| Naslov: | A phase Ib clinical trial of metformin and chloroquine in patients with IDH1-mutated solid tumors |
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| Avtorji: | ID Khurshed, Mohammed (Avtor)
ID Molenaar, Remco J. (Avtor)
ID Linde, Myra E van (Avtor)
ID Mathôt, Ron A (Avtor)
ID Struys, Eduard A. (Avtor)
ID Wezel, Tom van (Avtor)
ID Noorden, Cornelis J. F. van (Avtor)
ID Klümpen, Heinz-Josef (Avtor)
ID Bovée, Judith V. M. G. (Avtor)
ID Wilmink, Johanna W (Avtor) |
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| Datoteke: |  URL - Izvorni URL, za dostop obiščite https://www.mdpi.com/2072-6694/13/10/2474
 PDF - Predstavitvena datoteka, prenos (3,11 MB)
MD5: 30853BE4A98387F63009427B6A5F9665
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| Jezik: | Angleški jezik |
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| Tipologija: | 1.01 - Izvirni znanstveni članek |
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| Organizacija: |  NIB - Nacionalni inštitut za biologijo
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| Povzetek: | Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial. |
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| Ključne besede: | metformin, chloroquine, cancer, isocitrate dehydrogenase, pharmacokinetics, glioblastoma, intrahepatic cholangiocarcinoma, chondrosarcoma |
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| Status publikacije: | Objavljeno |
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| Verzija publikacije: | Objavljena publikacija |
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| Datum objave: | 19.05.2021 |
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| Leto izida: | 2021 |
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| Št. strani: | str. 1-16 |
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| Številčenje: | Vol. 13, iss. 10 |
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| PID: | 20.500.12556/DiRROS-19451  |
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| UDK: | 577.2 |
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| ISSN pri članku: | 2072-6694 |
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| COBISS.SI-ID: | 97801987 |
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| Opomba: | Nasl. z nasl. zaslona;
Opis vira z dne 17. 2. 2022;
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| Datum objave v DiRROS: | 19.07.2024 |
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| Število ogledov: | 273 |
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| Število prenosov: | 187 |
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| Metapodatki: |    |
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