Improving hematopoietic stem cell mobilization by the EGFR inhibitor Erlotinib

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造血干细胞的护理标准是通过细胞因子粒细胞集落刺激因子（G-CSF）将造血干细胞从骨髓转移到外周血。然后用单采法从血液中收集造血干细胞。细胞因子G-CSF的动员已成为临床干细胞移植的首选造血干细胞来源。一般来说，较高的造血干细胞动员效率会导致更多的造血干细胞移植，从而导致更好的移植恢复。AMD3100是一种小分子药物，可特异性抑制趋化因子SDF-1与其受体CXCR4的结合，也可导致HSPC的动员，与G-CSF联合使用可能成为一种新的治疗标准。尽管这两种动员剂有效，但仍有10%的正常供体和50%的癌症患者无法动员足够数量的干细胞，从而阻碍或延迟自体或异体HSC移植。因此，需要开发新的药物来进一步提高护理标准。基于小鼠数量性状位点筛选（正向遗传学），我们已经确定表皮生长因子受体（EGFR）信号作为一种新的动员效率修饰因子。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联合治疗可显著增加HSPCs的动员。因此，我们将重点关注的产品/程序是，与相关临床前模型的标准护理相比，药物Erlotinib与药物G-CSF或AMD3100联合对EGFR信号的药理抑制将改善HSPCs的动员。厄洛替尼对EGFR信号的药理靶向为改善HSPC的动员提供了一种新颖和创新的方法。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