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EJNMMI Research
Published in: EJNMMI Research 1/2013

Open Access 01-12-2013 | Original research

[18 F]FDG-PET imaging is an early non-invasive pharmacodynamic biomarker for a first-in-class dual MEK/Raf inhibitor, RO5126766 (CH5126766), in preclinical xenograft models

Authors: Tetyana Tegnebratt, Li Lu, Lucy Lee, Valerie Meresse, Jean Tessier, Nobuya Ishii, Naoki Harada, Pavel Pisa, Sharon Stone-Elander

Published in: EJNMMI Research | Issue 1/2013

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Abstract

Background

Positron emission tomography (PET) with [2-18 F]-2-fluoro-2-deoxy-D-glucose ([18 F]FDG-PET) was acquired at multiple time-points a) to monitor the early response to RO5126766 (CH5126766) in xenograft models b) to evaluate non-invasive small animal [18 F]FDG-PET imaging as a biomarker for MEK inhibitors for translation into dose-finding studies in cancer patients and c) to explore the underlying mechanism related to FDG uptake in tumors treated with RO5126766.

Methods

[18 F]FDG uptake was studied in HCT116 (K-ras), COLO205 (B-raf) mutants and COLO320DM (wild type) xenografts from day 0 to 3 of RO5126766 treatment using a microPET Focus 120 and complemented with in vitro incubations, ex-vivo phosphor imaging and immunohistochemical (IHC) analyses.

Results

In the HCT116 (K-ras) and COLO205 (B-raf) mutant xenografts, significant decreases in [18 F]FDG uptake were detected in vivo on day 1 with 0.3 mg/kg and ex vivo on day 3 with 0.1 mg/kg RO5126766. [18 F]FDG changes correlated with decreases in tumor cells proliferation (Ki-67) and with changes in expression levels of GLUT1. No effects were observed in drug resistant COLO320DM cells. The cellular fractionation and Western blotting analyses suggested that the change of [18 F]FDG uptake associated with RO5126766 is due to translocation of GLUT1 from membrane to cytosol, similar to the results reported in the literature with EGFR tyrosine kinase inhibitors, which also target the MAPK pathway.

