Publications
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Fuentes-Martín, Raúl; Duran, Pilar Ayuda; Hanes, Robert; Gallego-Yerga, Laura; Wolterinck, Lisanne & Enserink, Jorrit
[Show all 8 contributors for this article]
(2024).
Promising anti-proliferative indolic benzenesulfonamides alter mechanisms with sulfonamide nitrogen substituents.
European Journal of Medicinal Chemistry.
ISSN 0223-5234.
275,
p. 1–20.
doi:
10.1016/j.ejmech.2024.116617.
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Agents that cause apoptotic cell death by interfering with tubulin dynamics, such as vinblastine and paclitaxel, are an important class of chemotherapeutics. Unfortunately, these compounds are substrates for multidrug resistance (MDR) pumps, allowing cancer cells to gain resistance to these chemotherapeutics. The indolesulfonamide family of tubulin inhibitors are not excluded by MDR pumps and have a promising activity profile, although their high lipophilicity is a pharmacokinetic limitation for their clinical use. Here we present a new family of N-indolyl-3,4,5-trimethoxybenzenesulfonamide derivatives with modifications on the indole system at positions 1 and 3 and on the sulfonamide nitrogen. We synthesized and screened against HeLa cells 34 novel indolic benzenesulfonamides. The most potent derivatives (1.7–109 nM) were tested against a broad panel of cancer cell lines, which revealed that substituted benzenesulfonamides analogs had highest potency. Importantly, these compounds were only moderately toxic to non-tumorigenic cells, suggesting the presence of a therapeutic index. Consistent with known clinical anti-tubulin agents, these compounds arrested the cell cycle at G2/M phase. Mechanistically, they induced apoptosis via caspase 3/7 activation, which occurred during M arrest. The substituents on the sulfonamide nitrogen appeared to determine different mechanistic results and cell fates. These results suggest that the compounds act differently depending on the bridge substituents, thus making them very interesting as mechanistic probes as well as potential drugs for further development.
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Duran, Pilar Ayuda; Hermansen, Johanne Uthus; Giliberto, Mariaserena; Yin, Yanping; Hanes, Robert & Gordon, Sandra
[Show all 13 contributors for this article]
(2023).
Standardized assays to monitor drug sensitivity in hematologic cancers.
Cell death discovery.
9(1),
p. 1–13.
doi:
10.1038/s41420-023-01722-5.
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Abstract The principle of drug sensitivity testing is to expose cancer cells to a library of different drugs and measure its effects on cell viability. Recent technological advances, continuous approval of targeted therapies, and improved cell culture protocols have enhanced the precision and clinical relevance of such screens. Indeed, drug sensitivity testing has proven diagnostically valuable for patients with advanced hematologic cancers. However, different cell types behave differently in culture and therefore require optimized drug screening protocols to ensure that their ex vivo drug sensitivity accurately reflects in vivo drug responses. For example, primary chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) cells require unique microenvironmental stimuli to survive in culture, while this is less the case for acute myeloid leukemia (AML) cells. Here, we present our optimized and validated protocols for culturing and drug screening of primary cells from AML, CLL, and MM patients, and a generic protocol for cell line models. We also discuss drug library designs, reproducibility, and quality controls. We envision that these protocols may serve as community guidelines for the use and interpretation of assays to monitor drug sensitivity in hematologic cancers and thus contribute to standardization. The read-outs may provide insight into tumor biology, identify or confirm treatment resistance and sensitivity in real time, and ultimately guide clinical decision-making.
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Hanes, Robert; Ayuda-Duran, Maria del Pilar; Rønneberg, Leiv; Nakken, Sigve; Hovig, Eivind & Zucknick, Manuela
[Show all 7 contributors for this article]
(2022).
screenwerk: a modular tool for the design and analysis of drug combination screens.
Bioinformatics.
ISSN 1367-4803.
39(1).
doi:
10.1093/bioinformatics/btac840.
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Abstract Motivation There is a rapidly growing interest in high-throughput drug combination screening to identify synergizing drug interactions for treatment of various maladies, such as cancer and infectious disease. This creates the need for pipelines that can be used to design such screens, perform quality control on the data and generate data files that can be analyzed by synergy-finding bioinformatics applications. Results screenwerk is an open-source, end-to-end modular tool available as an R-package for the design and analysis of drug combination screens. The tool allows for a customized build of pipelines through its modularity and provides a flexible approach to quality control and data analysis. screenwerk is adaptable to various experimental requirements with an emphasis on precision medicine. It can be coupled to other R packages, such as bayesynergy, to identify synergistic and antagonistic drug interactions in cell lines or patient samples. screenwerk is scalable and provides a complete solution for setting up drug sensitivity screens, read raw measurements and consolidate different datasets, perform various types of quality control and analyze, report and visualize the results of drug sensitivity screens. Availability and implementation The R-package and technical documentation is available at https://github.com/Enserink-lab/screenwerk; the R source code is publicly available at https://github.com/Enserink-lab/screenwerk under GNU General Public License v3.0; bayesynergy is accessible at https://github.com/ocbe-uio/bayesynergy. Selected modules are available through Galaxy, an open-source platform for FAIR data analysis at https://oncotools.elixir.no Supplementary information Supplementary data are available at Bioinformatics online.
