Genomic Biomarkers for Molecular Imaging: Predicting the Future

Thakur, Mathew L.

doi:10.1053/j.semnuclmed.2009.03.006

Cited by 25 publications

(18 citation statements)

References 39 publications

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“…None of the other imaging modalities, such as mammography, ultrasonography, CT, or MRI, has been shown to stratify benign lesions from malignant ones also. The need for a molecular imaging probe that will address these serious issues is compelling (13,24).…”

Section: Discussionmentioning

confidence: 99%

“…Targeting VPAC1 receptors, therefore, provides an opportunity for the early and accurate imaging of breast cancer. We have performed extensive preclinical molecular imaging studies, both ex vivo and in athymic nude mice bearing human breast cancer xenografts, that offer highly promising results (12,13). In these studies we have targeted VPAC1 receptors that are overexpressed on all breast cancers (14).…”

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confidence: 99%

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Imaging Spontaneous MMTVneu Transgenic Murine Mammary Tumors: Targeting Metabolic Activity Versus Genetic Products

Thakur¹,

Devadhas²,

Zhang³

et al. 2009

J Nucl Med

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Despite the great strides made in imaging breast cancer (BC) in humans, the current imaging modalities miss up to 30% of BC, do not distinguish malignant lesions from benign ones, and require histologic examinations for which invasive biopsy must be performed. Annually in the United States, approximately 5.6 million biopsies find benign lesions. More than 50% of human BCs overexpress cyclin D1, and all BCs exhibit VPAC1 oncogene products. Together, these gene products may provide an excellent biomarker for the early and accurate detection of BC. We have evaluated 4 biologically active peptide analogs that have high affinity for VPAC1. The transgenic MMTVneu mice spontaneously develop BC and metastatic lesions that overexpress cyclin D1 and VPAC1 biomarkers. The MMTVneu mouse, therefore, provides an excellent animal model that mimics the pathogenesis of human BC. The objective of this investigation was to determine the ability of 1 of the peptide analogs, 64 Cu-TP3805, to detect BC in MMTVneu mice using 18 F-FDG as a gold standard. Methods: The transgenic MMTVneu mouse colony was maintained. Offspring were screened for transgenic status by reverse transcriptase polymerase chain reaction (RT-PCR). Nine mice with visible, palpable, or unknown metastatic lesions were entered into the protocol. 18 F-FDG (6,475 6 1,628 kBq [175 6 44 mCi]) PET served as a control, followed by a CT scan and 24-48 h later by PET with 64 Cu-TP3805 (4,588 6 962 kBq [124 6 26 mCi]). RT-PCR on excised tumors determined VPAC1 expression, and histology ascertained the pathology. Results: Ten tumors were detected by PET. Four tumors were detected both by 18 F-FDG and by 64 Cu-TP3805. Additionally, 4 tumors were imaged with 64 Cu-TP3805 only. These 8 tumors overexpressed VPAC1 receptors and were malignant by histology. The 2 remaining tumors were visualized with 18 F-FDG only. These tumors did not express the VPAC1 oncogene product and had benign histology. The standard uptake value ranged from 3.1 to 18.3 for 64 Cu-TP3805 and 0.9 to 1.4 for 18 F-FDG. Conclusion: 64 Cu-TP3805 identified all malignant lesions unequivocally that overexpressed the VPAC1 oncogene surface product. The 2 benign tumors that did not express the VPAC1 receptor were not imaged. 64 Cu-TP3805 promises to have the potential for the early and accurate imaging of primary and metastatic BC.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Imaging Spontaneous MMTVneu Transgenic Murine Mammary Tumors: Targeting Metabolic Activity Versus Genetic Products

Thakur¹,

Devadhas²,

Zhang³

et al. 2009

J Nucl Med

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“…These are showing promise in several applications, including the detection of occult tumors. Although a full discussion is beyond the scope of this paper, this area is reviewed in several recent papers [Josephs et al 2009;Thakur, 2009;Hargreaves, 2008].…”

