules; Development; Doctor of Philosophy; Educational workshop; Environment; Erinaceidae; Event; Foundations; Gene Expression Profiling; Genetic; Genetic Models; Genetic Transcription; Genomics; Goals; Growth; Knowledge; Ligands; Light; Malignant Neoplasms; Malignant neoplasm of cerebellum; Mediating; Mediator of activation protein; Medicine; Membrane; Mentors; Modeling; Molecular; Molecular Biology; Molecular Conformation; Mus; Neuraxis; Oncogenic; Outcome; Pathway interactions; Patients; Pharmacology; Repression; Research; Research Personnel; Research Project Grants; Scientist; Signal Transduction; Subgroup; Surface; Technical Expertise; Testing; Therapeutic; Training; Treatment Side Effects; Tumor Biology; Work; cancer type; cell growth; demographics; experience; genetic approach; hands on research; improved; inhibitor/antagonist; medulloblastoma; mouse genetics; mouse model; multidisciplinary; new therapeutic target; novel; pre-clinical; progenitor; programs; response; smoothened signaling pathway; therapeutic target; therapeutically effective; trafficking; transcriptome; tumorigenesis

PROJECT SUMMARY/ABSTRACT The objective of this proposal is to train David R. Raleigh, MD, PhD, a candidate with an excellent foundation for basic science research, to become an independent investigator of brain tumor biology. The proposed research also aims to improve treatments for patients with medulloblastoma, a common pediatric brain cancer. The proposed research addresses limitations that have hindered therapeutic advancements for patients with medulloblastoma by identifying novel, druggable targets that transduce oncogenic Hedgehog signaling via the primary cilium. The candidate's central hypothesis is that the oxysterol synthase Hsd11β2 generates ciliary oxysterols that activate Hedgehog signaling and induce Cdk6 to drive uncontrolled cell proliferation. This work will elucidate (1) how oncogenic Hh signaling is transduced to cause cell growth; and (2) whether blocking this signaling is an effective therapeutic strategy for Hh-associated medulloblastoma. Toward those goals, the following specific aims are proposed: (1) determine how Hsd11β2 contributes to ciliary Hedgehog signaling; and (2) define how Hedgehog signaling misactivates Cdk6 in medulloblastoma. The candidate's training and research plan incorporates a combination of coursework, workshops, mentoring, and hand-on research experience set in the outstanding academic environment of UCSF, a center of excellence in medicine and research endowed with a well-integrated community of clinicians and scientists. The candidate's mentor is Dr. Jeremy Reiter, a recognized expert and pioneer in mouse genetic models and the molecular mechanisms of vertebrate Hedgehog signaling through the primary cilium., both in development and in cancer. The candidate's multidisciplinary advisory committee includes distinguished scientists with expertise in all areas covered by the research strategy of this award. Successful completion of the proposed research will produce compelling preclinical rationale for testing specific targeted inhibitors in patients within biomarker-defined subsets of Hedgehog-associated medulloblastoma. The intermediate-term goal is for the candidate to acquire the knowledge, technical skill and expertise necessary to submit a successful R01 proposal. Long-term goals are for the integrated, preclinical platform of Hedgehog-associated medulloblastoma developed in this proposal to inform treatment decisions and improve survival of medulloblastoma patients.

