Abstract 2903: Therapeutic targeting of leukemia and lymphoma with a neuropilin-1 binding pro-apoptotic peptide

Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short cell-internalizing peptide ligands that bind to specific cell surface receptors on malignant hematopoietic cells. Such targeting motifs could also serve as vehicles for preferential delivery of cytotoxic agents to leukemias and lymphomas. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence FF/YXLRS, which bound to human leukemia and lymphoma cell lines as well as to primary human acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) bone marrow specimens obtained from patients. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, the functional relevance of this internalizing receptor was evaluated in the context of disease progression via the targeted delivery of a pro-apoptotic peptidomimetic to leukemia and lymphoma cells, and a potent anti-leukemia cell effect was observed both with cell lines and patient samples when the targeting motif was synthesized in tandem to the pro-apoptotic sequence D(KLAKLAK)2. Markedly, the pro-apoptotic peptide did not have an effect on purified mononuclear cells from normal bone marrow cells. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with ALL or AML compared to normal bone marrow specimens. Taken together, our results indicate that NRP-1 could, potentially, be used as a target for ligand-directed therapy in human leukemias and lymphomas - as well as in many human solid tumors, which are also know to over-express NRP-1 - and that the prototype CGFYWLRSC-GG-D(KLAKLAK)2 is a promising drug candidate in this setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2903. doi:1538-7445.AM2012-2903