Pictilisib (GDC-0941) is an inhibitor of phosphatidylinositol 3-kinase (PI3K), part of a signaling cascade involved in breast cancer development. The purpose of this study was to evaluate the pharmacokinetics of pictilisib noninvasively by radiolabeling it with C and to assess the usability of the resulting [C]-pictilisib as a positron-emission tomography (PET) tracer to screen for pictilisib-sensitive tumors. In this study, pictilisib was radiolabeled with [C]-methyl iodide to obtain C-methylated pictilisib ([C]-pictilisib) using an automated synthesis module with a high radiolabeling yield. Considerably higher uptake ratios were observed in MCF-7 (PIK3CA mutation, pictilisib-sensitive) cells than those in MDA-MB-231 (PIK3CA wild-type, pictilisib-insensitive) cells at all evaluated time points, indicating good binding of [C]-pictilisib. Dynamic micro-PET scans in mice and biodistribution results showed that [C]-pictilisib was mainly excreted via the hepatobiliary tract into the intestines. MCF-7 xenografts could be clearly visualized on the static micro-PET scans, while MDA-MB-231 tumors could not. Biodistribution results of two xenograft models showed significantly higher uptake and tumor-to-muscle ratios in the MCF-7 xenografts than those in MDA-MB-231 xenografts, exhibiting high targeting specificity. In conclusion, [C]-pictilisib was first successfully prepared, and it exhibited good potential to identify pictilisib-sensitive tumors noninvasively, which may have a great impact in the treatment of cancers with an overactive PI3K/Akt/mTOR signal pathway. However, the high activity in hepatobiliary system and intestines needs to be addressed.
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http://dx.doi.org/10.1155/2019/1760184 | DOI Listing |
Int J Biol Macromol
November 2024
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon 999077, Hong Kong, China. Electronic address:
The Neuroblastoma RAS (NRAS) oncogene homologue plays crucial roles in diverse cellular processes such as cell proliferation, survival, and differentiation. Several strategies have been developed to inhibit NRAS or its downstream effectors; however, there is no effective drug available to treat NRAS-driven cancers and thus new approaches are needed to be established. The mRNA sequence expressing NRAS containing several guanine(G)-rich regions may form quadruplex structures (G4s) and regulate NRAS translation.
View Article and Find Full Text PDFMol Oncol
December 2023
The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Blocking the mitogen-activated protein kinase (MAPK) pathway with the MEK1/2 inhibitor trametinib has produced promising results in patients with head and neck squamous cell carcinoma (HNSCC). In the current study, we showed that trametinib treatment leads to overexpression and activation of the epidermal growth factor receptor (EGFR) in HNSCC cell lines and patient-derived xenografts. Knockdown of EGFR improved trametinib treatment efficacy both in vitro and in vivo.
View Article and Find Full Text PDFJ Cell Mol Med
December 2022
Department of Pediatric Hematology and Oncology, Center for Pediatrics, University Hospital Bonn, Bonn, Germany.
Biochem J
October 2022
Newcastle University Biosciences Institute, Wolfson Childhood Cancer Research Centre, Newcastle University, Level 6, Herschel Building, Brewery Lane, Newcastle upon Tyne NE1 7RU, U.K.
The development of resistance and the activation of bypass pathway signalling represents a major problem for the clinical application of protein kinase inhibitors. While investigating the effect of either a c-Rel deletion or RelAT505A phosphosite knockin on the Eµ-Myc mouse model of B-cell lymphoma, we discovered that both NF-κB subunit mutations resulted in CHK1 inhibitor resistance, arising from either loss or alteration of CHK1 activity, respectively. However, since Eµ-Myc lymphomas depend on CHK1 activity to cope with high levels of DNA replication stress and consequent genomic instability, it was not clear how these mutant NF-κB subunit lymphomas were able to survive.
View Article and Find Full Text PDFMolecules
August 2022
College of Life Sciences, Northwest Normal University, Lanzhou 730070, China.
Pictilisib (GDC-0941) is a well-known dual inhibitor of class I PI3K and mTOR and is presently undergoing phase 2 clinical trials for cancer treatment. The present work investigated the dynamic behaviors and interaction mechanism between GDC-0941 and human serum albumin (HSA). Molecular docking and MD trajectory analyses revealed that GDC-0941 bound to HSA and that the binding site was positioned in subdomain IIA at Sudlow's site I of HSA.
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