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Dive into the research topics where Sean Carlin is active.

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Featured researches published by Sean Carlin.


The Journal of Nuclear Medicine | 2013

A Pretargeted PET Imaging Strategy Based on Bioorthogonal Diels–Alder Click Chemistry

Brian M. Zeglis; Kuntal K. Sevak; Thomas Reiner; Priya Mohindra; Sean Carlin; Pat Zanzonico; Ralph Weissleder; Jason S. Lewis

The specificity of antibodies have made immunoconjugates promising vectors for the delivery of radioisotopes to cancer cells; however, their long pharmacologic half-lives necessitate the use of radioisotopes with long physical half-lives, a combination that leads to high radiation doses to patients. Therefore, the development of targeting modalities that harness the advantages of antibodies without their pharmacokinetic limitations is desirable. To this end, we report the development of a methodology for pretargeted PET imaging based on the bioorthogonal Diels–Alder click reaction between tetrazine and transcyclooctene. Methods: A proof-of-concept system based on the A33 antibody, SW1222 colorectal cancer cells, and 64Cu was used. The huA33 antibody was covalently modified with transcyclooctene, and a NOTA-modified tetrazine was synthesized and radiolabeled with 64Cu. Pretargeted in vivo biodistribution and PET imaging experiments were performed with athymic nude mice bearing A33 antigen–expressing, SW1222 colorectal cancer xenografts. Results: The huA33 antibody was modified with transcyclooctene to produce a conjugate with high immunoreactivity, and the 64Cu-NOTA–labeled tetrazine ligand was synthesized with greater than 99% purity and a specific activity of 9–10 MBq/μg. For in vivo experiments, mice bearing SW1222 xenografts were injected with transcyclooctene-modified A33; after allowing 24 h for accumulation of the antibody in the tumor, the mice were injected with 64Cu-NOTA–labeled tetrazine for PET imaging and biodistribution experiments. At 12 h after injection, the retention of uptake in the tumor (4.1 ± 0.3 percent injected dose per gram), coupled with the fecal excretion of excess radioligand, produced images with high tumor-to-background ratios. PET imaging and biodistribution experiments performed using A33 directly labeled with either 64Cu or 89Zr revealed that although absolute tumor uptake was higher with the directly radiolabeled antibodies, the pretargeted system yielded comparable images and tumor-to-muscle ratios at 12 and 24 h after injection. Further, dosimetry calculations revealed that the 64Cu pretargeting system resulted in only a fraction of the absorbed background dose of A33 directly labeled with 89Zr (0.0124 mSv/MBq vs. 0.4162 mSv/MBq, respectively). Conclusion: The high quality of the images produced by this pretargeting approach, combined with the ability of the methodology to dramatically reduce nontarget radiation doses to patients, marks this system as a strong candidate for clinical translation.


Science Translational Medicine | 2015

Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo

Sriram Venneti; Mark Dunphy; Hanwen Zhang; Kenneth L. Pitter; Patrick Zanzonico; Carl Campos; Sean Carlin; Gaspare La Rocca; Serge K. Lyashchenko; Karl Ploessl; Daniel Rohle; Antonio Omuro; Justin R. Cross; Cameron Brennan; Wolfgang A. Weber; Eric C. Holland; Ingo K. Mellinghoff; Hank F. Kung; Jason S. Lewis; Craig B. Thompson

Glutamine-based PET imaging takes advantage of gliomas’ glutamine addiction and can be used to assess metabolic nutrient uptake in gliomas. A PET approach to brain tumors Positron emission tomography, or PET, is a common method of imaging tumors by detecting their uptake of a radioactively labeled tracer. Radiolabeled glucose, in particular, is often used for this type of imaging, because tumor cells are often highly dependent on glycolysis and require large amounts of glucose to maintain their metabolism. Unfortunately, this method cannot be used to image brain tumors, because regular brain cells are also highly dependent on glucose. Now, Venneti et al. have used mouse models and human patients to show that radiolabeled glutamine, which is also taken up by tumor cells, can be used to image brain tumors and distinguish them from normal brain and even from tumors that are no longer growing. Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (18F-FDG). However, 18F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analog 4-18F-(2S,4R)-fluoroglutamine (18F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced 18F-FGln tumor avidity, corresponding with decreased tumor burden. 18F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where 18F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that 18F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas.


