Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors

Smith‐Jones, Peter; Solit, David B.; Akhurst, Timothy; Afroze, Farzana; Rosen, Neal; Larson, Steven M.

doi:10.1038/nbt968

Cited by 279 publications

(241 citation statements)

References 21 publications

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“…The 72-h tumor/muscle ratio was 93, and the tumor/blood ratio was 9. IgG antibodies clear through the hepatic system and tend to accumulate in the spleen; this was seen in the study, but the uptake in both organs was 50% less than the accumulation observed in the tumor (18). The blocking study with Ecotin-RR resulted in a greater than 80% decrease in 111 In-A11 uptake in the tumor.…”

Section: Resultsmentioning

confidence: 54%

“…Proteolytic activity has been confirmed as a viable marker for cancer imaging in vivo using near-infrared (NIR) and nuclear imaging modalities (16)(17)(18). Most approaches have used smallmolecule probes that target either metallo-or cysteine proteases.…”

mentioning

confidence: 99%

“…The multiple points of contact made by antibodies with target proteases allows for the engineering of antibodies that can selectively and potently inhibit individual members of large protease families (22). There are a growing number of antibody-based platforms for cancer detection and treatment that have been Federal Drug Administration-approved such as ProstaScint, Bexxar, Zevalin, and Herceptin (18,23,24).…”

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confidence: 99%

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Imaging a functional tumorigenic biomarker in the transformed epithelium

LeBeau

Lee

Murphy

et al. 2012

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

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Proteases responsible for the increased peritumoral proteolysis associated with cancer represent functional biomarkers for monitoring tumorigenesis. One attractive extracellular biomarker is the transmembrane serine protease matriptase. Found on the surface of epithelial cells, the activity of matriptase is regulated by its cognate inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1). Quantitative mass spectrometry allowed us to show that, in selected cancers, HAI-1 expression decreases, leading to active matriptase. A preclinical probe specific for the measurement of emergent active matriptase was developed. Using an active-site-specific, recombinant human antibody for matriptase, we found that the selective targeting of active matriptase can be used to visualize the tumorigenic epithelium. Live-cell fluorescence imaging validated the selectivity of the antibody in vitro by showing that the probe localized only to cancer cell lines with active matriptase on the surface. Immunofluorescence with the antibody documented significant levels of active matriptase in 68% of primary and metastatic colon cancer sections from tissue microarrays. Labeling of the active form of matriptase in vivo was measured in human colon cancer xenografts and in a patient-derived xenograft model using near-infrared and single-photon emission computed tomography imaging. Tumor uptake of the radiolabeled antibody, 111 In-A11, by active matriptase was high in xenografts (28% injected dose per gram) and was blocked in vivo by the addition of a matriptase-specific variant of ecotin. These findings suggest, through a HAI-1-dependent mechanism, that emergent active matriptase is a functional biomarker of the transformed epithelium and that its proteolytic activity can be exploited to noninvasively evaluate tumorigenesis in vivo.cancer biomarker | molecular imaging

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Section: Resultsmentioning

confidence: 54%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Imaging a functional tumorigenic biomarker in the transformed epithelium

LeBeau

Lee

Murphy

et al. 2012

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

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“…Some of these Hsp90 inhibitors have shown efficacy for growth inhibition in cell culture and xenograft models in living mice (9,19). Recently, a noninvasive imaging method was developed to monitor Her2 degradation by Hsp90 inhibitors in a breast cancer xenograft model (20). In spite of these advances, longitudinal studies for monitoring the efficacies of Hsp90 inhibitors cannot be achieved noninvasively without sacrificing the mice at each time point before excision of tumors for in vitro analyses.…”

Section: Introductionmentioning

confidence: 99%

Molecular Imaging of the Efficacy of Heat Shock Protein 90 Inhibitors in Living Subjects

et al. 2008

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Heat shock protein 90A (Hsp90A)/p23 and Hsp90B/p23 interactions are crucial for proper folding of proteins involved in cancer and neurodegenerative diseases. Small molecule Hsp90 inhibitors block Hsp90A/p23 and Hsp90B/p23 interactions in part by preventing ATP binding to Hsp90. The importance of isoform-selective Hsp90A/p23 and Hsp90B/p23 interactions in determining the sensitivity to Hsp90 was examined using 293T human kidney cancer cells stably expressing split Renilla luciferase (RL) reporters. Interactions between Hsp90A/p23 and Hsp90B/p23 in the split RL reporters led to complementation of RL activity, which was determined by bioluminescence imaging of intact cells in cell culture and living mice using a cooled charge-coupled device camera. The three geldanamycin-based and seven purinescaffold Hsp90 inhibitors led to different levels of inhibition of complemented RL activities (10-70%). However, there was no isoform selectivity to both classes of Hsp90 inhibitors in cell culture conditions. The most potent Hsp90 inhibitor, PU-H71, however, led to a 60% and 30% decrease in RL activity (14 hr) in 293T xenografts expressing Hsp90A/p23 and Hsp90B/p23 split reporters respectively, relative to carrier control-treated mice. Molecular imaging of isoform-specific Hsp90A/p23 and Hsp90B/p23 interactions and efficacy of different classes of Hsp90 inhibitors in living subjects have been achieved with a novel genetically encoded reporter gene strategy that should help in accelerating development of potent and isoformselective Hsp90 inhibitors. [Cancer Res 2008;68(1):216-26]

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“…Note that markers can be both prognostic and predictive, as is the case, for ER and HER2 expression. Examples of molecular imaging paralleling these tissue-based assays are emerging using PET ER imaging (30,31), PET or MR imaging of 5-FU (32,33), and SPECT and PET imaging of HER2 expression (34,35). Recent data from our center illustrate the use of 18 F-fluorestradiol (FES) PET to image ER expression in metastatic breast cancer as a predictor of response to salvage endocrine therapy (Figure 4).…”

Section: Examples Of Tissue-based Assays Include the Expression Of Ermentioning

confidence: 99%

Molecular Imaging Research in the Outcomes Era

et al. 2007

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SummaryAdvances in molecular imaging, combined with the goal of personalized cancer therapy, call for new approaches to clinical study design for trials testing imaging to guide therapy. The role of cancer imaging must expand and move beyond tumor detection and localization to incorporate quantitative evaluation of regional tumor phenotype. Imaging study design and outcome analysis must move beyond metrics designed to measure the performance for detection to include measures of prognosis, prediction of therapeutic success, and early therapy response. This implies changes in how studies are carried and out, and importantly in the regulatory oversight of cancer imaging. Demonstration that a biochemical or molecular imaging method correctly and accurately measures a specific biologic feature should be sufficient for approval for clinical trials. It may be possible that a combination of imaging procedures known to accurately depict tumor phenotype may be prognostic, even if the individual study cannot be directly validated against patient outcomes. Therefore, it will be important to be able to apply a range of possible imaging studies to different targeted cancer therapy trials. Academia and industry must work together with regulatory agencies and payers to facilitate well designed clinical studies, with appropriate outcome measures, to test the effectiveness of imaging in helping to direct cancer therapy. These will assure the appropriate use of imaging to direct treatment and make an important step towards individualized cancer therapy.

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Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors

Cited by 279 publications

References 21 publications

Imaging a functional tumorigenic biomarker in the transformed epithelium

Imaging a functional tumorigenic biomarker in the transformed epithelium

Molecular Imaging of the Efficacy of Heat Shock Protein 90 Inhibitors in Living Subjects

Molecular Imaging Research in the Outcomes Era

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