Discovery and Application of Peptides Specific for Acute Myelogenous Leukemic Cells

Yulia Katzman, Chemical Engineering, Ariel University, Ariel, Israel
Michael Firer, Chemical Engineering, Ariel University, Ariel, Israel

Acute Myeloid Leukemia (AML) refers to a group of diseases with considerable diversity in molecular pathogenesis and clinical outcomes, in which mutations in key genes disturb the normal mechanisms of cell growth, proliferation and differentiation of hematopoietic progenitor cells. Despite advances in the understanding of AML pathogenesis, classification, genomic landscape, and prognostic factors, the basic therapeutic approach to patients with AML has changed little over the last 20 years. The current prognosis is poor, as a result of biologic complexity, high rates of chemotherapy drug resistance and poor host factors, with a 5-year relative survival rate of only 24%. Chemoresistance is a critical challenge in the management of acute myeloid leukemia (AML) disease. The treatment of relapsed with AML patients remains a major challenge, especially in elderly individuals, where intensive therapy is associated with a high toxicity, a low remission rate and a median survival of only about seven months. To overcome these challenges, this research aims to use peptide phage display libraries to discover peptides that are specifically internalized by patients’ AML cells. These peptides would be used to prepare Peptide-Drug-Conjugates (PDCs) for targeted delivery of anti-cancer drugs into the cancer cells. Targeted drug delivery methods have been exploited to improve specific delivery of cytotoxic drugs to target cells in an effort to lower their side effects, this approach may also result in a lowering of drug dose and overcoming in the problem of drug resistance in cancer cells.

Phages expressing 7-mer cyclic peptides were exposed to 5 different human AML cell lines, which represent the pathological spectrum of the disease, mononuclear cells that were isolated from human peripheral blood of a healthy voluntary donor and patients with AML. We used NGS (Next Generation Sequencing) and bioinformatics to delineate the amino acid sequences of the peptides displayed by phage that were internalized by the cells. Selected peptides are now being synthesized to test and validate their ability to specifically target AML cells. We will study the potential of the most promising peptides to act as drug carriers for targeted destruction of AML cells and drug resistant leukemic cell lines in vitro and in an appropriate xenograft model of AML.