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Grad, Iwona; Hanes, Robert; Ayuda-Duran, Maria del Pilar; Kuijjer, Marieke Lydia; Enserink, Jorrit & Meza, Leonardo Zepeda
[Show all 7 contributors for this article]
(2021).
Discovery of novel candidates for anti-liposarcoma therapies by medium-scale high-throughput drug screening.
PLOS ONE.
16(3),
p. 1–23.
doi:
10.1371/journal.pone.0248140.
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Sarcomas are a heterogeneous group of mesenchymal orphan cancers and new treatment alternatives beyond traditional chemotherapeutic regimes are much needed. So far, tumor mutation analysis has not led to significant treatment advances, and we have attempted to bypass this limitation by performing direct drug testing of a library of 353 anti-cancer compounds that are either FDA-approved, in clinical trial, or in advanced stages of preclinical development on a panel of 13 liposarcoma cell lines. We identified and validated six drugs, targeting different mechanisms and with good efficiency across the cell lines: MLN2238 –a proteasome inhibitor, GSK2126458 –a PI3K/mTOR inhibitor, JNJ-26481585 –a histone deacetylase inhibitor, triptolide–a multi-target drug, YM155 –a survivin inhibitor, and APO866 (FK866)–a nicotinamide phosphoribosyl transferase inhibitor. GR50s for those drugs were mostly in the nanomolar range, and in many cases below 10 nM. These drugs had long-lasting effect upon drug withdrawal, limited toxicity to normal cells and good efficacy also against tumor explants. Finally, we identified potential genomic biomarkers of their efficacy. Being approved or in clinical trials, these drugs are promising candidates for liposarcoma treatment.
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Rønneberg, Leiv; Cremaschi, Andrea; Hanes, Robert; Enserink, Jorrit & Zucknick, Manuela
(2021).
bayesynergy: flexible Bayesian modelling of synergistic interaction effects in in vitro drug combination experiments.
Briefings in Bioinformatics.
ISSN 1467-5463.
22(6),
p. 1–12.
doi:
10.1093/bib/bbab251.
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Abstract The effect of cancer therapies is often tested pre-clinically via in vitro experiments, where the post-treatment viability of the cancer cell population is measured through assays estimating the number of viable cells. In this way, large libraries of compounds can be tested, comparing the efficacy of each treatment. Drug interaction studies focus on the quantification of the additional effect encountered when two drugs are combined, as opposed to using the treatments separately. In the bayesynergy R package, we implement a probabilistic approach for the description of the drug combination experiment, where the observed dose response curve is modelled as a sum of the expected response under a zero-interaction model and an additional interaction effect (synergistic or antagonistic). Although the model formulation makes use of the Bliss independence assumption, we note that the posterior estimates of the dose–response surface can also be used to extract synergy scores based on other reference models, which we illustrate for the Highest Single Agent model. The interaction is modelled in a flexible manner, using a Gaussian process formulation. Since the proposed approach is based on a statistical model, it allows the natural inclusion of replicates, handles missing data and uneven concentration grids, and provides uncertainty quantification around the results. The model is implemented in the open-source Stan programming language providing a computationally efficient sampler, a fast approximation of the posterior through variational inference, and features parallel processing for working with large drug combination screens.
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Melvold, Katrine; Giliberto, Mariaserena; Karlsen, Linda; Ayuda-Duran, Maria del Pilar; Hanes, Robert & Holien, Toril
[Show all 11 contributors for this article]
(2021).
Mcl-1 and Bcl-xL levels predict responsiveness to dual MEK/Bcl-2 inhibition in B-cell malignancies.
Molecular Oncology.
ISSN 1574-7891.
p. 1–18.
doi:
10.1002/1878-0261.13153.