Section: Molecular Imagingmentioning

confidence: 99%

Predictive and prognostic molecular markers for cancer medicine

et al. 2010

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Over the last 10 years there has been an explosion of information about the molecular biology of cancer. A challenge in oncology is to translate this information into advances in patient care. While there are well-formed routes for translating new molecular information into drug therapy, the routes for translating new information into sensitive and specific diagnostic, prognostic and predictive tests are still being developed. Similarly, the science of using tumor molecular profiles to select clinical trial participants or to optimize therapy for individual patients is still in its infancy. This review will summarize the current technologies for predicting treatment response and prognosis in cancer medicine, and outline what the future may hold. It will also highlight the potential importance of methods that can integrate molecular, histopathological and clinical information into a synergistic understanding of tumor progression. While these possibilities are without doubt exciting, significant challenges remain if we are to implement them with a strong evidence base in a widely available and cost-effective manner.

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“…12,13) Radiolabeled inhibitors are believed to clarify pharmacokinetics, expression levels and functions of target molecules, and to estimate the therapeutic efficacy of the inhibitors. Although 18 F-gefitinib was investigated to monitor EGFR expression and mutation status, tumor uptake was not correlated with EGFR expression levels and mutation status.…”

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confidence: 99%

Monitoring of Gefitinib Sensitivity with Radioiodinated PHY Based on EGFR Expression

Yoshimoto

Hirata

Kanai

et al. 2014

Biological & Pharmaceutical Bulletin

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Epidermal growth factor receptor (EGFR) is attractive target for tumor diagnosis and therapy, as it is specifically and abundantly expressed in tumor cells. EGFR-tyrosine kinase (TK) inhibitors such as gefitinib and erlotinib are widely used in the treatment of non-small cell lung cancer (NSCLC). In this study, we investigated whether radioiodinated 4-(3-iodo-phenoxy)-6,7-diethoxy-quinazoline (PHY), which is a candidate EGFR-TK imaging agent for single photon emission computed tomography (SPECT) is able to predict gefitinib sensitivity. We used four NSCLC cell lines-A549 (wild-type EGFR), H1650 (mutant EGFR; del E746_A750), H1975 (mutant EGFR; L858R, T790M) and H3255 (mutant EGFR; L858R)-and one epidermoid carcinoma cell line, A431 (wild-type EGFR). Cell proliferation assay and Western blotting revealed that A431 and H3255 with high EGFR expression showed high sensitivity to gefitinib. On the other hand, A549, H1650 and H1975 showed much lower sensitivity to gefitinib. The blocking study revealed that gefitinib decreased tumor uptake in 125 I-PHY in A431-bearing mice. Moreover, in vivo tumor uptake of 125 I-PHY was correlated with the IC 50 of gefitinib for cell proliferation. In the present study, tumor uptake of 125 I-PHY was correlated with the gefitinib sensitivity and this uptake was based on expression levels of EGFR, but not on mutation status. Although the mutation status is the most important factor for predicting gefitinib sensitivity, the abundant expression of EGFR is essential for therapy with EGFR-TK inhibitors. Therefore, radioiodinated PHY is a potential imaging agent to predict gefitinib sensitivity based on EGFR expression levels though further modifications of the imaging agent is needed to accurately estimate the mutation status.Key words tumor imaging; gefitinib; epidermal growth factor receptor tyrosine kinase; lung cancer; single photon emission computed tomography Epidermal growth factor receptor (EGFR) is overexpressed in a variety of tumors including non-small cell lung cancer (NSCLC), head and neck cancer, glioma and ovarian cancer.

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Genomic Biomarkers for Molecular Imaging: Predicting the Future

Cited by 25 publications

References 39 publications

Imaging Spontaneous MMTVneu Transgenic Murine Mammary Tumors: Targeting Metabolic Activity Versus Genetic Products

Imaging Spontaneous MMTVneu Transgenic Murine Mammary Tumors: Targeting Metabolic Activity Versus Genetic Products

Predictive and prognostic molecular markers for cancer medicine

Monitoring of Gefitinib Sensitivity with Radioiodinated PHY Based on EGFR Expression

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