Non-Invasive PET Imaging of EGFR Degradation Induced by a Heat Shock Protein 90 Inhibitor

Niu, Gang; Cai, Weibo; Chen, Kai; Chen, Xiaoyuan

doi:10.1007/s11307-007-0123-2

Cited by 37 publications

(30 citation statements)

References 38 publications

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“…In contrast, tumor uptake of 18 F-FDG (the most widely used tumor tracer, which visualizes glucose uptake) did not change after HSP90 therapy (31). Likewise, 64 Cu-DOTA-cetuximab was used to monitor EGFR degradation by 17-AAG in a PC-3 prostate cancer xenograft model (32). Uptake of 64 Cu-DOTA-cetuximab in 17-AAG-treated animals was lower (239%) than in nontreated animals at 48 h after the last administration of 17-AAG, which corresponded to a decreased EGFR staining in tumor samples.…”

Section: Discussionmentioning

confidence: 99%

⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

Nagengast¹,

Korte²,

Munnink³

et al. 2010

J Nucl Med

106

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Angiogenesis is a critical step in tumor development, in which vascular endothelial growth factor (VEGF) is a key growth aspect. Heat shock protein 90 (HSP90), a molecular chaperone, is essential for the activity of key proteins involved in VEGF transcription. Currently, no biomarkers to predict the effect of, or monitor, HSP90 inhibition therapy in individual patients exist. 89 Zr-bevacizumab PET provides a noninvasive tool to monitor tumor VEGF levels. The aim of this study was to investigate 89 Zr-bevacizumab PET for early antiangiogenic tumor response evaluation of treatment with the new HSP90 inhibitor NVP-AUY922. In xenografts of A2780 and its cisplatin-resistant CP70 human ovarian cancer subline, 89 Zr-bevacizumab smallanimal PET was performed before and after NVP-AUY922 treatment and verified with histologic response and ex vivo tumor VEGF levels. Compared with pretreatment values, 2 wk of NVP-AUY922 treatment decreased 89 Zr-bevacizumab uptake by 44.4% (P 5 0.0003) in A2780 xenografts, whereas tumor uptake was not affected in CP70 xenografts. The same pattern was observed in A2780 and CP70 tumor VEGF levels, measured with enzyme-linked immunosorbent assay, and mean vessel density after NVP-AUY922 treatment. These findings coincided with reduction in the proliferation rate, assessed by Ki67 staining, in A2780 tumor tissue only. Conclusion: 89 Zr-bevacizumab PET was in line with the antiangiogenic response and direct antitumor effects after NVP-AUY922 treatment, supporting the specificity of 89 Zr-bevacizumab PET as a sensitive technique to monitor the antiangiogenic response of HSP90 inhibition in vivo.

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Section: Discussionmentioning

confidence: 99%

⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

Nagengast¹,

Korte²,

Munnink³

et al. 2010

J Nucl Med

106

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“…EGFR antibody and EGF can be radiolabeled as EGFR molecular imaging probes (20)(21)(22)(23). However, they can only detect the level of EGFR expression on the cell membrane; they cannot detect intracellular TK activity directly or determine the status of the EGFR signaling pathway accurately.…”

Section: Discussionmentioning

confidence: 99%

PET-Based Biodistribution and Radiation Dosimetry of Epidermal Growth Factor Receptor–Selective Tracer ¹¹C-PD153035 in Humans

Liu¹,

Li²,

Li³

et al. 2009

J Nucl Med

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The present study estimated the biodistribution and radiationabsorbed dose of epidermal growth factor receptor (EGFR) radioligand 11 C-PD153035 in whole-body PET examinations of healthy volunteers. Methods: Two-dimensional whole-body PET was performed on 9 subjects after injection of 11 C-PD153035 at 329.3 6 77.8 MBq (mean 6 SD). A total of 12 frames were acquired for approximately 90 min in 7 segments of the body. Regions of interest were drawn on PET images of source organs. Residence time was calculated as the area under the timeactivity curve. Radiation dosimetry was calculated from organ residence time by use of MIRDOSE3 software. Results: The renal and hepatobiliary systems played important roles in 11 C-PD153035 excretion from the body, accounting for the excretion of approximately 23% and 19% of the injected radioactivity, respectively. Blood-pool activity was only moderate and declined over time. Tracer accumulation in the lungs, bone marrow, and muscles was slight, resulting in low background activity in the chest. The organs with the highest radiation-absorbed doses were the urinary bladder and the gallbladder; the effective doses were 6.08E202 6 1.85E202 and 2.40E202 6 8.01E203 mGy/ MBq, respectively. The effective dose equivalent was 7.43E203 6 1.10E203 mSv/MBq, and the dose-limiting organ was the urinary bladder. Conclusion: On the basis of the estimated absorbed dose, 11 C-PD153035 displayed a favorable radiation dose profile in humans and therefore could be used in multiple PET examinations of the same subject per year. 11 C-PD153035 is a promising ligand for the investigation of EGFR in humans, especially in chest tumors such as non-small cell lung cancer.

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“…Among solid tumors that have shown favorable preclinical and clinical responses to Hsp90 inhibitors are breast and prostate carcinomas (7,(12)(13)(14)(15)(16)(17). Because these cancers have a propensity to metastasize to bone, it is important to determine the impact of Hsp90 inhibitors on tumor cells growing in this unique milieu.…”

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confidence: 99%

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Yano

Tsutsumi

Soga

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Srcdependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy.cancer ͉ geldanamycin ͉ heat shock protein 90 ͉ osteoclastogenesis

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Non-Invasive PET Imaging of EGFR Degradation Induced by a Heat Shock Protein 90 Inhibitor

Abstract: The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using (64)Cu-DOTA-cetuximab, which indicates that this approach may be valuable in monitoring the therapeutic response to Hsp90 inhibitor 17-AAG in EGFR-positive cancer patients.

Cited by 37 publications

References 38 publications

⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

PET-Based Biodistribution and Radiation Dosimetry of Epidermal Growth Factor Receptor–Selective Tracer ¹¹C-PD153035 in Humans

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

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Non-Invasive PET Imaging of EGFR Degradation Induced by a Heat Shock Protein 90 Inhibitor

Abstract: The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using (64)Cu-DOTA-cetuximab, which indicates that this approach may be valuable in monitoring the therapeutic response to Hsp90 inhibitor 17-AAG in EGFR-positive cancer patients.

Cited by 37 publications

References 38 publications

89Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

89Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

PET-Based Biodistribution and Radiation Dosimetry of Epidermal Growth Factor Receptor–Selective Tracer 11C-PD153035 in Humans

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

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⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

PET-Based Biodistribution and Radiation Dosimetry of Epidermal Growth Factor Receptor–Selective Tracer ¹¹C-PD153035 in Humans