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Elucidating the drivers of medulloblastoma initiation and recurrence

阐明髓母细胞瘤发生和复发的驱动因素

基本信息

批准号：
9233218
负责人：
DAVID J ROBBINS
金额：
$ 19.19万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233218
关键词：
Attenuated Basal Cell Nevus Syndrome Basal cell carcinoma Biopsy Brain Brain Neoplasms Cell Culture Techniques Cells Cessation of life Childhood Childhood Malignant Brain Tumor Clinic Clinical Clinical Management Clinical Trials Combined Modality Therapy Data Dominant-Negative Mutation Drug Industry Engineering Erinaceidae Exhibits FDA approved Family Genes Genetically Engineered Mouse Genomics Goals Human In Vitro Laboratories Lead Malignant - descriptor Modeling Molecular Genetics Morbidity - disease rate Mutation Pathway interactions Patients Pharmacotherapy Play Population Primary Neoplasm Publishing Recurrence Refractory Relapse Resistance Role Signal Transduction Stem cells Subgroup TP53 gene Technology Testing Therapeutic Tumor Debulking Underserved Population WNT Signaling Pathway Work attenuation base beta catenin cancer stem cell cancer therapy clinical development improved in vivo induced pluripotent stem cell inhibitor/antagonist knock-down medulloblastoma mouse model new therapeutic target novel pre-clinical prevent public health relevance self-renewal small molecule small molecule inhibitor smoothened signaling pathway stemness targeted treatment tool transcription factor tumor tumor initiation

项目摘要

DESCRIPTION (provided by applicant): Medulloblastoma (MB) is the most common malignant pediatric brain cancer. While the bulk of patients respond to multimodal therapy, significant treatment induced morbidity, and relapse (which almost always results in death) remain significant barriers in the clinical management of these patients. Thus, significant effort has gone into identifying novel targeted therapies for this cancer that both shrink the primary tumor and prevent relapse. One of these compounds, vismodegib, which is FDA-approved for metastatic basal cell carcinoma patients, has shown promise in various clinical trials for hedgehog (HH) subgroup of MB patients. Our unpublished results, along with recently published data from the Dirks group, suggests that a population of MB cancer stem cells (CSC) in HH driven MB is refractory to vismodegib, an observation likely to lead to MB recurrence in patients treated with this SMO inhibitor. Thus, this class of inhibitors may only target the tumor bulk whil leaving the cancer stem cell reservoir, which is likely responsible for tumor relapse, untouched. We focus our work in finding alternative targets to SMO for CSCs eradication within HH subgroup of MB. New candidate treatments for MB targeting CSC reservoir will be screened ex vivo on Ptch1, p53-/- CSCs cultures (Aim 1). Selected therapeutic approach will be combined with vismodegib on the ND2:SmoA1 murine model of MB to study tumor-free survival in Aim 2. Relevance of our findings in murine models of MB will be further validated in a PTCH1 driven human MB model (Aim 3). Our long-term goal is to develop a therapeutic strategy that shrinks primary tumor and targets CSC reservoir.