Molecular Imaging of Therapeutic Response to Epidermal Growth Factor Receptor Blockade in Colorectal Cancer

Manning, H. Charles; Merchant, Nipun B.; Foutch, A. Coe; Virostko, John; Wyatt, Shelby K.; Shah, Chirayu; McKinley, Eliot T.; Xie, Jingping; Mutic, Nathan J.; Washington, Mary Kay; LaFleur, Bonnie; Tantawy, Mohammed Noor; Peterson, Todd E.; Ansari, M S; Baldwin, Ronald M.; Rothenberg, Mace L.; Bornhop, Darryl J.; Gore, John C.; Coffey, Robert J.

doi:10.1158/1078-0432.ccr-08-0239

Cited by 92 publications

(108 citation statements)

References 43 publications

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“…Although several factors can influence Qdot clearance, the low liver uptake of our probe could be related to passivating effects of surface PEG or hydrazinonicotinamide (29). In any case, superior binding and in vivo kinetic properties of our probe provided high-contrast tumor images that compare favorably to previous EGF-conjugated fluorophore (30)(31)(32) or Qdot (33) probes. However, scintigraphic imaging with single photon-emitting radiopharmaceuticals, compared with PET techniques, has several limitations, including lower sensitivity, resolution, and quantitative capacity.…”

Section: Discussionmentioning

confidence: 80%

^99mTc-Hydrazinonicotinamide Epidermal Growth Factor–Polyethylene Glycol–Quantum Dot Imaging Allows Quantification of Breast Cancer Epidermal Growth Factor Receptor Expression and Monitors Receptor Downregulation in Response to Cetuximab Therapy

Jung¹,

Choe²,

Paik³

et al. 2011

J Nucl Med

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Therapy of cancer, including basallike breast tumors, that targets the epidermal growth factor receptor (EGFR) would greatly benefit from noninvasive methods that can quantitatively monitor receptor status and treatment response. Methods: Here, we investigated the potential of a novel technique based on streptavidin cadmium selenide/zinc sulfide quantum dots (Qdots) multiplexed with polyethylene glycol (PEG), epidermal growth factor (EGF), and 99m Tc-hydrazinonicotinamide. In vitro binding affinity and specificity were evaluated in cultured cells. Biodistribution studies and in vivo imaging were performed in murine breast tumor xenografts of basallike phenotype MDA-MB-468 cells and EGFR-negative cells. Results: 99m Tchydrazinonicotinamide EGF-PEG-Qdot showed specific and high-affinity EGFR targeting on confocal microscopy, immunoblotting, and binding assays. When intravenously injected, MDA-MB-468 tumors were visualized with high contrast by both optical and scintigraphic imaging. Scintigraphic image-based quantification correctly discriminated high-EGFR-expressing MDA-MB-468 tumors from other tumors, and image-based tumor uptake closely correlated to EGFR content. Importantly, serial imaging of MDA-MB-468 tumors responding to cetuximab therapy could detect a significant reduction of tumor uptake that was paralleled by downregulation of EGFR expression. Furthermore, high baseline uptake predicted good response to cetuximab therapy. Conclusion: 99m Tc-hydrazinonicotinamide EGF-PEGQdot provides EGFR-targeted imaging of breast tumors and may allow noninvasive monitoring of EGFR status in living subjects before and after targeted therapies.Key Words: molecular imaging; oncology; breast cancer; epidermal growth factor receptor; scintigraphy Epi dermal growth factor receptors (EGFRs) play a key role in tumor growth, invasion, and metastasis (1-3) and have become a promising therapeutic target in many cancers (4,5). Breast carcinoma is the most common cancer in women and a major cause of mortality, accounting for 7% of all cancer-related deaths. EGFR is overexpressed in up to 35% of breast cancers and is associated with poorer prognosis (6,7). Recent data suggest potential benefits of EGFRtargeted agents not only for treating breast tumors but also for lowering their progression rate (8). The efficacy of targeted therapy depends on the expression status of the molecule being aimed for, and lessons from clinical trials with EGFR antagonists have illuminated the critical importance of this factor in selecting patients most likely to respond (4,5).Molecular profiling work on breast tumors identifies a distinct and highly malignant subtype called basallike breast cancer, which is linked with higher tumor grade, more frequent metastasis, and poor clinical outcome (9,10). This subgroup, with its characteristic molecular signature of negative estrogen/progesterone/HER2 receptor expression and positive EGFR expression, represents breast tumors that could most likely benefit from EGFR-targeted therapy because they lack other re...

