Modeling Oral Cancer in Primary Organoid Culture

这是斯坦福大学的血液肿瘤学研究员Salahueland博士的K 08申请表 医学院。萨拉赫丁博士已经开始了他在癌症生物学方面的博士后研究，并希望 使自己成为口腔癌转化研究的年轻研究者。口腔癌K 08奖 研究将提供萨拉赫丁博士的支持，以实现他的职业发展的以下目标：1） 证明一种新的三维“类器官”体外口腔癌模型的实用性2）要精通 分析临床、免疫学和基因组学数据以产生新的假设，以及3）实验性地 在类器官模型中测试这些假设，以用于进一步的转化研究和临床调查。监督 博士Salahueli的训练，他将由卡尔文郭博士指导，他是类器官培养方面的知名人士， 癌症生物学Salahueland博士还将由口腔癌专家John Sunwoo博士共同指导， 免疫学除了他的导师，萨拉赫丁博士还召集了一批顾问/合作者， 将为萨拉赫丁博士提出的口腔癌生物学研究提供专业知识。 头颈部鳞状细胞癌（HNSCC），包括口腔癌，是第六常见的 癌症，也是癌症相关死亡的主要原因。然而，HNSCC是一种异质性疾病， 临床分层包括人乳头状瘤病毒（HPV）阳性癌症，后者携带 更有利的预后。相反，HPV阴性患者的复发转移性疾病率较高。 此外，HNSCC的生存率在过去十年中没有显著提高，这是由于我们的有限的 与其他实体瘤相比，了解疾病生物学知识。 为了确定HNSCC中新的驱动突变和耐药机制，基因组规模测序已经 确定了候选致癌基因座，但这些数据尚未在临床前研究中迅速转化。一个主要 肿瘤转化研究中的一个障碍是体外标准的实质性缺陷 临床前模型。目前的技术依赖于癌细胞系、生长在肿瘤细胞中的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。这些模型不是最优的 并且需要一种可以快速验证候选物的体外平台 致癌基因座为了克服这些局限性，Salahueland博士开发了一种新型的口腔癌类器官 验证候选致癌基因座（AIM 1），表征免疫逃避（AIM 2），并鉴定合成 致命疗法总之，拟议的培训和研究计划将加强萨拉赫丁博士的过渡， 作为口腔癌转化研究的医生科学家的独立性。

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.