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Most patients with chronic lymphocytic leukemia (CLL) initially respond to targeted therapies, but eventually relapse and develop resistance. Novel treatment strategies are therefore needed to improve patient outcomes. Here, we performed direct drug testing on primary CLL cells and identified synergy between eight different mitogen-activated protein kinase kinase (MEK) inhibitors and the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax. Drug sensitivity was independent of immunoglobulin heavy-chain gene variable region (IGVH) and tumor protein p53 (TP53) mutational status, and CLL cells from idelalisib-resistant patients remained sensitive to the treatment. This suggests that combined MEK/Bcl-2 inhibition may be an option for high-risk CLL. To test whether sensitivity could be detected in other B-cell malignancies, we performed drug testing on cell line models of CLL (n = 4), multiple myeloma (MM; n = 8), and mantle cell lymphoma (MCL; n = 7). Like CLL, MM cells were sensitive to the MEK inhibitor trametinib, and synergy was observed with venetoclax. In contrast, MCL cells were unresponsive to MEK inhibition. To investigate the underlying mechanisms of the disease-specific drug sensitivities, we performed flow cytometry-based high-throughput profiling of 31 signaling proteins and regulators of apoptosis in the 19 cell lines. We found that high expression of the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) or B-cell lymphoma-extra large (Bcl-xL) predicted low sensitivity to trametinib + venetoclax. The low sensitivity could be overcome by combined treatment with an Mcl-1 or Bcl-xL inhibitor. Our findings suggest that MEK/Bcl-2 inhibition has therapeutic potential in leukemia and myeloma, and demonstrate that protein expression levels can serve as predictive biomarkers for treatment sensitivities.
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Hanes, Robert; Munthe, Else; Grad, Iwona; Han, Jianhua; Karlsen, Ida Tveit & Cormack, Emmet Mc
[Show all 9 contributors for this article]
(2019).
Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma.
Cells.
8(2).
doi:
10.3390/cells8020189.
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Background: FGFR inhibition has been proposed as treatment for dedifferentiated liposarcoma (DDLPS) with amplified FRS2, but we previously only demonstrated transient cytostatic effects when treating FRS2-amplified DDLPS cells with NVP-BGJ398. Methods: Effects of the more potent FGFR inhibitor LY2874455 were investigated in three DDLPS cell lines by measuring effects on cell growth and apoptosis in vitro and also testing efficacy in vivo. Genome, transcriptome and protein analyses were performed to characterize the signaling components in the FGFR pathway. Results: LY2874455 induced a stronger, longer-lasting growth inhibitory effect and moderate level of apoptosis for two cell lines. The third cell line, did not respond to FGFR inhibition, suggesting that FRS2 amplification alone is not sufficient to predict response. Importantly, efficacy of LY2874455 was confirmed in vivo, using an independent FRS2-amplified DDLPS xenograft model. Expression of FRS2 was similar in the responding and non-responding cell lines and we could not find any major difference in downstream FGFR signaling. The only FGF expressed by unstimulated non-responding cells was the intracellular ligand FGF11, whereas the responding cell lines expressed extracellular ligand FGF2. Conclusion: Our study supports LY2874455 as a better therapy than NVP-BGJ398 for FRS2-amplified liposarcoma, and a clinical trial is warranted.
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Serguienko, Anastassia; Hanes, Robert; Grad, Iwona; Wang, Mengyu; Myklebost, Ola & Munthe, Else
(2017).
PP2A regulatory subunit b55γ is a gatekeeper of osteoblast maturation and lineage maintenance.
Stem Cells and Development.
ISSN 1547-3287.
26(19),
p. 1375–1383.
doi:
10.1089/scd.2017.0129.
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Berdal, Margrete; Appelbom, Hege; Eikrem, Jorunn H.; Lund, Åse; Busund, Lill-Tove & Hanes, Robert
[Show all 8 contributors for this article]
(2011).
Aminated beta-1,3-D-glucan has a dose-dependent effect on wound healing in diabetic db/db mice.
Wound Repair and Regeneration.
ISSN 1067-1927.
19(5),
p. 579–587.
doi:
10.1111/j.1524-475X.2011.00715.x.
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Inflammatory responses are common in diabetes and are operative in angiopathy, neuropathy, and wound healing. There are indications of incomplete macrophage activation in diabetes, and reduced expression of growth factors. We have previously found that up to fifteen topical applications of the macrophage-stimulant, aminated beta-1,3-D-glucan (AG), improved wound healing in db/db mice. The present open-label study was undertaken to examine dose-dependent effects of AG over 40 days in db/db mice. AG was given as a single dose (group 1), one dose every 10th day (group 2), five initial doses on consecutive days (group 3), and >=15 doses (group 4). Controls were db/db mice receiving PDGF+IGF-1 (group 5), topical placebo (NaCl 9 mg/mL) and insulin (group 6), placebo (group 7), and a nondiabetic group receiving placebo (group 8). Seven to fourteen animals were allocated to each group. Percentage wound closure seventeen days after surgery in groups 1 and 2 were (mean+/-SE) 25.5 +/-5.3 and 32.2 +/-6.3, respectively. Corresponding closure in groups 3, 4, and 5 was 55.7 +/-5.0, 57.3 +/-5.0, and 55.6 +/-4.8, respectively(p<0.05 versus groups 1 and 2). Groups 6, 7, and 8 closed 32.0 +/-4.5, 38.2 +/-5.3, and 98.5 +/-0.4%, respectively. Significant association between the number of AG-dosages and wound closure indicates dose-related effects in db/db mice.
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Published
Nov. 10, 2021 11:16 AM
- Last modified
Jan. 24, 2025 11:15 AM