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: 10459474
• 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/10459474
• 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; Prognosis; 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; antibody test; base; cancer stem cell; clay; clinical application; curative treatments; effective therapy; high risk; improved; in vivo; inhibitor therapy; kinase inhibitor; neoplastic cell; novel; novel strategies; novel therapeutics; patient derived xenograft model; 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.

项目摘要/摘要 应聘者：应聘者是一名内科科学家，是血液科的助理教授。 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项目中 在大学期间，他在Brian Druker的指导下进行台式翻译研究，专注于 慢性髓系白血病。申请者的论文调查了患者体内发生的耐药突变 用激酶抑制剂伊马替尼治疗。在加州大学旧金山分校担任研究员期间，他专注于开发一种新型的CD46- 靶向抗体-药物结合物(ADC)在刘斌实验室治疗多发性骨髓瘤。 环境：在科罗拉多大学，申请者加入了一个癌症干细胞导师团队 细胞在主要导师克雷格·乔丹和共同导师克莱·史密斯方面的专业知识。申请者将继续关闭 与博士后导师刘斌合作，并与骨髓瘤建立了新的合作关系 约翰·霍普金斯大学的细胞专家威廉·松井。多伦多大学骨髓瘤临床项目主任 科罗拉多州的托默·马克博士是另一个项目的共同导师，他将帮助培训申请者设计临床试验 根据他的实验室发现。申请人在本奖项期间的培训计划包括 生物信息学、免疫学、生物统计学以及负责任的研究课程和方案 在转化性研究、拨款撰写和临床试验方案开发方面。 研究：多发性骨髓瘤(MM)目前的治疗方法是无法治愈的。这意味着“MM启动细胞” (MM-IC)存活并有再生疾病的能力。MM-IC是否有一个不成熟的 表型或在遗传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 在所有患者中复发并最终死亡。当MM对蛋白水解酶抑制剂和 免疫调节药物(又名“双难治”)，预后较差。因此，目前需要(1) 治疗多发性骨髓瘤的有效方法和(2)治疗双难病的有效方法。申请者的长期身份 目标是通过开发新的MM-IC靶向疗法来满足这一需求。这项提案将测试ADC 靶向细胞表面补体抑制剂CD46。从理论上讲，如果CD46存在，这个ADC可以治愈 嗯-IC。具有挑衅性的是，CD46基因位于染色体1q上，这在多发性骨髓瘤中经常被遗传扩增 (1Q+)。这种1Q+是一种高风险特征，存在于大多数双难治患者中。我们发现CD46是 MM患者组织标本中1Q+的阳性率最高。这一提议的中心假设是CD46-ADC具有 有选择地消除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。第二个将决定CD46-ADC能否消除MM-IC。如果受以下支持 来自这项提议的数据，结果将直接应用于MM中CD46-ADC的临床试验中的患者护理。

项目成果

Cellular proliferation by multiplex immunohistochemistry identifies aggressive disease behavior in relapsed multiple myeloma.

通过多重免疫组织化学的细胞增殖鉴定复发性多发性骨髓瘤的侵袭性疾病行为。

• DOI: 10.1080/10428194.2018.1551537
• 发表时间: 2019
• 期刊: Leukemia & lymphoma
• 影响因子: 2.6
• 作者: Forsberg,PeterA;Hammes,Andrew;Abbott,Diana;Sherbenou,DanielW;Rossi,Adriana;Jayabalan,David;Niesvizky,Ruben;Mark,TomerM;Ely,Scott
• 通讯作者: Ely,Scott

CD46-ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts.

CD46-ADC减少了多发性骨髓瘤患者衍生的异种移植物的植入。

• DOI: 10.3390/cancers15225335
• 发表时间: 2023-11-09
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Vanwyngarden, Michael J.;Walker, Zachary J.;Su, Yang;de Acha, Olivia Perez;Stevens, Brett M.;Forsberg, Peter A.;Mark, Tomer M.;Matsui, William;Liu, Bin;Sherbenou, Daniel W.
• 通讯作者: Sherbenou, Daniel W.

Emerging Therapeutic Strategies to Overcome Drug Resistance in Multiple Myeloma.

• DOI: 10.3390/cancers13071686
• 发表时间: 2021-04-02
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Davis LN;Sherbenou DW
• 通讯作者: Sherbenou DW

Harnessing the T Cell to Treat Multiple Myeloma: Dawn of a New Therapeutic Paradigm.

• DOI: 10.3389/fonc.2022.925818
• 发表时间: 2022
• 期刊: FRONTIERS IN ONCOLOGY
• 影响因子: 4.7
• 作者: Keller, Alana L.;Sherbenou, Daniel W.;Forsberg, Peter A.;Mark, Tomer M.
• 通讯作者: Mark, Tomer M.

Exploiting Protein Translation Dependence in Multiple Myeloma with Omacetaxine-Based Therapy.

• DOI: 10.1158/1078-0432.ccr-20-2246
• 发表时间: 2021-02-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Walker ZJ;Idler BM;Davis LN;Stevens BM;VanWyngarden MJ;Ohlstrom D;Bearrows SC;Hammes A;Smith CA;Jordan CT;Mark TM;Forsberg PA;Sherbenou DW
• 通讯作者: Sherbenou DW