Improving hematopoietic stem cell mobilization by the EGFR inhibitor Erlotinib

描述(申请人提供)：造血干细胞和祖细胞移植(HSPC)是多种癌症的一线治疗方法。目前获取HSPC用于移植的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。然后通过分离从血液中收集HSPC。细胞因子G-CSF动员已成为临床干细胞移植首选的HSPC来源。一般来说，HSPC动员的效率越高，移植的HSPC数量就越多，从而导致更好的移植恢复。最近FDA批准的AMD3100是一个小分子，它特异性地抑制趋化因子SDF-1与其受体CXCR4的结合，也导致HSPC动员，与G-CSF联合使用可能成为一种新的护理标准。尽管这两种激动剂有效，但高达10%的正常捐献者和50%的癌症患者未能动员足够数量的干细胞，从而阻碍或推迟了自体或异基因HSC移植。因此，需要开发新的药物来进一步提高护理标准。基于对小鼠的数量性状基因座筛选(正向遗传学)，我们已经确定表皮生长因子受体(EGFR)信号是一种新的动员效率的调节剂。与单独使用G-CSF或AMD3100相比，FDA批准的特定EGFR抑制剂Erlotinib与G-CSF或AMD3100联合治疗显著增加HSPC的动员。因此，我们将重点研究的产品/程序是，与相关临床前模型中的护理标准相比，药物Erlotinib与药物G-CSF或AMD3100联合抑制EGFR信号转导将改善HSPC的动员。Erlotinib的药物靶向EGFR信号转导为提高HSPC动员提供了一种新颖和创新的方法。1 与公共卫生相关：患者由于细胞因子粒细胞集落形成因子(G-CSF)对外周血缺乏有效的造血干细胞和祖细胞(HSPC)动员，常常使随后的干细胞移植等挽救生命的细胞疗法无法进行。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Erlotinib对表皮生长因子受体(EGFR)信号的药理抑制提高了HSPC的动员效率。在这个项目中，我们将重点开发Erlotinib对EGFR信号的抑制作用，Erlotinib是一种新产品，用于改善干细胞动员和癌症患者的成功治疗。1

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