Targeting Cancer Initiating Cells in Multiple Myeloma

项目总结/摘要 候选人：申请人是一名医生科学家，是血液学系的助理教授， 科罗拉多大学安舒茨医学中心。在俄勒冈州健康和科学的医学博士/博士课程 大学期间，他在Brian Druker的指导下进行了台式翻译研究，重点是 慢性粒细胞白血病申请人的论文研究了患者体内产生的耐药性突变 用激酶抑制剂伊马替尼治疗。在加州大学旧金山分校的奖学金，他专注于开发一种新的CD 46- 靶向抗体-药物偶联物（ADC）治疗多发性骨髓瘤。 环境：在科罗拉多大学，申请人加入了一个癌症干细胞指导团队 主要导师克雷格乔丹和共同导师克莱史密斯的细胞专业知识。申请人将继续关闭 与博士后导师Bin Liu合作，并与骨髓瘤启动了新的合作 约翰霍普金斯的细胞专家威廉·松井。明尼苏达大学骨髓瘤临床项目主任 来自科罗拉多的Tomer Mark博士是另一位项目共同导师，将帮助培训申请人设计临床试验 根据他的实验室发现制定的方案申请人在此奖项期间的培训计划包括 生物信息学，免疫学，生物统计学和负责任的研究课程，以及程序的行为 在转化研究，赠款写作和临床试验方案的制定。 研究：多发性骨髓瘤（MM）是无法治愈的与目前的治疗。这意味着“MM起始细胞” （MM-IC）存活并具有再生疾病的能力。MM-IC是否具有不成熟的 表型或相当遗传上不同的亚克隆。无论如何，我们目前无法消除MM-IC引线 复发并最终导致所有患者死亡。当MM对蛋白酶抑制剂产生耐药性时， 免疫调节药物（又名“双重难治性”），预后差。因此，目前需要（1） MM的治愈性治疗和（2）双重难治性疾病的有效治疗。申请人长期 我们的目标是通过开发新的MM-IC靶向疗法来满足这一需求。本提案将测试ADC， 靶向细胞表面补体抑制剂CD 46。从理论上讲，如果CD 46存在于 MM-IC CD 46基因位于染色体1 q上，在MM中经常发生基因扩增 (1q+).这种1 q+是一种高风险特征，存在于大多数双重难治性患者中。我们发现CD 46是 在MM患者组织样本中1 q+最高。该提议的中心假设是CD 46-ADC具有以下功能： 选择性消除1 q + MM-IC的独特潜力。第一个目标是确定CD 46-ADC是否可以选择性地 消除1 q+遗传亚克隆。第二个将确定CD 46-ADC是否可以消除MM-IC。如果支持 从这个建议的数据，结果将直接应用于患者护理的CD 46-ADC在MM的临床试验。

PROJECT SUMMARY/ABSTRACT Candidate: The applicant is a physician scientist who is an assistant professor in the Hematology Division at the University of Colorado Anschutz Medical Center. In the MD/PhD program at Oregon Health and Science University, he performed benchtop translational research under the mentorship of Brian Druker, focused on chronic myeloid leukemia. The applicant’s thesis investigated drug resistance mutations that develop in patients treated with the kinase inhibitor imatinib. In fellowship at UCSF, he focused on the development of a novel CD46- targeted antibody-drug conjugate (ADC) for multiple myeloma in the laboratory of Bin Liu. Environment: At the University of Colorado, the applicant has joined with a mentoring team with cancer stem cell expertise in primary mentor Craig Jordan and co-mentor Clay Smith. The applicant will continue close collaboration with postdoctoral mentor Bin Liu and has established a new collaboration with myeloma initiating cell expert William Matsui at Johns Hopkins. The Director of the myeloma clinical program at the University of Colorado, Dr. Tomer Mark, is another project co-mentor and will help train the applicant to design clinical trial protocols based on his laboratory findings. The applicant’s training plan during the period of this award includes bioinformatics, immunology, biostatistics and responsible conduct of research coursework, as well as programs in translational research, grant writing and clinical trial protocol development. Research: Multiple myeloma (MM) is incurable with current treatments. This implies that “MM-initiating cells” (MM-IC) survive and have ability to regenerate the disease. It is controversial whether MM-IC have an immature phenotype or are rather genetically distinct subclones. Regardless, our current inability to eliminate MM-IC leads to relapse and eventually death in all patients. When MM becomes resistant to protease inhibitors and immunomodulatory drugs (aka “double-refractory”), the prognosis is poor. Thus, currently there is a need for (1) curative therapy for MM and (2) effective treatments for double-refractory disease. The applicant’s long-term goal is to address this need by developing new MM-IC targeted therapies. This proposal will test an ADC that targets the cell surface complement inhibitor CD46. In theory, this ADC could be curative if CD46 is present on MM-IC. Provocatively, the CD46 gene is located on chromosome 1q, which is often genetically amplified in MM (1q+). This 1q+ is a high-risk feature and is present in most double-refractory patients. We found CD46 was highest in MM patient tissue samples with 1q+. The central hypothesis of this proposal is that CD46-ADC has unique potential to selectively eliminate 1q+ MM-IC. The first aim will determine if CD46-ADC can selectively eliminate 1q+ genetic subclones. The second will determine if CD46-ADC can eliminate MM-IC. If supported by data from this proposal, the results will be applied to patient care directly in clinical trials of CD46-ADC in MM.