Charles River Discovery Research Services Germany GmbH is a professional research organization that offers a range of services in the field of preclinical pharmacology. The company specializes in areas such as tumor modeling, in vivo, 2D and 3D assays, and molecular solutions. Founded by Heinz-Herbert Fiebig in 1993, the company is based in Freiburg, Germany.

Drugs associated with Charles River Discovery Research Services Germany GmbH

BAY-Tie2

Target

RTKs

Mechanism

RTK inhibitors

Active Org.-

Originator Org.

Bayer AG

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date-

100 Clinical Results associated with Charles River Discovery Research Services Germany GmbH

0 Patents (Medical) associated with Charles River Discovery Research Services Germany GmbH

211

Literatures (Medical) associated with Charles River Discovery Research Services Germany GmbH

21 Apr 2025·Cancer Research

Abstract 4448: Novel tyrosine kinase/MEK inhibitor combinations impair the viability and invasive potential of TNBC cell lines

Author: Brummer, Tilman ; Lehmann, Ariane ; Schueler, Julia ; Asdih, Célia ; Metzger, Patrick ; Boerries, Melanie ; Griffin, Ricarda ; Klar, Rhena ; Traichel, Jasmin ; Oswald, Eva

AbstractThis study demonstrates that the tyrosine kinase inhibitors ALW-II-41-27 and ponatinib enhance the efficacy of MEK inhibition in multiple TNBC cell lines, suggesting potential for combination therapy. This project aimed to identify compensatory mechanisms triggered by MAPK inhibitors (MAPKi) in TNBC and to develop novel treatment strategies to effectively block these mechanisms. To this end, we performed a conditioned medium (CM) experiment in which we identified secreted cytokines as potential mediators of drug resistance. We then performed a cytokine array and receptor tyrosine kinase (RTK) array to identify the cytokines and RTKs implicated in this process. Finally, we targeted some of these previously identified RTKs in combination with trametinib and tested the efficacy of the combination on the viability of 11 TNBC cell lines. Two combinations were tested for further experiments to characterize their efficacy and mechanism of action, including colony forming assay, transcriptomic analysis and wound healing assays. We identified several cytokines secreted in response to the pan-Raf inhibitor CCT196969, the MEK inhibitor (MEKi) trametinib and the ERK inhibitor (ERKi) ulixertinib such as FGF-basic, FGF-19, MIF and angiogenin. CM from drug treated cells induced the activation of several RTKs such as FGFR1, FGFR3, Insulin-R, ALK and DTK in untreated TNBC cells. To validate the significance of these upregulated RTKs, we used a panel of kinase inhibitors. This led us to identify two synergistic combinations: trametinib with the EPHA2 inhibitor ALW-II-41-27 and trametinib with ponatinib, which targets multiple RTKs, including EPHA2. These combinations demonstrated efficacy in other TNBC cell lines over a longer period and, notably, prevented cell re-growth even after an additional eight days without treatment. This was in contrast to trametinib single treatment, where cells resumed growth under similar conditions. Our transcriptomic analyses of the combination treatment with trametinib and ALW-II-41-27, either singly or in combination, across a panel of cell lines revealed significant pathway alterations. Notably, we observed increased HER2 and HER3 transcription following trametinib treatment, which we could confirm at the protein level by Western blotting. Lastly, the trametinib/ALW-II-41-27 combination revealed a significant reduction in cell migration and invasion compared to trametinib treatment alone. These findings indicate that ponatinib and ALW-II-41-27 combined with MAPKi could be a promising novel therapeutic approach for TNBC.Citation Format:Célia Asdih, Ariane Lehmann, Jasmin Traichel, Eva Oswald, Julia Schueler, Rhena Klar, Patrick Metzger, Melanie Boerries, Tilman Brummer, Ricarda Griffin. Novel tyrosine kinase/MEK inhibitor combinations impair the viability and invasive potential of TNBC cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4448.

