Antje M. Wengner

Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus

To understand the link between peripheral immune activation and neuronal precursor biology, we investigated the effect of T‐cell activation on adult hippocampal neurogenesis in female C57Bl/6 mice. A peripheral adaptive immune response triggered by adjuvant‐induced rheumatoid arthritis (2 μg / μl methylated BSA) or staphylococcus enterotoxin B (EC50 of 0.25 μg/ml per 20 g body weight) was associated with a transient increase in hippocampal precursor cell proliferation and neurogenesis as assessed by immunohistochemistry and confocal microscopy. Both treatments were paralleled by an increase in corticosterone levels in the hippocampus 1‐ to 2‐fold over the physiological amount measured by quantitative radioimmunoassay. In contrast, intraperitoneal administration of the innate immune response activator lipopolysaccaride (EC50 of 0.5 μg/ml per 20 g body weight) led to a chronic 5‐fold increase of hippocampal glucocorticoid levels and a decrease of adult neurogenesis. In vitro exposure of murine neuronal progenitor cells to corticosterone triggered either cell death at high (1.5 nM) or proliferation at low (0.25 nM) concentrations. This effect could be blocked using a viral vector system expressing a transdomain of the glucocorticoid receptor. We suggest an evolutionary relevant communication route for the brain to respond to environmental stressors like inflammation mediated by glucocorticoid levels in the hippocampus.—Wolf, S. A., Steiner, B., Wengner, A., Lipp, M., Kammertoens, T., Kempermann, G. Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus. FASEBJ. 23, 3121–3128 (2009). www.fasebj.org

Abstract 321: Synergistic activity of the ATR inhibitor BAY 1895344 in combination with DNA damage inducing and DNA repair compromising therapies in preclinical tumor models

The DNA damage response (DDR) system consists of complex signalling pathways that secure the integrity of the genome in eukaryotic cells. DDR pathway activation follows recognition of DNA damage and results in cell cycle arrest, suppression of general translation, induction of DNA repair, cell survival or even cell death. Proteins that directly recognize aberrant DNA structures recruit and activate kinases of the DDR, such as ATR (ataxia telangiectasia and Rad3-related). ATR responds to a broad spectrum of DNA damages, including double-strand breaks (DSB) and lesions derived from interference with DNA replication as well as increased replication stress. Therefore, inhibition of ATR kinase activity could be the basis for a novel anti-cancer therapy in tumors with increased DNA damage, deficiency in DDR or replication stress. The potential of combining ATR kinase inhibitor with DNA damage inducing or DNA repair compromising anti-cancer therapeutics was studied in preclinical tumor models. We assessed the novel ATR kinase inhibitor (ATRi) BAY 1895344 in combination with external beam radiation therapy (EBRT), poly ADP ribose polymerase (PARP) inhibition or anti-androgen (AA) therapy. In cellular anti-proliferation assays as well as in tumor xenograft studies we could demonstrate synergistic activity of BAY 1895344 in combination treatment with the PARP inhibitor AZD-2281 in the homologous recombination (HR) defective breast cancer model MDA-MB-436, and with the non-steroidal AA darolutamide in the hormone-dependent prostate cancer model LAPC-4. Strong synergistic anti-tumor activity of BAY 1895344 could be further demonstrated in combination with EBRT inducing long-lasting tumor growth inhibition in the colorectal cancer xenograft model LOVO. The mechanism-based potential of combining DNA damage induction by EBRT with ATRi BAY 1895344 suggests a potential new treatment option for radiation therapy-resistant patients. Furthermore, the inhibition of parallel DDR pathways, as a combination of ATRi BAY 1895344 with a PARP inhibitor, indicates novel treatment opportunities in breast cancer patients with homologous recombination deficiencies, as does the synergism of BAY 1895344 and AA darolutamide therapy in hormone-dependent prostate cancer patients. BAY 1895344 is currently under clinical investigation in patients with advanced solid tumors and lymphomas (NCT03188965). Citation Format: Antje Margret Wengner, Gerhard Siemeister, Ulrich Luecking, Julien Lefranc, Kirstin Meyer, Eleni Lagkadinou, Bernard Haendler, Pascale Lejeune, Dominik Mumberg. Synergistic activity of the ATR inhibitor BAY 1895344 in combination with DNA damage inducing and DNA repair compromising therapies in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 321.

Abstract 855: Increased in vitro potency and in vivo efficacy of FGFR2-targeted thorium-227 conjugate (FGFR2-TTC) in combination with the ATR inhibitor BAY 1895344

Targeted Thorium-227 Conjugates (TTCs) consist of the alpha emitter Thorium-227 (227Th) coupled, by a 3, 2-HOPO chelator, to a tumor specific antibody. The alpha particles release high energy over a short range (2- 10 cell diameters), resulting in a potent local irradiation of the tumor with limited damage to surrounding tissue. Here, we describe the in vitro and in vivo evaluation of an FGFR2 targeted thorium-227 conjugate (FGFR2-TTC) in combination with the ATR inhibitor BAY 1895344. FGFR2 (fibroblast growth factor receptor 2) is a receptor tyrosine kinase and overexpression of FGFR2 has been described in different cancers, while its expression in healthy human tissues is moderate to low. This renders FGFR2 an attractive antigen to explore the concept of targeted alpha therapy (TAT). The mode-of-action of TTCs is based on the induction of clustered DNA double strand breaks and G2 cell cycle arrest. We hypothesized that combination of FGFR2-TTC with inhibitors of DNA damage response (DDRi9s) may enhance potency and efficacy. The ataxia telangiectasia and Rad3-related protein (ATR) kinase is a central mediator of DDR. ATR kinase responds to a broad spectrum of DNA damage, including double-strand breaks (DSB) and lesions derived from interference with DNA replication as well as increased replication stress. Inhibition of ATR kinase activity induces cell death especially in tumors with increased DNA damage, deficiency in DNA damage repair or replication stress. Therefore, we investigated whether the combination of the FGFR2-TTC with the ATRi BAY 1895344 results in enhanced tumor sensitivity in vitro and in vivo. In in vitro cytotoxicity assays, the combination of FGFR2-TTC and BAY 1895344 resulted in increased potency of the FGFR2-TTC on three different cancer cell lines (KATO III (gastric), MFM-223 (triple negative breast cancer), SUM52-PE (triple negative breast cancer)). Mechanistic analysis demonstrated that the combination treatment resulted in reduced levels of G2 arrest and increased levels of DNA damage in comparison to single agent treatments. The combination was further evaluated in vivo using the MFM-223 breast cancer xenograft model. An increased anti-tumor efficacy of a low dose of FGFR2-TTC (100 kBq/kg) was observed in combination with BAY 1895344 compared to animals treated with vehicle. The presented data support the mechanism-based rationale for combining DNA damage induction by FGFR2-TTC with DNA damage repair inhibition using ATRi BAY 1895344. Our findings warrant further exploration of TTCs in combination with BAY 1895344 for cancer therapy. Citation Format: Katrine Wickstroem, Urs B. Hagemann, Antje M. Wengner, Anette Sommer, Alexander Kristian, Christine Ellingsen, Roger M. Bjerke, Jenny Karlsson, Olav B. Ryan, Lars Linden, Bertolt Kreft, Dominik Mumberg, Hanno Wild, Karl Ziegelbauer, Alan Cuthbertson. Increased in vitro potency and in vivo efficacy of FGFR2-targeted thorium-227 conjugate (FGFR2-TTC) in combination with the ATR inhibitor BAY 1895344 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 855.