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Metabolic Imaging Allows Early Prediction of Response to Vandetanib

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Metabolic Imaging Allows Early Prediction of Response to Vandetanib Metabolic Imaging Allows Early Prediction of Response to Vandetanib Martin A. Walter1,2,MatthiasR.Benz2,IsabelJ.Hildebrandt2, Rachel E. Laing2, Verena Hartung3, Robert D. Damoiseaux4, Andreas Bockisch3, Michael E. Phelps2,JohannesCzernin2, and Wolfgang A. Weber2,5 1Institute of Nuclear Medicine, University Hospital, Bern, Switzerland; 2Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California; 3Institute of Nuclear Medicine, University Hospital, Essen, Germany; 4Molecular Shared Screening Resources, UCLA, Los Angeles, California; and 5Department of Nuclear Medicine, University Hospital, Freiburg, Germany The RET (rearranged-during-transfection protein) protoonco- The RET (rearranged-during-transfection protein) proto- gene triggers multiple intracellular signaling cascades regulat- oncogene, located on chromosome 10q11.2, encodes for ing cell cycle progression and cellular metabolism. We therefore a tyrosine kinase of the cadherin superfamily that activates hypothesized that metabolic imaging could allow noninvasive detection of response to the RET inhibitor vandetanib in vivo. multiple intracellular signaling cascades regulating cell sur- Methods: The effects of vandetanib treatment on the full- vival, differentiation, proliferation, migration, and chemo- genome expression and the metabolic profile were analyzed taxis (1). Gain-of-function mutations in the RET gene result in the human medullary thyroid cancer cell line TT. In vitro, tran- in uncontrolled growth and cause human cancers and scriptional changes of pathways regulating cell cycle progres- cancer syndromes, such as Hu¨rthle cell cancer, sporadic sion and glucose, dopa, and thymidine metabolism were papillary thyroid carcinoma, familial medullary thyroid correlated to the results of cell cycle analysis and the uptake of 3H-deoxyglucose, 3H-3,4-dihydroxy-L-phenylalanine, and carcinoma, and multiple endocrine neoplasia types 2A 3H-thymidine under vandetanib treatment. In vivo, the tumor and 2B (2). metabolism under vandetanib was monitored by small-animal The signaling pathways downstream of RET are activated PET of tumor-bearing mice. Results: Vandetanib treatment by autophosphorylation of several tyrosine and serine res- resulted in the transcriptional downregulation of various effector idues (Fig. 1A) and regulate several genes involved in pathways with consecutive downregulation of cyclin expression tumor progression (3). Among other effects, activated Rac and a G0/G1 arrest. In vitro, vandetanib treatment resulted in the decreased expression of genes regulating glucose, 3,4-dihy- (Ras-related C3 botulinum toxin substrate) (4), STAT3 droxy-L-phenylalanine, and thymidine metabolism, with a sub- (signal transducer and activator of transcription 3) (5), sequent reduction in the functional activity of the corresponding Src (v-src sarcoma [Schmidt-Ruppin A-2] viral oncogene pathways. In vivo, metabolic imaging with PET was able to homolog) (5), Ras (v-Ha-ras Harvey rat sarcoma viral assess changes in the tumoral glucose metabolism profile as oncogene homolog) (6), and PI3K (phosphatidylinositol- early as 3 d after initiation of vandetanib treatment. Conclusion: 3-kinase) (7) each results in the upregulation of cyclin We describe a metabolic imaging approach for the noninvasive detection of successful vandetanib treatment. Our results activity, which consequently leads to accelerated cell cycle suggest that PET may be useful for identifying patients who progression (8). Growth factor receptor–bound proteins 7 and respond to vandetanib early in the course of treatment. 10 (Grb7 and Grb10) presumably contribute to the invasive Key Words: animal imaging; endocrinology; oncology; early cell potential (9), whereas phospholipase Cg (PLCg) plays a treatment monitoring; medullary thyroid cancer; positron central role in calcium signaling and cell survival (10). emission tomography; tyrosine kinase inhibitor; vandetanib With its signaling network leading to neoplastic trans- J Nucl Med 2011; 52:231–240 formation, the RET protooncogene is a highly attractive tar- DOI: 10.2967/jnumed.110.081745 get for selective cancer therapy. Vandetanib (zd6474; Fig. 1B) is an orally bioavailable small-molecule inhibitor of the RET tyrosine kinase. It effectively inhibits the increased activity of ret as a consequence of RET/PTC3 mutations in papillary thyroid cancer and M918T RET mutations occur- ring in MEN2B-associated and sporadic medullary thyroid Received Jul. 27, 2010; revision accepted Nov. 3, 2010. cancers (MTCs) (11). The pharmacokinetics of vandetanib For correspondence or reprints contact: Martin A. Walter, Department of allow once-daily oral administration, and