Author: Trneny, Marek ; Tuskova, Liliana ; Curik, Nikola ; Klanova, Magdalena ; Hoferkova, Eva ; Kelemen, Cristina Daniela ; Dolnikova, Alexandra ; Andera, Ladislav ; Helman, Karel ; Mraz, Marek ; Machova Polakova, Katerina ; Klener, Pavel ; Sovilj, Dana ; Kazantsev, Dmitry ; Pokorna, Eva

AbstractVenetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient–derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.

01 Jul 2024·CPT: Pharmacometrics & Systems Pharmacology

Quantitative systems pharmacology modeling of tumor heterogeneity in response to BH3‐mimetics using virtual tumors calibrated with cell viability assays

Article

Author: Decleves, Xavier ; Fouliard, Sylvain ; Derippe, Thibaud ; Mager, Donald E.

AbstractBoth primary and acquired resistance mechanisms that involve intra‐tumoral cell heterogeneity limit the use of BH3‐mimetics to trigger tumor cell apoptosis. This article proposes a new quantitative systems pharmacology (QSP)‐based methodology in which cell viability assays are used to calibrate virtual tumors (VTs) made of virtual cells whose fate is determined by simulations from an apoptosis QSP model. VTs representing SU‐DHL‐4 and KARPAS‐422 cell lines were calibrated using in vitro data involving venetoclax (anti‐BCL2), A‐1155463 (anti‐BCLXL), and/or A‐1210477 (anti‐MCL1). The calibrated VTs provide insights into the combination of several BH3‐mimetics, such as the distinction between cells eliminated by at least one of the drugs (monotherapies) from the cells eliminated by a pharmacological combination only. Calibrated VTs can also be used as initial conditions in an agent‐based model (ABM) framework, and a minimal ABM was developed to bridge in vitro SU‐DHL‐4 cell viability results to tumor growth inhibition experiments in mice.

01 Jun 2024·Biomedicine & Pharmacotherapy

Evaluation of BH3 mimetics as a combination therapy with irradiation in head and neck squamous cell carcinoma

Article

Author: Ianevski, Filipp ; Turunen, Laura ; Al-Samadi, Ahmed ; Wahbi, Wafa ; Korelin, Katja ; Belevich, Ilya ; Salo, Tuula ; Oostveen, Mayke ; Cavalcante, Bruno

INTRODUCTIONHead and neck squamous cell carcinoma (HNSCC) is a common cancer with a five-year survival rate around 60%, indicating a need for new treatments. BH3 mimetics are small molecules that inhibit anti-apoptotic Bcl-2 family proteins, resulting in apoptosis induction.METHODSWe performed a high-throughput screen using a Myogel matrix to identify the synergy between irradiation and the novel BH3 mimetics A-1155463, A-1331852, and navitoclax in 12 HNSCC cell lines, normal (NOF) and cancer-associated fibroblasts (CAF), and dysplastic keratinocytes (ODA). Next, we examined synergy in an apoptosis assay, followed by a clonogenic assay and a Myogel spheroid on selected HNSCC cell lines. Finally, we applied zebrafish larvae xenograft to validate the effects of navitoclax and A-1331852.RESULTSAll three BH3 mimetics exhibited a strong synergy with irradiation in eight HNSCC cell lines and ODAs, but not in NOFs and CAFs. A-1155463 and A-1331852 induced apoptosis and reduced proliferation, and together with irradiation, significantly increased apoptosis and arrested proliferation. A-1331852 and navitoclax significantly decreased the clonogenicity compared with the control, and combination treatment led to a decreased clonogenicity compared with monotherapy or irradiation. However, unlike navitoclax or A-1155463, only A-1331852 significantly reduced cancer cell invasion. Furthermore, in spheroid and zebrafish, irradiation appeared ineffective and failed to significantly increase the drug effect. In the zebrafish, A-1331852 and navitoclax significantly reduced the tumor area and metastasis.CONCLUSIONSOur findings encourage the further preclinical investigation of BH3 mimetics, particularly A-1331852, as a single agent or combined with irradiation as a treatment for HNSCC.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	AbbVie, Inc.	08 May 2014

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