18 Jun 2024·Neuro-Oncology

HGG-15. SYNERGISTIC EFFECTS OF COMBINED MEK/CDK4/6 INHIBITOR TREATMENT ON BRAFV600E POSITIVE HIGH-GRADE GLIOMA

Author: Lämmerer, Anna ; Mager, Leah ; Peyrl, Andreas ; Haberler, Christine ; Dorfer, Christian ; Schueler, Julia ; Walter, Romina ; Gabler, Lisa ; Berger, Walter ; Bruckner, Katharina ; Lötsch-Gojo, Daniela ; Mayr, Lisa ; Müllauer, Leonhard ; Madlener, Sibylle ; Lang, Alexandra ; Azizi, Amedeo A ; Kirchhofer, Dominik ; Gojo, Johannes

AbstractBACKGROUNDPediatric high-grade glioma (pHGG) is associated with poor overall survival and standard care has remained unchanged for the past decade. BRAFV600E mutations occur in 5-10% and dabrafenib in combination with mekinist is approved in this subtype. Nevertheless, acquired resistance to targeted therapeutics is a common setback in highly aggressive tumors. Homozygous CDKN2A/B loss co-occurs in approximately 60% of this pHGG subtype. Taking advantage of those combined molecular alterations and exploiting acquired resistance mechanisms is of utmost importance to increase overall survival in these patients.METHODSFour HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss were tested for the effects of CDK4/6 inhibitor monotherapy (palbociclib, ribociclib, abemaciclib) and/or combination treatment with trametinib on cell survival, cell cycle, apoptosis and senescence.RESULTSAbemaciclib showed the highest efficacy of CDK4/6 inhibitors comparable to trametinib monotherapy in our cell models. Abemaciclib led to a cell cycle arrest and combined treatment with trametinib induced distinctly increased levels of apoptosis in our tumor models when compared to monotherapy and a great proportion of surviving cells were senescent. One cell model was orthotopically implanted in mice and abemaciclib and combined treatment with trametinib showed a slightly increased response when compared to trametinib alone.CONCLUSIONSSummarizing, treatment with abemaciclib showed promising therapeutic effects in HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss comparable to trametinib alone. Levels of apoptosis were distinctly higher with combinatorial abemaciclib and trametinib treatment when compared to monotherapy alone and senescence was induced in a great number of surviving cells. In vivo abemaciclib was more efficient when compared to trametinib alone. Currently we are working on in vivo experiments and the effect on sustained induction of senescence and mechanisms of tumor cell growth after discontinuation of therapy and in a combinatorial metronomic approach and in combination with radiotherapy.

04 Jun 2024·Molecular Cancer Therapeutics

Patient-Derived Tumor Xenograft Study with CDK4/6 Inhibitor Plus AKT Inhibitor for the Management of Metastatic Castration-Resistant Prostate Cancer

Article

Author: Miller, Erin ; Knight, Joshua A. ; Tan, Winston ; Bilgili, Ahmet ; Barrett, Michael T. ; Parent, Ephraim E. ; Meurice, Nathalie ; Metz, Thomas M. ; Kase, Adam M. ; Gleba, Justyna ; Pawlush, Matthew L. ; Copland, John A. ; Marlow, Laura ; Petit, Joachim ; Reynolds, Jordan ; Hickman, Peyton G. ; Alasonyalilar Demirer, Aylin ; Zhou, Yumei ; Cai, Hancheng ; Orme, Jacob ; Miller, James L. ; Durham, William F. ; Wickland, Daniel P. ; Edenfield, Brandy

AbstractMetastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer patient derived-tumor xenograft (PDTX) models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi).Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using whole-exome sequencing. PDTX 3D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular-targeted therapies. CDK4/6i's were combined with AKTi's to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6i. This combination was evaluated in PDTX three-dimensional (3D) spheroids and in vivo experiments with responses measured by tumor volumes, PSA, and Ga-68 PSMA-11 PET-CT imaging.We demonstrated CDK4/6i's with AKTi's possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single-agent CDK4/6i's. Despite this, combination therapy with AKTi's was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, whereas tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT.These preclinical data demonstrating antitumor synergy by overcoming single-agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in patients with mCRPC whose tumor expresses wild-type retinoblastoma 1.

100 Deals associated with Charles River Discovery Research Services Germany GmbH

100 Translational Medicine associated with Charles River Discovery Research Services Germany GmbH

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Drug(Targets)	Indications	Global Highest Phase

BAY-Tie2 ( RTKs )	Neoplasms More	Pending

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