grade 3 or 4 tox- Molecular and Medical Pharmacology, David Geffen School of Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095-6942. icity is found in about 33% of patients (12). The efficacy of E-mail: [email protected] vandetanib in medullary thyroid cancer is currently being Guest Editor: Norbert Avril, Queen Mary, University of London COPYRIGHT ª 2011 by the Society of Nuclear Medicine, Inc. evaluated in several phase II trials (13). These trials use PET IN VANDETANIB TREATMENT • Walter et al. 231 FIGURE 1. (A) RET receptor and vandeta- nib. Single-pass transmembranous RET receptor plays central role in intracellular signaling cascades that regulate cellular survival, differentiation, proliferation, migra- tion, and chemotaxis. (B) Structure of RET inhibitor vandetanib and network of RET- mediated signaling events. RET autophos- phorylation sites are shown with their direct targets. (C) In TT cell model, vandetanib dis- played IC50 of 5.0 mM. (D) In untreated TT cells, no expression of genes involved in Src and Shank3 pathways was present, whereas 3 d of treatment with vandetanib resulted in downregulation of genes involved mainly in STAT3 and Grb 7 and Grb10 pathways. conventional tumor size criteria (World Health Organization mainly because of increased GLUT transcription (19,20). or Response Evaluation Criteria in Solid Tumors (14)), Finally, activation of STAT3 significantly induces GLUT which are limited in assessing responses because cytostatic expression and glucose uptake (21,22). This possible rela- drugs might not, or might only slowly, induce tumor shrink- tionship between RET signaling and tumor metabolic activity age. Thus, there is a need for more sensitive readouts of is of clinical interest because tumor glucose metabolism can successful RET kinase inhibition. be assessed quantitatively and noninvasively by PET with the Accelerated metabolism of glucose is a characteristic glucose analog 18F-FDG. Several studies have indicated that feature of most cancer cells, including MTC, and is caused 18F-FDG uptake is increased in subgroups of metastatic by increased expression activity of glucose transporters MTC and that 18F-FDG PET can be used for restaging of (GLUTs) as well as various glycolytic enzymes (15). Cur- patients with rising tumor markers. Using this clinical expe- rent literature data suggest that the activated RET protoon- rience and the experimental data discussed, we hypothesized cogene can modulate glucose metabolism via 5 pathways: that 18F-FDG PET may be used to monitor treatment with PI3K (16) and PLCg (17) are physiologic mediators of the RET inhibitor vandetanib in patients with MTC. insulin and increase glucose metabolism by upregulation In addition to 18F-FDG PET, PET with radiolabeled 3,4- of GLUT expression and hexokinase activity. Activated dihydroxy-L-phenylalanine (DOPA) has been successfully Src results in increased transcription of GLUT1 leading used for staging of MTC. DOPA is taken up by the L-type to an increase in cellular glucose uptake (18). Increased amino acid transport system and is then metabolized to Ras GTPase expression leads to increased glucose transport, dopamine by DOPA decarboxylase. PET with radiolabeled 232 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 52 • No. 2 • February 2011 DOPA may thus represent an alternative approach for imag- curve, sigmoidal dose–response), using an algorithm provided by ing the biologic consequences of vandetanib treatment in Prism, version 5 (GraphPad Software). MTC. Finally, mutated RET has been shown to trigger cell Cell Cycle Analyses proliferation and increase cellular thymidine uptake (23). Cells were plated in 6-well plates (1 · 105 cells in 1 mL of This process can be imaged clinically by PET with the medium). On the basis of the IC50 experiments, vandetanib at a thymidine analog fluorothymidine and may be another final concentration of 5 mM was added after 24 h. For controls, alternative for monitoring the effects of RET inhibition in vehicle (DMSO) without vandetanib was added. Cells were incu- MTC patients. bated at 37°C, 5% CO2. At varying time points (24, 48, and 72 h), Thus, experimental and clinical data suggest that PET cells were trypsinized, washed, and resuspended in phosphate- with radiolabeled 18F-FDG, DOPA, or fluorothymidine may buffered saline (PBS). Cell suspensions were stained with propi- be used to assess response to vandetanib treatment in vivo. dium iodide (Calbiochem) and RNase A (Sigma) in a hypotonic However, it is clear that glucose, DOPA, and thymidine buffer. The DNA content was then analyzed by a FACScan flow metabolism are regulated by a complex network of several cytometer (Becton Dickinson) using the CellQuest 3.1 software signaling pathways. To determine whether these metabolic (Becton Dickinson) for acquisition and the ModFit LT 2.0 soft- ware
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