Conclusions

RO5126766 inhibition resulted in a rapid time - and dose - dependent decline in [18 F]FDG uptake in both mutant xenografts. These results strongly resemble the clinical observations obtained with MEK/Raf inhibitors support the use of preclinical [18 F]FDG-PET as a translational tool for decision support in preclinical and early clinical development of MEK inhibitors.
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Literature
1.
Friday BB, Adjei AA: Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res 2008, 14: 342–346. 10.1158/1078-0432.CCR-07-4790CrossRefPubMed
2.
Sullivan RJ, Atkins MB: Molecular targeted therapy for patients with melanoma: the promise of MAPK pathway inhibition and beyond. Expert Opin Investig Drugs 2010, 19: 1205–1216. 10.1517/13543784.2010.504709CrossRefPubMed
3.
Pratilas CA, Solit DB: Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. Clin Cancer Res 2010, 16: 3329–3334. 10.1158/1078-0432.CCR-09-3064CrossRefPubMed
4.
LoRusso PM, Krishnamurthi SS, Rinehart JJ, Nabell LM, Malburg L, Chapman PB, DePrimo SE, Bentivegna S, Wilner KD, Tan W, Ricart AD: Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res 2010, 16: 1924–1937. 10.1158/1078-0432.CCR-09-1883CrossRefPubMed
5.
O'Neil BH, Goff LW, Kauh JS, Strosberg JR, Bekaii-Saab TS, Lee RM, Kazi A, Moore DT, Learoyd M, Lush RM, et al.: Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2011, 29: 2350–2356. 10.1200/JCO.2010.33.9432CrossRefPubMed
6.
Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, et al.: Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 2013, 31: 482–489. 10.1200/JCO.2012.43.5966CrossRefPubMed
7.
Turajlic S, Ali Z, Yousaf N, Larkin J: Phase I/II RAF kinase inhibitors in cancer therapy. Expert Opin Investig Drugs 2013, 22: 739–749. 10.1517/13543784.2013.797964CrossRefPubMed
8.
Solit DB, Santos E, Pratilas CA, Lobo J, Moroz M, Cai S, Blasberg R, Sebolt-Leopold J, Larson S, Rosen N: 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography is a sensitive method for imaging the response of BRAF-dependent tumors to MEK inhibition. Cancer research 2007, 67: 11463–11469. 10.1158/0008-5472.CAN-07-2976CrossRefPubMed
9.
Su H, Bodenstein C, Dumont RA, Seimbille Y, Dubinett S, Phelps ME, Herschman H, Czernin J, Weber W: Monitoring tumor glucose utilization by positron emission tomography for the prediction of treatment response to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res 2006, 12: 5659–5667. 10.1158/1078-0432.CCR-06-0368CrossRefPubMed
10.
Sohn HJ, Yang YJ, Ryu JS, Oh SJ, Im KC, Moon DH, Lee DH, Suh C, Lee JS, Kim SW: [18F]Fluorothymidine positron emission tomography before and 7 days after gefitinib treatment predicts response in patients with advanced adenocarcinoma of the lung. Clin Cancer Res 2008, 14: 7423–7429. 10.1158/1078-0432.CCR-08-0312CrossRefPubMed
11.
Schelling M, Avril N, Nahrig J, Kuhn W, Romer W, Sattler D, Werner M, Dose J, Janicke F, Graeff H, Schwaiger M: Positron emission tomography using [(18)F]Fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer. J Clin Oncol 2000, 18: 1689–1695.PubMed
12.
Stroobants S, Goeminne J, Seegers M, Dimitrijevic S, Dupont P, Nuyts J, Martens M, van den Borne B, Cole P, Sciot R, et al.: 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer 2003, 39: 2012–2020. 10.1016/S0959-8049(03)00073-XCrossRefPubMed
13.
Weber WA, Petersen V, Schmidt B, Tyndale-Hines L, Link T, Peschel C, Schwaiger M: Positron emission tomography in non-small-cell lung cancer: prediction of response to chemotherapy by quantitative assessment of glucose use. J Clin Oncol 2003, 21: 2651–2657. 10.1200/JCO.2003.12.004CrossRefPubMed
14.
McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Franklin RA, Montalto G, Cervello M, Libra M, Candido S, Malaponte G, et al.: Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. Oncotarget 2012, 3: 1068–1111.PubMed
15.
Belden S, Flaherty KT: MEK and RAF inhibitors for BRAF-mutated cancers. Expert reviews in molecular medicine 2012, 14: 17.CrossRef
16.
McArthur GA, Puzanov I, Amaravadi R, Ribas A, Chapman P, Kim KB, Sosman JA, Lee RJ, Nolop K, Flaherty KT, et al.: Marked, homogeneous, and early [18F]fluorodeoxyglucose-positron emission tomography responses to vemurafenib in BRAF-mutant advanced melanoma. J Clin Oncol 2012, 30: 1628–1634. 10.1200/JCO.2011.39.1938CrossRefPubMed
17.
Leijen S, Middleton MR, Tresca P, Kraeber-Bodere F, Dieras V, Scheulen ME, Gupta A, Lopez-Valverde V, Xu ZX, Rueger R, et al.: Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors. Clin Cancer Res 2012, 18: 4794–4805. 10.1158/1078-0432.CCR-12-0868CrossRefPubMed
18.
Martinez-Garcia M, Banerji U, Albanell J, Bahleda R, Dolly S, Kraeber-Bodere F, Rojo F, Routier E, Guarin E, Xu ZX, et al.: First-in-Human, Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of RO5126766, a First-in-Class Dual MEK/RAF Inhibitor in Patients with Solid Tumors. Clin Cancer Res 2012, 18: 4806–4819. 10.1158/1078-0432.CCR-12-0742CrossRefPubMed
19.
