Investigating CD56 signaling in multiple myeloma growth and immune escape

项目摘要/摘要 弗朗西丝卡·科蒂尼医学博士是血液科有资格获得终身教职的助理教授。 俄亥俄州立大学综合内科(70%研究，30%临床) 癌症中心。科蒂尼博士的职业目标是成为一名独立而多产的内科科学家，他的 研究将结合多发性骨髓瘤(MM)发病机制和肿瘤免疫学的各个方面来发展 为多发性骨髓瘤患者量身定做的疗法。 多发性骨髓瘤是一种不治之症，影响脆弱的成年人，导致高昂的医疗费用和质量低下 生活的一部分。尽管在遗传方面存在重大差异，但目前还没有针对MM患者的量身定制的治疗方法 异常、基因表达谱或免疫特征。为了填补这一空白，科蒂尼博士发现了一种表面 标记物CD56存在于70%的患者中，与预后不良有关。因此， 到目前为止，科蒂尼博士已经用强有力的初步数据证明了她的项目的可行性，表明CD56 促进多发性骨髓瘤生长和肿瘤从免疫系统逃逸。科蒂尼博士K08的主要目标 建议从以下方面来描述与CD56前列腺癌表型相关的机制：1.mm 生长；2.抗MM疗法的抵抗力；3.氧化应激的调节；4.逃避自然杀手 (NK)细胞介导的细胞毒作用。科蒂尼博士提议的最后一步是找到促进CD56的策略 MM的降解和诱导肿瘤的消退。这些知识将导致科学驱动的临床试验和 改善高危CD56阳性多发性骨髓瘤患者的预后。 为了支持她的独立之路，科蒂尼博士成立了一个指导委员会，由 作者：Don Benson博士，医学博士，博士(主要导师：MM生物学、肿瘤免疫学和翻译学方面的专业知识 和临床科学)，杨益平医学博士，博士(共同导师：肿瘤免疫学专业知识，赠款撰写，和 领导技能)，刘贝博士(咨询委员会成员：MM小鼠模型方面的专业知识)，以及 Natarajan Muthusamy，DVM，博士(咨询委员会成员：信号和翻译方面的专业知识 科学)。她还将利用另外两个在基因组学方面有经验的合作者(皮尔利博士) 和药物开发(Gerard Hilinski博士)。她制定了一项职业发展计划，目标是 (1)学习肿瘤免疫学、药物开发和动物模型方面的技能；(2)在 分析和解释基因组数据和设计临床试验的相关性；(3)提高专业知识 在领导力、资助金撰写和团队管理方面。这些目标将补充科蒂尼博士目前的 作为MM领域的内科科学家，帮助实现独立的知识总结说，科蒂尼博士的 研究有可能根据疾病特征确定治疗方案，从而改善 并减少患者的毒副作用。

PROJECT SUMMARY/ABSTRACT Francesca Cottini, MD, is a Tenure-eligible Assistant Professor in the Division of Hematology, Department of Internal Medicine (70% research, 30% clinical) at The Ohio State University Comprehensive Cancer Center. Dr. Cottini’s career goal is to become an independent and productive physician scientist whose research will combine aspects of multiple myeloma (MM) pathogenesis and tumor immunology to develop tailored therapies for MM patients. MM is an incurable disease that affects vulnerable adults causing high healthcare costs and poor quality of life. No tailored therapies exist to treat patients with MM, despite major differences in terms of genetic abnormalities, gene expression profiles, or immune signatures. To fill this gap, Dr. Cottini has identified a surface marker, named CD56, which is present in 70 percent of patients and is associated with poor prognosis. Thus far, Dr. Cottini has demonstrated the feasibility of her project with strong preliminary data, showing that CD56 promotes MM growth and tumor escape from the immune system. The main objective of Dr. Cottini’s K08 proposal is to characterize the mechanisms associated with CD56 protumoral phenotype in terms of: 1. MM growth; 2. resistance to anti-MM therapies; 3. regulation of oxidative stress; and 4. escape from natural killer (NK) cell-mediated cytotoxicity. The final step of Dr. Cottini’s proposal is to find strategies to promote CD56 degradation in MM and induce tumor regression. This knowledge will lead to science-driven clinical trials and improve outcomes in high-risk CD56 positive MM patients. To support her pathway to independence, Dr. Cottini has established a mentoring committee consisting of: Drs. Don Benson MD, PhD (Primary Mentor: expertise in MM biology, tumor immunology, and translational and clinical science), Yiping Yang MD, PhD (co-Mentor: expertise in tumor immunology, grant writing, and leadership skills), Bei Liu, PhD (Advisory Committee Member: expertise in MM murine animal models), and Natarajan Muthusamy, DVM, PhD (Advisory Committee Member: expertise in signaling and translational science). She will also take advantages of two additional collaborators, with experience in genomics (Dr. Pearlly Yan) and drug development (Dr. Gerard Hilinski). She formulated a career development plan with objectives of (1) learning skills in tumor immunology, drug development, and animal models; (2) developing knowledge in the analysis and interpretation of genomic data and design of correlatives for clinical trials; (3) improving expertise in leadership, grant writing, and team management. These objectives will complement Dr. Cottini’s current knowledge to help achieving independence as a physician scientist in the field of MM. To conclude, Dr. Cottini’s studies have the potential to identify therapeutic options based on disease characteristics and hence improve outcomes and reduce toxicities in patients.