Anti-EGFL7 as a novel targeted therapy in Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a cancer of the blood resulting from unrestricted proliferation of immature blasts, leading to devastating manifestations of disease and poor patient prognosis. The long-term overall survival for patients with AML is only 30-40% in younger (<60 years) and <10% in older (≥60 years) adult AML patients. This highlights the urgent need for novel therapeutic approaches for adult AML patients. Non‑random chromosomal abnormalities are identified in 50-55% of all AML patients. In contrast, about 45-50% of all AML cases are cytogenetically normal (CN-AML). We recently reported that among CN-AML cases, EGFL7 is highly expressed in a large cohort of patients and is associated with poor prognosis. We further demonstrate that AML blasts secrete EGFL7 protein. Functionally, EGFL7 protein increases blast cell growth, survival, and self-renewal. Targeting primary AML blasts with an anti-EGFL7 antibody (Parsatuzumab) leads to a decrease in blast cell growth and an increase in blast differentiation and apoptosis. In vivo experiments demonstrate prolonged survival in anti-EGFL7 (Parsatuzumab) treated mice compared to IgG1 controls, in three different AML mouse models. However, given the complexity of AML, it is unlikely that Parsatuzumab alone will cure AML. Using AML cell lines and primary patient samples, we now demonstrate that Parsatuzumab synergizes strongly with the FLT3 inhibitor Gilteritinib in AML cells. Gilteritinib, also known as XOSPATA, is an existing FDA-approved treatment for AML that acts to inhibit mutations within the receptor tyrosine kinase, FLT3, on leukemia cells, inducing apoptosis. In combining the apoptotic effects of both Gilteritinib and Parsatuzumab, we hope to introduce a novel treatment regimen for AML which eliminates cancer cells specifically without the complications and toxicities of standard chemotherapeutic regimens.