Lyrdal D, Boijsen M, Suurkula M, Lundstam S, Stierner U: Evaluation of sorafenib treatment in metastatic renal cell carcinoma with 2-fluoro-2-deoxyglucose positron emission tomography and computed tomography. Nuclear medicine communications 2009, 30: 519–524. 10.1097/MNM.0b013e32832cc220CrossRefPubMed
20.
Leyton J, Smith G, Lees M, Perumal M, Nguyen QD, Aigbirhio FI, Golovko O, He Q, Workman P, Aboagye EO: Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901. Mol Cancer Ther 2008, 7: 3112–3121. 10.1158/1535-7163.MCT-08-0264CrossRefPubMed
21.
Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, et al.: Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008, 14: 1351–1356. 10.1038/nm.1890CrossRefPubMed
22.
Vergez S, Delord JP, Thomas F, Rochaix P, Caselles O, Filleron T, Brillouet S, Canal P, Courbon F, Allal BC: Preclinical and clinical evidence that Deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography is a reliable tool for the detection of early molecular responses to erlotinib in head and neck cancer. Clin Cancer Res 2010, 16: 4434–4445. 10.1158/1078-0432.CCR-09-2795CrossRefPubMed
23.
Cullinane C, Dorow DS, Kansara M, Conus N, Binns D, Hicks RJ, Ashman LK, McArthur GA, Thomas DM: An in vivo tumor model exploiting metabolic response as a biomarker for targeted drug development. Cancer Res 2005, 65: 9633–9636. 10.1158/0008-5472.CAN-05-2285CrossRefPubMed
24.
Ishii N, Harada N, Joseph EW, Ohara K, Miura T, Sakamoto H, Matsuda Y, Tomii Y, Tachibana-Kondo Y, Iikura H, et al.: Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res 73(13):4050–4060.
25.
Kraeber-Bodere F, Carlier T, Naegelen VM, Shochat E, Lumbroso J, Trampal C, Nagarajah J, Chua S, Hugonnet F, Stokkel M, et al.: Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials. J Nucl Med 2012, 53: 1836–1846. 10.2967/jnumed.112.109421CrossRefPubMed
26.
Samen E, Thorell JO, Lu L, Tegnebratt T, Holmgren L, Stone-Elander S: Synthesis and preclinical evaluation of [(11)C]PAQ as a PET imaging tracer for VEGFR-2. Eur J Nucl Med Mol Imaging 2009, 36: 1283–1295. 10.1007/s00259-009-1111-3CrossRefPubMed
27.
Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D, Phelps ME, Weber WA: Impact of animal handling on the results of 18F-FDG PET studies in mice. J Nucl Med 2006, 47: 999–1006.PubMed
28.
Avril N: GLUT1 expression in tissue and (18)F-FDG uptake. J Nucl Med 2004, 45: 930–932.PubMed
29.
Songji Z, Yuji K, al e: Biologic Correlates of Intratumoral Heterogeneity in 18F-FDG Distribution with Regional Expression of Glucose Transporters and Hexokinase-II in Experimental Tumor. J Nucl Med 2005, 46: 675–682.
30.
Gatenby RA, Gillies RJ: Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004, 4: 891–899. 10.1038/nrc1478CrossRefPubMed
31.
Chung JK, al e: Mechanisms related to (18F) Fluorodeoxyglucose uptake of human coln cancers transplanted in nude mice. J Nucl Med 1999, 40: 339–346.PubMed
32.
Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JK, Markowitz S, Zhou S, et al.: Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 2009, 325: 1555–1559. 10.1126/science.1174229CrossRefPubMed
33.
Brepoels L, Stroobants S, Verhoef G, De Groot T, Mortelmans L, De Wolf-Peeters C: (18)F-FDG and (18)F-FLT uptake early after cyclophosphamide and mTOR inhibition in an experimental lymphoma model. J Nucl Med 2009, 50: 1102–1109. 10.2967/jnumed.109.062208CrossRefPubMed
34.
Kinross KM, Brown DV, Kleinschmidt M, Jackson S, Christensen J, Cullinane C, Hicks RJ, Johnstone RW, McArthur GA: In vivo activity of combined PI3K/mTOR and MEK-inhibition in a KrasG12D;Pten deletion mouse model of ovarian cancer. Mol Cancer Ther 10(8):1440–1449.
35.
Soret M, Bacharach SL, Buvat I: Partial-volume effect in PET tumor imaging. J Nucl Med 2007, 48: 932–945. 10.2967/jnumed.106.035774CrossRefPubMed
36.
Bergstrom M, Awad R, Estrada S, Malman J, Lu L, Lendvai G, Bergstrom-Pettermann E, Langstrom B: Autoradiography with positron emitting isotopes in positron emission tomography tracer discovery. Mol Imaging Biol 2003, 5: 390–396. 10.1016/j.mibio.2003.09.004CrossRefPubMed
37.
Fritz V, Fajas L: Metabolism and proliferation share common regulatory pathways in cancer cells. Oncogene 2010, 29: 4369–4377. 10.1038/onc.2010.182CrossRefPubMed
38.
Levine AJ, Puzio-Kuter AM: The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 2010, 330: 1340–1344. 10.1126/science.1193494CrossRefPubMed
39.
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB: The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. CELL METAB 2008, 7: 11–20. 10.1016/j.cmet.2007.10.002CrossRefPubMed
40.
Bading JR, Shields AF: Imaging of cell proliferation: status and prospects. J Nucl Med 2008,49(Suppl 2):64S-80S.CrossRefPubMed
Metadata
Title
[18 F]FDG-PET imaging is an early non-invasive pharmacodynamic biomarker for a first-in-class dual MEK/Raf inhibitor, RO5126766 (CH5126766), in preclinical xenograft models
Authors
Tetyana Tegnebratt
Li Lu
Lucy Lee
Valerie Meresse
Jean Tessier
Nobuya Ishii
Naoki Harada
Pavel Pisa
Sharon Stone-Elander
Publication date
01-12-2013
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2013
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/2191-219X-3-67

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