Targeting Cancer Initiating Cells in Multiple Myeloma

靶向多发性骨髓瘤中的癌症起始细胞

• 批准号: 9982246
• 负责人: Daniel Sherbenou
• 金额: $ 22.19万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-08 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982246
• 关键词: Address; American; Antibody-drug conjugates; Award; Bioinformatics; Biological Assay; Biometry; CD46 Antigen; Cell surface; Cells; Cessation of life; Chromosomes; Chronic Myeloid Leukemia; Clinical; Clinical Trials; Clinical Trials Design; Clinical trial protocol document; Collaborations; Colorado; Complement Inactivators; Cytometry; Data; Development; Diagnosis; Disease; Doctor of Philosophy; Drug resistance; Environment; Evolution; Fellowship; Flow Cytometry; Fluorescent in Situ Hybridization; Genes; Genetic; Goals; Health Sciences; Hematology; Hematopoietic Neoplasms; Imatinib; Immunology; Immunomodulators; In Vitro; In complete remission; Jordan; Laboratories; Laboratory Finding; Lead; Malignant Neoplasms; Measures; Medical center; Mentors; Mentorship; Multiple Myeloma; Natural regeneration; Oregon; Outcome; Patient Care; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Population; Preclinical Testing; Prior Therapy; Protease Inhibitor; Proteasome Inhibitor; Proteins; Publishing; Refractory; Refractory Disease; Regimen; Relapse; Research; Research Project Grants; Residual Neoplasm; Resistance; Resistance development; Resolution; Sampling; Scientist; Surface; Testing; Therapeutic; Time; Tissue Sample; Training; Translational Research; Universities; Validation; Writing; Xenograft procedure; base; cancer stem cell; clay; clinical application; curative treatments; effective therapy; high risk; improved; in vivo; kinase inhibitor; neoplastic cell; novel; novel strategies; novel therapeutics; outcome forecast; professor; programs; protocol development; resistance mutation; responsible research conduct; stem; stemness; targeted treatment; theories; treatment response

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.

项目概要/摘要 候选人： 申请人是一名医学科学家，是该大学血液学部的助理教授 科罗拉多大学安舒茨医学中心。在俄勒冈健康与科学学院的医学博士/博士课程中 大学期间，他在布莱恩·德鲁克 (Brian Druker) 的指导下进行了台式转化研究，重点关注 慢性粒细胞白血病。申请人的论文研究了患者体内发生的耐药突变 用激酶抑制剂伊马替尼治疗。在 UCSF 的奖学金期间，他专注于开发一种新型 CD46- Bin Liu 实验室针对多发性骨髓瘤的靶向抗体药物偶联物 (ADC)。 环境：在科罗拉多大学，申请人加入了癌症干细胞导师团队 主要导师 Craig Jordan 和联合导师 Clay Smith 的细胞专业知识。申请人将继续关闭 与博士后导师刘斌合作，并与骨髓瘤建立了新的合作 约翰·霍普金斯大学的细胞专家 William Matsui。英国大学骨髓瘤临床项目主任 科罗拉多州的 Tomer Mark 博士是另一位项目联合导师，将帮助培训申请人设计临床试验 基于他的实验室发现的协议。申请人在本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项目 从事转化研究、资助写作和临床试验方案制定。 研究：目前的治疗方法无法治愈多发性骨髓瘤 (MM)。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是否尚不成熟尚存在争议 表型或基因上相当不同的亚克隆。无论如何，我们目前无法消除 MM-IC 引线 所有患者都会复发并最终死亡。当 MM 对蛋白酶抑制剂产生抗药性并且 免疫调节药物（又名“双难药”），预后较差。因此，目前需要（1） MM 的治愈性治疗和（2）双难治性疾病的有效治疗。申请人的长期 目标是通过开发新的 MM-IC 靶向疗法来满足这一需求。该提案将测试 ADC 靶向细胞表面补体抑制剂 CD46。理论上，如果 CD46 存在，该 ADC 可能具有治疗作用 MM-IC。令人兴奋的是，CD46 基因位于 1q 染色体上，该基因通常在 MM 中基因扩增 (1q+)。该 1q+ 是一个高风险特征，存在于大多数双难治患者中。我们发现CD46是 1q+ 的 MM 患者组织样本中最高。该提案的中心假设是 CD46-ADC 选择性消除 1q+ MM-IC 的独特潜力。第一个目标将确定 CD46-ADC 是否可以选择性地 消除 1q+ 遗传亚克隆。第二个将确定 CD46-ADC 是否可以消除 MM-IC。如果支持 该提案的数据，结果将直接应用于 CD46-ADC 多发性骨髓瘤临床试验中的患者护理。