| 1. |
- Berglund, Erik, et al.
(författare)
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Intracellular concentration of the tyrosine kinase inhibitor imatinib in gastrointestinal stromal tumor cells.
- 2014
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 25:4, s. 415-22
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Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract. In most GISTs, the underlying mechanism is a gain-of-function mutation in the KIT or the PDGFRA gene. Imatinib is a tyrosine kinase inhibitor that specifically blocks the intracellular ATP-binding sites of these receptors. A correlation exists between plasma levels of imatinib and progression-free survival, but it is not known whether the plasma concentration correlates with the intracellular drug concentration. We determined intracellular imatinib levels in two GIST cell lines: the imatinib-sensitive GIST882 and the imatinib-resistant GIST48. After exposing the GIST cells to imatinib, the intracellular concentrations were evaluated using LC-MS (TOF). The concentration of imatinib in clinical samples from three patients was also determined to assess the validity and reliability of the method in the clinical setting. Determination of imatinib uptake fits within detection levels and values are highly reproducible. The GIST48 cells showed significantly lower imatinib uptake compared with GIST882 in therapeutic doses, indicating a possible difference in uptake mechanisms. Furthermore, imatinib accumulated in the tumor tissues and showed intratumoral regional differences. These data show, for the first time, a feasible and reproducible technique to measure intracellular imatinib levels in experimental and clinical settings. The difference in the intracellular imatinib concentration between the cell lines and clinical samples indicates that drug transporters may contribute toward resistance mechanisms in GIST cells. This highlights the importance of further clinical studies to quantify drug transporter expression and measure intracellular imatinib levels in GIST patients.
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| 2. |
- Fröbom, Robin, et al.
(författare)
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Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors
- 2020
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Ingår i: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 69:11, s. 2393-2401
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma.MethodsThe trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 106 viable and HLA-DR expressing cells per dose) were administered.ResultsNo severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months.ConclusionIlixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation.
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| 3. |
- Fröbom, Robin
(författare)
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Translational investigations of novel and current antitumoral therapies in gastrointestinal stromal tumors
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gastrointestinal stromal tumor (GIST) is the most common human sarcoma. Its incidence is around 10-15 per million person-years, translating into 150 new cases each year in Sweden. The molecular background for the absolute majority of GIST is characterized by gain-offunction mutations in KIT or PDGFRA genes, both encode receptor tyrosine kinases, allowing for targeted treatment with imatinib. This has revolutionized the treatment of GIST, which is inherently radio- and chemotherapy insensitive. However, durable remissions are uncommon relating to the development of resistance. The overall aim of the thesis was to explore novel and current treatments in GIST, as few treatment alternatives exist. In paper I, we examined the functional role of DOG1 protein, a diagnostic marker, in GIST. The protein is a calcium-activated chloride channel. We determined the expression of DOG1 and found a difference between imatinib-sensitive and imatinib-resistant cell lines with regards to subcellular localization. Electrophysiological registration confirmed the modulating ability of the DOG1 activator and inhibitor. Only modest effect was seen on proliferation, DOG1 inhibition induced a shift from early apoptotic to late apoptotic cells in the imatinib-resistant cell line. In paper II, we used a new potent inhibitor (CaCCinh-A01) of DOG1. We confirmed its inhibitory effect on chloride currents using patch-clamp technique. The cell viability was reduced. Furthermore, colony formation ability was markedly decreased after incubation with CaCCinh-A01. CaCCinh-A01 also led to a G1-cell cycle arrest, which was not seen with T16inh-A01 treatment. Therefore, paper I and II, confirms that DOG1 could potentially be a target for therapy. In paper III, we explored the antitumoral effects of a novel polymer-based therapy (PVAC). In vitro experiments revealed PVAC potently induced a population of non-viable cells, in a non-linear dose-response relationship. In vivo PVAC inhibited tumor growth in immunocompetent mice, and an increased CD3+ cell infiltration intratumorally was observed. In paper IV, we explored the commonly used tyrosine kinase inhibitors imatinib, sunitinib, and nilotinib possible interaction with ATP-binding sites, in which we used murine pancreatic β-cells as ATP-sensitive K+ (KATP) channel donors. By using patch-clamp technique, we showed that all three tyrosine kinase inhibitors decreased the channel activity. Further studies revealed an increased channel activity with imatinib in the presence of ATP and ADP. In paper V, the aim was to determine the safety and efficacy of intratumorally injected allogeneic pro-inflammatory dendritic cells (ilixadencel) in patients with advanced GIST and progression on tyrosine kinase inhibitors. The study showed an acceptable safety profile, and promising radiological response was observed in two out of six patients. To conclude, this translational thesis adds knowledge to new potential targets and novel antitumoral strategies, and increases our understanding of current treatment. Lastly, a clinical study found encouraging response in some patients and warrants further studies.
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| 4. |
- Sellberg, Felix, et al.
(författare)
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Polyvinyl Alcohol Carbazate as a Polymer-Based Antitumoral Agent
- 2021
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Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Development of treatment resistance is a major concern during treatment of cancer, and there is an unmet need for therapeutic strategies with novel modes of action. Polyvinyl alcohol carbazate (PVAC) is a polymer compound with unique biological properties. Herein, we describe the antitumoral effects of PVAC. Three well-established cell lines GIST-T1, B16.F10, and A375 were used to determine the in vitro antitumoral effects of PVAC. Assessments included light microscopy, cell viability, cell cycle, and apoptosis assays. In vivo treatment safety and efficacy were characterized in one immunocompetent (B16.F10) mouse model and one athymic nude (MDA-MB-231) mouse model. Excised tumors were measured, weighed, stained for Ki-67, CD3, and histopathologically evaluated. Intact PVAC expressed a non-linear dose-response antitumoral effect in vitro, whereas its separate components, PVA and carbazate, did not display antitumoral effects alone. In vivo, PVAC induced a significant intratumoral CD3(+) T-cell recruitment in immunocompetent mice (B16.F10), which was associated with tumor growth inhibition. Although growth inhibition was not significant in athymic mice (MDA-MB-231), histopathological evaluation detected an increase in stromal tissue and leukocyte infiltration. In conclusion, we present evidence for PVAC antitumoral effects both in vitro and in vivo. The mode of action was not elucidated in vitro, but a potential mechanism of in vivo activity was observed, characterized by an increase of immune cells into both immunocompetent and athymic mice. This finding warrants further study to validate its possible role as an immunomodulatory polymeric agent.
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