Abstract 5689: Anti-E2F-1 PEGylated liposomal encapsulated peptide regresses human small cell lung cancer & lymphoma xenografts

Abstract

Abstract The E2F family of transcription factors is critical to large number of key cellular processes, including replication, DNA repair, and differentiation. E2F-1 is unique among the E2F family of transcription factors in that it can act as a tumor suppressor or as an oncogene, depending on the cellular context. Given the critical functions of E2F target genes in replication, and differentiation, it is perhaps not surprising that dysregulation of E2Fs has been associated with the cancer phenotype. E2F-1,2 and-3, “activating” E2Fs, function as heterodimers with DP proteins and are regulated by the retinoblastoma protein. E2F-1 and 3 are over expressed in many human tumors and overexpression (suggesting oncogene addiction) is associated with a poor prognosis. We have used phage display to obtain peptides that bind tightly to the E2F consensus promoter recognition sequence. When one of these peptides was coupled to a modified penetration sequence to enhance uptake, the penetratin- peptide (PEP) potently inhibited some but not all malignant cell lines. Modeling studies and ChIP studies showed that part of the pentratin sequence was involved in the binding of the PEP to the E2 F1 promoter. The PEP down-regulated E2F-2 and 4, as well as E2F-1, and-down stream targets of E2F-1. The small cell lung carcinoma (SCLC) cell line and the Ramos cell line (Burkitt lymphoma) were sensitive to low micromolar concentrations of the PEP, and apoptosis was seen within 6 h. These cell lines have mutant p53, and over express E2F-1 and cMyc and BCL2, and are “oncogene addicted”. Normal cells (human bone marrow CD34+ hematopoeitic stem cells, human marrow mesenchymal cells and MEFs), were insensitive to high concentrations of the PEP. When encapsulated in PEGylated liposomes, the PEP caused marked regression of advanced SCLC xenografts in mice without appreciable toxicity. These results prompt us to explore further preclinical development of the PEP for tumor therapy. 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 5689. doi:1538-7445.AM2012-5689