Improving hematopoietic stem cell mobilization by the EGFR inhibitor Erlotinib

通过 EGFR 抑制剂厄洛替尼改善造血干细胞动员

基本信息

批准号：
8247250
负责人：
Jose A Cancelas
金额：
$ 39.03万
依托单位：
P2D, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8247250
关键词：
AMD3100 Allogenic Autologous Binding Biological Models Blood Blood Component Removal Bone Marrow CXCR4 Receptors CXCR4 gene Cancer Patient Cell Therapy Cell Transplants Clinical Data Development Effectiveness Epidermal Growth Factor Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib FDA approved Genetic Genetic Screening Granulocyte Colony-Stimulating Factor Harvest Hematopoietic Hematopoietic Stem Cell Mobilization Human Legal patent Life Malignant Neoplasms Modeling Mus Outcome Patients Pharmaceutical Preparations Phase III Clinical Trials Pre-Clinical Model Procedures Quantitative Trait Loci Receptor Signaling Recovery Regimen Source Stem cell transplant Stem cells Stromal Cell-Derived Factor 1 Testing Time Transplantation Xeno animal data base blood treatment chemokine clinically relevant cytokine granulocyte human data improved innovation novel patient population peripheral blood pre-clinical response small molecule standard of care stem

项目摘要

DESCRIPTION (provided by applicant): Hematopoietic stem and progenitor cell (HSPC) transplants are a first-line treatment for multiple forms of cancer. The current standard of care for obtaining HSPCs for a transplant is mobilizing HSPCs from bone marrow into peripheral blood by the cytokine granulocyte-colony stimulating factor (G-CSF). HSPCs are then collected from blood by apheresis. Mobilization by the cytokine G-CSF has become the preferred source of HSPCs for clinical stem cell transplants. In general a higher efficiency of mobilization of HSPCs results in greater numbers of HSPCs to transplant which result in better transplant recovery. AMD3100, which was recently FDA-approved, is a small molecule that specifically inhibits the binding of the chemokine SDF-1 to its receptor CXCR4 also resulting in HSPC mobilization, and in combination with G-CSF might become a new standard of care. Despite the effectiveness of these two mobilizing agents up to 10% of normal donors and 50% of cancer patients fail to mobilize adequate numbers of stem cells thereby impeding or delaying autologous or allogeneic HSC transplants. Consequently, novel drugs need to be developed to further improve the standard of care. Based on a quantitative trait locus screen in mice (forward genetics) we have identified epidermal growth factor receptor (EGFR) signaling as a novel modifier of mobilization efficiency. Treatment with the FDA- approved specific EGFR inhibitor Erlotinib in combination with G-CSF or AMD3100 significantly increases mobilization of HSPCs compared to G-CSF or AMD3100 alone. Therefore, the product/procedure that we will focus on is that pharmacological inhibition of EGFR signaling by the drug Erlotinib in combination with the drugs G-CSF or AMD3100 will improve mobilization of HSPCs compared to the standard of care in relevant pre-clinical models. Pharmacological targeting of EGFR signaling by Erlotinib presents a novel and innovative approach to improve HSPC mobilization. 1 PUBLIC HEALTH RELEVANCE: Inefficient mobilization of hematopoietic stem and progenitor cells (HSPCs) to peripheral blood in response to the cytokine granulocyte-colony-forming factor (G-CSF) in patients frequently precludes subsequent life saving cell therapies like stem cell transplants. Thus novel drugs are needed to further improve mobilization efficiency of HSPCs. Preliminary data supports that pharmacological inhibition of epidermal- growth-factor factor receptor (EGFR) signaling by the FDA-approved drug Erlotinib enhances HSPCs mobilization efficiency. In this project we will focus on developing inhibition of EGFR signaling by Erlotinib a a novel product to improve stem cell mobilization and the successful treatment of cancer patients. 1

描述（由申请人提供）：造血干细胞和祖细胞（HSPC）移植是多种癌症的一线治疗方法。目前获得用于移植的 HSPC 的护理标准是通过细胞因子粒细胞集落刺激因子 (G-CSF) 将 HSPC 从骨髓动员到外周血中。然后通过单采术从血液中收集 HSPC。细胞因子 G-CSF 的动员已成为临床干细胞移植的首选 HSPC 来源。一般来说，HSPC 的动员效率越高，移植的 HSPC 数量就越多，从而实现更好的移植恢复。 AMD3100 最近获得 FDA 批准，是一种小分子，可特异性抑制趋化因子 SDF-1 与其受体 CXCR4 的结合，从而导致 HSPC 动员，与 G-CSF 结合可能成为新的护理标准。尽管这两种动员剂有效，但高达 10% 的正常供体和 50% 的癌症患者未能动员足够数量的干细胞，从而阻碍或延迟自体或同种异体 HSC 移植。因此，需要开发新药物以进一步提高护理标准。基于小鼠数量性状位点筛选（正向遗传学），我们确定表皮生长因子受体 (EGFR) 信号传导是动员效率的新型调节剂。与单独使用 G-CSF 或 AMD3100 相比，FDA 批准的特异性 EGFR 抑制剂厄洛替尼与 G-CSF 或 AMD3100 联合治疗显着增加了 HSPC 的动员。因此，我们将重点关注的产品/程序是，与相关临床前模型中的护理标准相比，药物厄洛替尼与药物 G-CSF 或 AMD3100 组合对 EGFR 信号传导的药理学抑制将改善 HSPC 的动员。厄洛替尼对 EGFR 信号传导的药理学靶向提供了一种改善 HSPC 动员的新颖且创新的方法。 1 公共健康相关性：造血干细胞和祖细胞（HSPC）响应细胞因子粒细胞集落形成因子（G-CSF）而无效地动员到外周血中，常常会妨碍后续的救生细胞疗法（如干细胞移植）。因此需要新的药物来进一步提高 HSPC 的动员效率。初步数据支持 FDA 批准的药物厄洛替尼对表皮生长因子受体 (EGFR) 信号传导的药理学抑制可提高 HSPC 的动员效率。在这个项目中，我们将重点开发厄洛替尼抑制 EGFR 信号传导的新产品，以改善干细胞动员和癌症患者的成功治疗。 1