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Section: Discussionmentioning

confidence: 80%

^99mTc-Hydrazinonicotinamide Epidermal Growth Factor–Polyethylene Glycol–Quantum Dot Imaging Allows Quantification of Breast Cancer Epidermal Growth Factor Receptor Expression and Monitors Receptor Downregulation in Response to Cetuximab Therapy

Jung¹,

Choe²,

Paik³

et al. 2011

J Nucl Med

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“…To our knowledge, several investigators recently used 18 F-FLT-PET to evaluate treatment response in animal models following EGFR targeted therapy such as erlotinib and cetuximab. However, those studies performed 18 F-FLT-PET at later timing than our study (25), and did not use lung cancer cell line (26) or cetuximab (27).…”

Section: Discussionmentioning

confidence: 95%

18F-Fluorothymidine PET/CT as an early predictor of tumor response to treatment with cetuximab in human lung cancer xenografts

Takeuchi

Kuge

Zhao³

et al. 2011

Oncol Rep

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Abstract. We investigated whether 18 F-fluorothymidinepositron-emission tomography/computed tomography ( 18 F-FLT-PET/CT) is useful for the evaluation of the very early response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab therapy in human lung cancer xenografts. A human tumor xenograft model was established with a human non-small cell lung cancer cell line. The mice were randomly assigned to four groups: tumor growth follow-up, ex vivo study, PET/CT imaging and non-treated control. Mice were administered saline as control or cetuximab on day 1. An immunohistochemical study with Ki-67 was performed. Tumor volume treated with cetuximab was kept significantly smaller than control after day 8, although there was no difference on day 3. On day 3, 18 F-FLT distribution was higher in the tumor than in other tissues, and was significantly decreased by treatment with cetuximab. On PET/CT imaging, 18 F-FLT distribution in the tumor was clearly visualized, and the maximum standardized uptake value (SUV) was significantly decreased after treatment with cetuximab (p<0.01). Ki-67 expression was also significantly decreased on day 3 (p= 0.01). These results suggest that 18 F-FLT-PET/CT can be a useful predictor to determine the response to molecular targeted drugs such as cetuximab at an earlier time point than the change of tumor size.

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“…2) (Kovar et al, 2006). Another study with EGF800 showed that probe accumulation in tumors reflected relative EGFR expression and EGFR occupancy by cetuximab (Manning et al, 2008).…”

Section: Natural Ligand Egfmentioning

confidence: 99%

Targeting EGFR and HER2 for Molecular Imaging of Cancer

Gong¹,

Sampath²,

Kovar³

et al. 2012

Molecular Imaging

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Molecular Imaging of Therapeutic Response to Epidermal Growth Factor Receptor Blockade in Colorectal Cancer

Abstract: Purpose:To evaluate noninvasive molecular imaging methods as correlative biomarkers of thera-

Cited by 92 publications

References 43 publications

^99mTc-Hydrazinonicotinamide Epidermal Growth Factor–Polyethylene Glycol–Quantum Dot Imaging Allows Quantification of Breast Cancer Epidermal Growth Factor Receptor Expression and Monitors Receptor Downregulation in Response to Cetuximab Therapy

^99mTc-Hydrazinonicotinamide Epidermal Growth Factor–Polyethylene Glycol–Quantum Dot Imaging Allows Quantification of Breast Cancer Epidermal Growth Factor Receptor Expression and Monitors Receptor Downregulation in Response to Cetuximab Therapy

18F-Fluorothymidine PET/CT as an early predictor of tumor response to treatment with cetuximab in human lung cancer xenografts

Targeting EGFR and HER2 for Molecular Imaging of Cancer

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