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Molecular Imaging and Biology

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01-12-2012 | Research Article

Evaluation of 2-Deoxy-2-[¹⁸F]Fluoro-D-glucose- and 3′-Deoxy-3′-[¹⁸F]Fluorothymidine–Positron Emission Tomography as Biomarkers of Therapy Response in Platinum-Resistant Ovarian Cancer

Authors: Meg Perumal, Euan A. Stronach, Hani Gabra, Eric O. Aboagye

Published in: Molecular Imaging and Biology | Issue 6/2012

Abstract

Purpose

We evaluated whether 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) and 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) could be used as imaging biomarkers of platinum resensitization in ovarian cancer.

Procedures

Paired platinum-sensitive and platinum-resistant ovarian cancer cells from the same patient, PEO1 and PEO4, grown as tumor xenografts in nude mice, were assessed by PET.

Results

The AKT inhibitor, API-2, resensitized platinum-resistant PEO4 tumors to cisplatin, leading to a markedly lower Ki67 labeling index (p ≤ 0.006, n = 6 per group). [¹⁸F]FDG-PET and [¹⁸F]FLT-PET imaging variables were lower after combination treatment compared with vehicle treatment (p ≤ 0.006, n = 6 per group). No changes were seen with either drug alone. PRAS40 phosphorylation status was a sensitive biochemical marker of pathway inhibition, whereas reductions thymidine kinase 1 expression defined the [¹⁸F]FLT response.

Conclusions

Therapeutic inhibition of AKT activation in acquired platinum-resistant disease can be imaged noninvasively by [¹⁸F]FDG-PET and [¹⁸F]FLT-PET warranting further assessment.

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Kelland LR (2005) Emerging drugs for ovarian cancer. Expert Opin Emerg Drugs 10:413–424PubMedCrossRef

Kolasa IK, Rembiszewska A, Felisiak A et al (2009) PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients. Cancer Biol Ther 8:21–26PubMedCrossRef

Stronach EA, Alfraidi A, Rama N et al (2011) HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer. Cancer Res 71:4412–4422PubMedCrossRef

Stronach EA, Chen M, Maginn EN et al (2011) DNA-PK mediates AKT activation and apoptosis inhibition in clinically acquired platinum resistance. Neoplasia 13:1069–1108PubMed

Langdon SP, Lawrie SS, Hay FG et al (1988) Characterization and properties of nine human ovarian adenocarcinoma cell lines. Cancer Res 48:6166–6172PubMed

Cooke SL, Ng CKY, Melnyk N et al (2010) Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma. Oncogene 29:4905–4913PubMedCrossRef

Sakai W, Swisher EM, Jacquemont C et al (2009) Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res 69:6381–6386PubMedCrossRef

Workman P, Aboagye EO, Balkwill F et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577PubMedCrossRef

Yang L, Dan HC, Sun M et al (2004) Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res 64:4394–4399PubMedCrossRef

10.

Leyton J, Alao JP, Da Costa M et al (2006) In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3′-deoxy-3′-[¹⁸F]fluorothymidine positron emission tomography. Cancer Res 66:7621–7629PubMedCrossRef

11.

Leyton J, Latigo JR, Perumal M et al (2005) Early detection of tumor response to chemotherapy by 3′-deoxy-3′-[¹⁸F]fluorothymidine positron emission tomography: the effect of cisplatin on a fibrosarcoma tumor model in vivo. Cancer Res 65:4202–4210PubMedCrossRef

12.

Leyton J, Smith G, Lees M et al (2008) Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901. Mol Cancer Ther 7:3112–3121PubMedCrossRef

13.

Altomare DA, Zhang L, Deng J et al (2010) GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt. Clin Cancer Res 16:486–496PubMedCrossRef

14.

Rhodes N, Heerding DA, Duckett DR et al (2008) Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res 68:2366–2374PubMedCrossRef

15.

Workman P, Clarke PA, Guillard S et al (2006) Drugging the PI3 kinome. Nat Biotechnol 24:794–796PubMedCrossRef

16.

Agarwal R, Kaye S (2003) Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer 3:502–516PubMedCrossRef

17.

Liu P, Cheng H, Roberts TM et al (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8:627–644PubMedCrossRef

18.

Stronach EA, Cheraghchi-Bashi A, Chen M et al (2011) Targeting the AKT pathway in ovarian cancer. In: Kaye S, Brown R, Gabra H et al (eds) Emerging therapeutic targets in ovarian cancer. Springer, New York, pp 73–94CrossRef

19.

Bozulic L, Surucu B, Hynx D et al (2008) PKBalpha/Akt1 acts downstream of DNA–PK in the DNA double-strand break response and promotes survival. Mol Cell 30:203–213PubMedCrossRef

20.

Contractor KB, Aboagye EO (2009) Monitoring predominantly cytostatic treatment response with ¹⁸F-FDG PET. J Nucl Med 50:97S–105SPubMedCrossRef

21.

Kenny L, Coombes R, Vigushin D et al (2007) Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3′-deoxy-3′-[¹⁸F]fluorothymidine positron emission tomography. Eur J Nucl Med Mol Imaging 34:1339–1347PubMedCrossRef

22.

Iagaru AH, Mittra ES, McDougall IR et al (2008) ¹⁸F-FDG PET/CT evaluation of patients with ovarian carcinoma. Nucl Med Commun 29:1046–1051PubMedCrossRef

23.

Kurokawa T, Yoshida Y, Kawahara K et al (2004) Expression of GLUT-1 glucose transfer, cellular proliferation activity and grade of tumor correlate with [F-18]-fluorodeoxyglucose uptake by positron emission tomography in epithelial tumors of the ovary. Int J Cancer 109:926–932PubMedCrossRef

24.

Kenny LM, Vigushin DM, Al-Nahhas A et al (2005) Quantification of cellular proliferation in tumor and normal tissues of patients with breast cancer by [¹⁸F]fluorothymidine–positron emission tomography imaging: evaluation of analytical methods. Cancer Res 65:10104–10112PubMedCrossRef

25.

Barthel H, Wilson H, Collingridge DR et al (2004) In vivo evaluation of [¹⁸F]fluoroetanidazole as a new marker for imaging tumour hypoxia with positron emission tomography. Br J Cancer 90:2232–2242PubMed

26.

Rasey JS, Grierson JR, Wiens LW et al (2002) Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med 43:1210–1217PubMed

Title: Evaluation of 2-Deoxy-2-[18F]Fluoro-D-glucose- and 3′-Deoxy-3′-[18F]Fluorothymidine–Positron Emission Tomography as Biomarkers of Therapy Response in Platinum-Resistant Ovarian Cancer
Authors: Meg Perumal
Euan A. Stronach
Hani Gabra
Eric O. Aboagye
Publication date: 01-12-2012
Publisher: Springer-Verlag
Published in: Molecular Imaging and Biology / Issue 6/2012
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-012-0554-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Evaluation of 2-Deoxy-2-[¹⁸F]Fluoro-D-glucose- and 3′-Deoxy-3′-[¹⁸F]Fluorothymidine–Positron Emission Tomography as Biomarkers of Therapy Response in Platinum-Resistant Ovarian Cancer

Abstract

Purpose

Procedures

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Procedures

Results

Conclusions

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