Abstract 5473: The sensitivity of targeting genomic BCL2 by PNT2258 is linked to chromosomal rearrangements and proliferative rate of tumor types

Abstract

Abstract Background: The BCL2-mediated anti-apoptotic phenotype is a contributor to the genesis and maintenance of a broad variety of tumors. BCL2 is also implicated in the regulation of the cell cycle by playing a role in the transition between quiescence and the cycling state. Further, chromosomal rearrangements, including t(14;18), up-regulate BCL2 transcription, preventing tumor cell death in B-cell lymphomas. PNT2258 is a DNA interference (DNAi) therapeutic targeted against BCL2 that is undergoing clinical evaluation in patients with hematological malignancies. PNT2258 contains PNT100, a single-stranded phosphodiester DNA oligodeoxynucleotide, encapsulated in protective liposomes. Material and Methods: Lymphomas cell lines with distinct genetic characteristics, namely, WSU-FSCCL, characterized by t(14;18) BCL2 and t(8;14) CMYC rearrangements, WSU-DLCL2, characterized by t(14;18) BCL2 rearrangement, and WSU-WM, characterized as lacking t(14;18) BCL2, but having t(8;14) CMYC and t(12;17) rearrangements were tested for cell viability at 24, 48, 72, and 96 hours post-exposure to PNT2258 at concentrations of 2.5, 5, and 10 μM. Normalized maximum cell kill at 96 hours was used in each cell line to adjust for differences in growth rates and to calculate sensitivity. Results: Dose-dependent effects were observed across all three cell lines. WSU-FSCCL was the most proliferative cell line, and correspondingly most sensitive to the effects of PNT2258, with a control doubling time of 29.6h and 1% of viable control cells remaining at 96h at 10 μM. The next most sensitive cell line was WSU-DLCL2, having a 60.6h control doubling time and 11% of the viable control cells remaining at 96h at 10 μM. WSU-WM exhibited a control doubling time of 35.5h and 21% of viable control cells remaining at 96h at 10 μM. These findings parallel the single agent activity of PNT2258 against xenograft tumor models containing BCL2 or CMYC chromosomal rearrangements (AACR Meeting Abstracts, Apr 2007; 2007: 4889). Conclusions: The effects of the clinical therapeutic PNT2258 against cell lines with well-characterized growth and genetic drivers were examined. Findings show lymphoma cell lines harboring the t(14;18) rearrangement (WSU-FSCCL and WSU-DLCL2) were most sensitive to PNT2258 and in this context a higher proliferative rate is linked to sensitivity. These data suggest that commonly used clinical assays of proliferation and tumor “aggressiveness,” such as Ki-67 and PET/CT standardized uptake values (SUVs), may be useful in conjunction with cytogenetic analysis (e.g. for t(14;18) and/or t(8,14) by fluorescence in situ hybridization (FISH), to select patients with tumors that may be responsive to the effects of PNT2258. Citation Format: Michael J. Woolliscroft, Abdul-Shukkur Ebrahim, Richard A. Messmann, Shari K. Gaylor, Mina P. Sooch, Ayad Al-Katib, Wendi V. Rodrigueza. The sensitivity of targeting genomic BCL2 by PNT2258 is linked to chromosomal rearrangements and proliferative rate of tumor types. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5473. doi:10.1158/1538-7445.AM2014-5473