项目总结/摘要 本提案的目的是培训大卫R。罗利，医学博士，博士，候选人与 优秀的基础科学研究基础，成为独立的大脑研究者 肿瘤生物学这项拟议的研究还旨在改善患者的治疗 髓母细胞瘤，一种常见的小儿脑癌。拟议的研究涉及 这些局限性阻碍了髓母细胞瘤患者的治疗进展， 鉴定新的、可药物化的靶点，其通过免疫调节抑制致癌Hedgehog信号传导。 初级纤毛这位候选人的核心假设是氧化固醇合酶Hsd 11 β2 产生睫状氧化固醇，激活Hedgehog信号传导并诱导Cdk 6驱动 不受控制的细胞增殖这项工作将阐明（1）致癌Hh信号是如何 转导引起细胞生长;和（2）阻断这种信号传导是否是有效的 Hh相关髓母细胞瘤的治疗策略。为实现这些目标， 具体目标是：（1）确定Hsd 11 β2如何参与睫状Hedgehog 信号传导;和（2）定义Hedgehog信号传导如何在髓母细胞瘤中使Cdk 6失活。的 候选人的培训和研究计划包括课程作业，研讨会， 指导，并在优秀的学术环境中设置动手研究经验， UCSF是一个卓越的医学和研究中心，拥有良好的综合能力， 临床医生和科学家的社区。候选人的导师是杰里米·赖特博士， 在小鼠遗传模型和分子机制方面的公认专家和先驱 脊椎动物Hedgehog通过初级纤毛发出信号，无论是在发育还是癌症中。 候选人的多学科咨询委员会包括杰出的科学家， 该奖项的研究战略所涵盖的所有领域的专业知识。成功完成 拟议的研究将产生令人信服的临床前理由， 在Hedgehog相关的生物标志物定义的子集内的患者中的抑制剂 髓母细胞瘤中期目标是让候选人获得知识， 成功提交R 01建议书所需技术技能和专业知识。长期目标 是为刺猬相关髓母细胞瘤开发的综合临床前平台， 在这个建议中，为治疗决策提供信息，提高髓母细胞瘤患者的生存率。

项目成果

The Meningioma Enhancer Landscape Delineates Novel Subgroups and Drives Druggable Dependencies.

• DOI: 10.1158/2159-8290.cd-20-0160
• 发表时间: 2020-11
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Prager BC;Vasudevan HN;Dixit D;Bernatchez JA;Wu Q;Wallace LC;Bhargava S;Lee D;King BH;Morton AR;Gimple RC;Pekmezci M;Zhu Z;Siqueira-Neto JL;Wang X;Xie Q;Chen C;Barnett GH;Vogelbaum MA;Mack SC;Chavez L;Perry A;Raleigh DR;Rich JN
• 通讯作者: Rich JN

Sterol regulation of developmental and oncogenic Hedgehog signaling.

• DOI: 10.1016/j.bcp.2021.114647
• 发表时间: 2022-03
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Daggubati V;Raleigh DR;Sever N
• 通讯作者: Sever N

Preclinical models of meningioma: Cell culture and animal systems.

• DOI: 10.1016/b978-0-12-804280-9.00008-1
• 发表时间: 2020-01-01
• 期刊: Handbook of clinical neurology
• 作者: Choudhury, Abrar;Raleigh, David R
• 通讯作者: Raleigh, David R

Stereotactic Radiosurgery to More Than 10 Brain Metastases: Evidence to Support the Role of Radiosurgery for Ideal Hippocampal Sparing in the Treatment of Multiple Brain Metastases.

• DOI: 10.1016/j.wneu.2019.11.089
• 发表时间: 2020-03
• 期刊: World neurosurgery
• 影响因子: 2
• 作者: Susko MS;Garcia MA;Ma L;Nakamura JL;Raleigh DR;Fogh S;Theodosopoulos P;McDermott M;Sneed PK;Braunstein SE
• 通讯作者: Braunstein SE

Letter: Patterns of Intermediate- and High-Risk Meningioma Recurrence After Treatment With Postoperative External Beam Radiotherapy.

信件：术后外照射放射治疗后中危和高危脑膜瘤复发的模式。

• DOI: 10.1093/neuros/nyab143
• 发表时间: 2021
• 期刊: Neurosurgery
• 影响因子: 4.8
• 作者: Susko,MatthewS;Chen,WilliamC;Vasudevan,HarishN;Magill,StephenT;Lucas,Calixto-HopeG;OberheimBush,NancyAnn;Solomon,DavidA;Theodosopoulos,PhilipV;McDermott,MichaelW;Villanueva-Meyer,JavierE;Boreta,Lauren;Nakamura,JeanL;Sne
• 通讯作者: Sne