Investigating the Microenvironmental Dysregulation and Polypharmacy Impact during Acute Myeloid Leukemia in an in vitro model of the human bone marrow and in vivo models.

Project Summary and Abstract This award will support Azmeer Sharipol, M.S., long-term goal of developing the expertise and skills needed to become an independent investigator exploring the role of polypharmacy and microenvironmental dysregulation in acute myeloid leukemia (AML) using an applied microphysiological systems (MPS) approach. The standard daunorubicin and cytarabine (DNR) chemotherapy for AML result in a 5-year survival rate of less than 30%. 70% of patients >60 years old succumb to the disease after 1-year of diagnosis. Polypharmacy, which is the use of ³5 drugs to treat comorbidities, is common in vulnerable patients. However, it remains unclear whether polypharmacy has an impact on AML chemotherapy. AML studies mostly focused on finding the intrinsic mutations within the hematopoietic stem cell lineage that give rise to dysfunctional AML cells. However, the role of the bone marrow microenvironment (BMME) is often overlooked. Studies using in vivo models showed that AML cells can dysregulate the BMME through cell-cell interaction and chemokine signaling. Azmeer’s sponsor, Dr Benjamin Frisch, showed that AML cells inhibit osteoblastic cell function via C-C motif chemokine ligand 3 (CCL3) in a clinically relevant murine AML model. However, it is challenging to prove the AML-BMME signaling in human cases due to the lack of reliable in vitro model of the human BMME. Azmeer Sharipol will address these gaps in research through an innovative research plan that leverages his background in applied MPS. For the F99 phase, Azmeer will develop an in vitro human BMME-chip model using Emulate Chip-S1™ microfluidics systems and fibrin-hydrogel encapsulation containing osteoblastic, endothelial, and stromal cells compartments that are important regulator of stem cell maintenance and differentiation. Using the BMME-chip, he will elucidate the role of CCL3 in the dysregulation of the human BMME and investigate the targeting of CCL3 receptors, CCR1 and CCR5, using small molecule inhibitors to rescue BMME dysregulation in AML- BMME-chip. For the K00 phase, Azmeer will explore the effects of polypharmacy from common comorbidity drugs including metformin and captopril in addition to standard chemotherapies on the BMME function using the AML-BMME-chip, and in vivo models of AML. Azmeer Sharipol has worked closely with his sponsors to develop a training plan that emphasized on building new knowledge and methodological skills to prepare him a smooth transition into an independent research career path. The training plan includes improving knowledge in cancer biology, cancer cell signaling, clinical pharmacology, and bioinformatics analysis. Azmeer and his mentors also developed a plan for identifying a postdoctoral mentor. Together, the proposed research and training plan provide optimal opportunities and structure for Azmeer to develop new skills and progress toward cancer researcher.