Improving hematopoietic stem cell mobilization by the EGFR inhibitor Erlotinib
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AbstractDESCRIPTION (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 generala 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 (forwardgenetics) 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. Thusnovel 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
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