Modeling Oral Cancer in Primary Organoid Culture

在原代类器官培养中模拟口腔癌

基本信息

批准号：
10221669
负责人：
Ameen A Salahudeen
金额：
$ 13.5万
依托单位：
TEMPUS LABS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221669
关键词：
3-Dimensional Architecture Arts Award Basic Science Biological Biological Markers Biology Biophysics CRISPR interference Cancer Biology Cancer Etiology Cancer Model Cancer cell line Cell Line Cellular Morphology Cessation of life Clinical Clinical Immunology Clinical stratification Clustered Regularly Interspaced Short Palindromic Repeats Colorectal Cancer Complement Complementary DNA Data Dependence Disadvantaged Disease Exclusion Flow Cytometry Foundations Funding GNAQ gene Genes Goals Growth Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Hematology Histologic Human Human Papillomavirus Immune Evasion Immune response Immunodeficient Mouse Immunotherapy Implant In Vitro Investigation Knowledge Lymphocyte MEK inhibition MEKs Malignant Neoplasms Mediator of activation protein Medical Mentors Metastatic/Recurrent Modeling Mus Normal tissue morphology Oncogenes Oncogenic Oncology Oral mucous membrane structure Organoids Pathway interactions Patients Phenotype Physicians Pre-Clinical Model Prognosis Proteins Research Research Methodology Research Personnel Research Training Resistance Role Sampling Science Scientist Solid Neoplasm Survival Rate T-Lymphocyte TP53 gene Testing The Cancer Genome Atlas Therapeutic Tissues Training Transcend Transgenic Mice Translating Tumor Biology Tumor Suppressor Proteins Tumor-Derived Tumorigenicity Universities Up-Regulation Wild Type Mouse anticancer research cancer survival cancer therapy career development chemotherapy clinical investigation driver mutation exhaustion genome-wide genomic data genomic profiles improved in vivo in vivo Model inhibitor/antagonist malignant mouth neoplasm medical schools mouse model mouth squamous cell carcinoma new therapeutic target novel patient derived xenograft model post-doctoral training pre-clinical precision medicine preclinical study protein protein interaction resistance mechanism screening small hairpin RNA targeted treatment translational cancer research translational research program translational study tumor tumor immunology ubiquitin ligase ubiquitin-protein ligase

项目摘要

This is an application for a K08 for Dr. Salahudeen, a Hematology Oncology Fellow at Stanford University School of Medicine. Dr. Salahudeen has commenced his postdoctoral research in cancer biology and wishes to establish himself as a young investigator in oral cancer translational research. The K08 award for oral cancer research will provide Dr. Salahudeen support to achieve the following goals for his career development: 1) To demonstrate the utility of a novel 3-dimensional “organoid” in vitro oral cancer model 2) To become proficient in the analysis of clinical, immunology, and genomics data to generate new hypotheses, and 3) to experimentally test these hypotheses in the organoid model for further translational studies and clinical investigation. To oversee Dr. Salahudeen’s training, he will be mentored by Dr. Calvin Kuo, an established figure in organoid culture and cancer biology. Dr. Salahudeen will also be co-mentored by Dr. John Sunwoo, an expert in oral cancer and immunology. In addition to his mentors, Dr. Salahudeen has assembled a group of advisors/collaborators who will lend expertise to Dr. Salahudeen’s proposed research on oral cancer biology. Head and neck squamous cell carcinoma (HNSCC), including oral cancer, is the sixth most common cancer, and a leading cause of cancer-related death. However, HNSCC is a heterogeneous disease with many clinical stratifications including Human Papilloma Virus (HPV) positive cancers, the latter of which carries a more favorable prognosis. In contrast, HPV negative patients have a higher rate of recurrent metastatic disease. Furthermore, HNSCC survival rates have not significantly improved in the last decade due to our limited knowledge of disease biology as compared to other solid tumors. To identify new driver mutations and resistance mechanisms in HNSCC, genome-scale sequencing has identified candidate oncogenic loci but these data have not rapidly translated in preclinical studies. A major obstacle in cancer translational research has been the substantial deficiencies of standard in vitro preclinical models. The current art relies on cancer cell lines, patient derived xenografts grown in immunodeficient mice, or transgenic mice bearing common oncogenes or tumor. These models are not optimal for several reasons and there is a need for an in vitro platform that can rapidly validate candidate oncogenic loci. To overcome these limitations, Dr. Salahudeen has developed a novel oral cancer organoid platform to validate candidate oncogenic loci (AIM1), characterize immune evasion (AIM2), and identify synthetic lethal therapies. In summary, the proposed training and research plan will enhance Dr. Salahudeen’s transition to independence as a physician scientist in oral cancer translational research.

这是斯坦福大学血液肿瘤学研究员 Salahudeen 博士的 K08 申请医学院的 Salahudeen 博士已开始癌症生物学的博士后研究，并希望使自己成为口腔癌转化研究领域的年轻研究者。口腔癌 K08 奖。研究将为 Salahudeen 博士实现以下职业发展目标提供支持： 1) 展示新型 3 维“类器官”体外口腔癌模型的实用性 2) 精通分析临床、免疫学和基因组学数据以产生新的假设，以及 3) 进行实验在类器官模型中测试这些假设，以进行进一步的转化研究和临床研究。在 Salahudeen 博士的培训中，他将得到类器官培养领域的知名人物 Calvin Kuo 博士的指导。 Salahudeen 博士还将得到口腔癌和癌症领域专家 John Sunwoo 博士的共同指导。除了他的导师之外，Salahudeen 博士还组建了一组顾问/合作者。将为 Salahudeen 博士提出的口腔癌生物学研究提供专业知识。头颈鳞状细胞癌 (HNSCC)，包括口腔癌，是第六常见的癌症然而，HNSCC 是一种异质性疾病，有多种疾病。临床分层包括人乳头瘤病毒 (HPV) 阳性癌症，后者携带相比之下，HPV阴性患者的复发转移率较高。此外，由于我们有限的研究，HNSCC 的生存率在过去十年中并没有显着提高。与其他实体瘤相比的疾病生物学知识。为了确定 HNSCC 中新的驱动突变和耐药机制，基因组规模测序已确定了候选致癌位点，但这些数据尚未在临床前研究中迅速转化。癌症转化研究的障碍是体外标准的实质性缺陷目前的临床前模型依赖于癌细胞系、患者来源的异种移植物。免疫缺陷小鼠或携带常见癌基因或肿瘤的转基因小鼠这些模型并不是最佳的。出于多种原因，需要一个可以快速验证候选药物的体外平台为了克服这些局限性，Salahudeen 博士开发了一种新型口腔癌类器官。用于验证候选致癌位点 (AIM1)、表征免疫逃避 (AIM2) 和识别合成的平台总之，拟议的培训和研究计划将促进 Salahudeen 博士的过渡。作为口腔癌转化研究的医师科学家独立。