In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4793-4793
Abstract:
Rogaratinib is a potent small molecule pan-FGFR inhibitor that leads to downregulation of MAPK and PI3K signaling (1). In a recent Phase I study rogaratinib demonstrated good efficacy in urothelial bladder cancer (UBC) tumors with FGFR mRNA overexpression (2). Here, we explored the anti-tumor activity of rogaratinib in 2 indications, hepatocellular carcinoma (HCC) and head and neck cancer (HNSCC), where FGFR signaling plays an important role. In HCCs around 80% of tumors overexpress at least one FGF and/or FGFR (3), with main alterations in FGFR3 and FGFR4/FGF19. Head and neck cancer (HNSCC) displays FGFR1 amplification in about 35% of cases (4) and FGFR inhibition resulted in strong anti-tumor efficacy in HNSCC xenograft models with high FGFR1-3 mRNA expression levels. In vitro, HCC and HNSCC cell lines were profiled for inhibition of cell proliferation by rogaratinib or copanlisib. We furthermore tested the combination of FGFR inhibition by rogaratinib and PI3K inhibition by copanlisib in selected HCC cell lines showing synergy in three models with combination indices (Ci) below 0.8. In vivo, two HCC patient derived xenograft models with elevated levels of FGFR3/4 or FGFR4 showed strong monotherapy efficacy of rogaratinib treatment which was clearly superior to established therapies with multikinase inhibitors. Using a mouse-clinical trial set-up we profiled a set of patient derived HNSCC xenograft models for their sensitivity to cetuximab, rogaratinib and copanlisib in monotherapy as well as in combinations. The anti-tumor responses observed in selected models in monotherapy or in combination treatment support further investigation for the potential of FGFR and / or PI3K inhibition, especially in cetuximab resistant models. In conclusion, rogaratinib showed potential of tumor growth inhibition in xenograft models of HNSCC and HCC with overexpression of at least one FGFR subtype and warrants further investigation in these 2 indications. The combination with the PI3K inhibitor copanlisib provides options to improve efficacy. The importance of the specific molecular background will need further analysis. 1. Gauglhofer, C., S. Sagmeister, et al. (2011). Hepatology 53(3): 854-64. 2. Jerchel, I. S., A. Kamburov, et al. (2018). Cancer Research 78(13 Supplement): 4781-4781. 3. Joerger, M., P. A. Cassier, et al. (2018). J. Clin. Oncology 36 (suppl.)(abstr. 4513). 4. Tillman, B. N., M. Yanik, et al. (2016). Head Neck 38 Suppl 1: E1646-52. Citation Format: Oliver Politz, Sylvia Gruenewald, Isabel S. Jerchel, Alexander Walter, Peter Ellinghaus, Pascale Lejeune, Jens Hoffmann, Konrad Klinghammer, Dominik Mumberg. Preclinical evaluation of the combination rogaratinib and copanlisib in HNSCC and HCC in preclinical in vitro and in vivo models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4793.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2019-4793
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