Cancer Research | 2007

Visualization of hypoxia in microscopic tumors by immunofluorescent microscopy

Xiao-Feng Li; Sean Carlin; Muneyasu Urano; James A. Russell; C. Clifton Ling; Joseph A. O'Donoghue

Tumor hypoxia is commonly observed in primary solid malignancies but the hypoxic status of subclinical micrometastatic disease is largely unknown. The distribution of hypoxia in microscopic tumors was studied in animal models of disseminated peritoneal disease and intradermal (i.d.) growing tumors. Tumors derived from human colorectal adenocarcinoma cell lines HT29 and HCT-8 ranged in size from a few hundred microns to several millimeters in diameter. Hypoxia was detected by immunofluorescent visualization of pimonidazole and the hypoxia-regulated protein carbonic anhydrase 9. Tumor blood perfusion, cellular proliferation, and vascularity were visualized using Hoechst 33342, bromodeoxyuridine, and CD31 staining, respectively. In general, tumors of <1 mm diameter were intensely hypoxic, poorly perfused, and possessed little to no vasculature. Larger tumors (approximately 1-4 mm diameter) were well perfused with widespread vasculature and were not significantly hypoxic. Patterns of hypoxia in disseminated peritoneal tumors and i.d. tumors were similar. Levels of hypoxia in microscopic peritoneal tumors were reduced by carbogen breathing. Peritoneal and i.d. tumor models are suitable for studying hypoxia in microscopic tumors. If the patterns of tumor hypoxia in human patients are similar to those observed in these animal experiments, then the efficacy of systemic treatments of micrometastatic disease may be compromised by hypoxic resistance.


The Journal of Nuclear Medicine | 2011

Magnitude of Enhanced Permeability and Retention Effect in Tumors with Different Phenotypes: 89Zr-Albumin as a Model System

Carola Heneweer; Jason P. Holland; Vadim Divilov; Sean Carlin; Jason S. Lewis

Targeted nanoparticle-based technologies show increasing prevalence in radiotracer design. As a consequence, quantitative contribution of nonspecific accumulation in the target tissue, mainly governed by the enhanced permeability and retention (EPR) effect, becomes highly relevant for evaluating the specificity of these new agents. This study investigated the influence of different tumor phenotypes on the EPR effect, hypothesizing that a baseline level of uptake must be exceeded to visualize high and specific uptake of a targeted macromolecular radiotracer. Methods: These preliminary studies use 89Zr-labeled mouse serum albumin (89Zr-desferrioxamine-mAlb) as a model radiotracer to assess uptake and retention in 3 xenograft models of human prostate cancer (CWR22rv1, DU-145, and PC-3). Experiments include PET and contrast-enhanced ultrasound imaging to assess morphology, vascularization, and radiotracer uptake; temporal ex vivo biodistribution studies to quantify radiotracer uptake over time; and histologic and autoradiographic studies to evaluate the intra- and intertumoral distribution of 89Zr-desferrioxamine-mAlb. Results: Early uptake profiles show statistically significant but overall small differences in radiotracer uptake between different tumor phenotypes. By 20 h, nonspecific radiotracer uptake was found to be independent of tumor size and phenotype, reaching at least 5.0 percentage injected dose per gram in all 3 tumor models. Conclusion: These studies suggest that minimal differences in tumor uptake exist at early time points, dependent on the tumor type. However, these differences equalize over time, reaching around 5.0 percentage injected dose per gram at 20 h after injection. These data provide strong support for the introduction of mandatory experimental controls of future macromolecular or nanoparticle-based drugs, particularly regarding the development of targeted radiotracers.


The Journal of Nuclear Medicine | 2014

A Comparison of the Imaging Characteristics and Microregional Distribution of 4 Hypoxia PET Tracers

Sean Carlin; Hanwen Zhang; Megan Reese; Nicholas Ramos; Qing Chen; Sally-Ann Ricketts

We compared the imaging characteristics and hypoxia selectivity of 4 hypoxia PET radiotracers (18F-fluoromisonidazole [18F-FMISO], 18F-flortanidazole [18F-HX4], 18F-fluoroazomycin arabinoside [18F-FAZA], and 64Cu-diacetyl-bis(N4-methylsemicarbazone) [64Cu-ATSM]) in a single murine xenograft tumor model condition using small-animal PET imaging and combined ex vivo autoradiography and fluorescence immunohistochemistry. Methods: Nude mice bearing SQ20b xenograft tumors were administered 1 of 4 hypoxia PET tracers and images acquired 80–90 min after injection. Frozen sections from excised tumors were then evaluated for tracer distribution using digital autoradiography and compared with histologic markers of tumor hypoxia (pimonidazole, carbonic anydrase 9 [CA9]) and vascular perfusion (Hoechst 33342). Results: The highest tumor uptake was observed with 64Cu-ATSM (maximum standardized uptake values [SUVmax], 1.26 ± 0.13) and the lowest with 18F-FAZA (SUVmax, 0.41 ± 0.24). 18F-FMISO and 18F-HX4 had similar intermediate tumor uptake (SUVmax, 0.76 ± 0.38 and 0.65 ± 0.19, respectively). Digital autoradiographs of hypoxia tracer distribution were compared pixel by pixel with images of immunohistochemistry stains. The fluorinated nitroimidazoles all showed radiotracer uptake increasing with pimonidazole and CA9 staining. 64Cu-ATSM showed the opposite pattern, with highest radiotracer uptake observed in regions with the lowest pimonidazole and CA9 staining. Conclusion: The fluorinated nitroimidazoles showed similar tumor distributions when compared with immunohistochemistry markers of hypoxia. Variations in tumor standardized uptake value and normal tissue distribution may determine the most appropriate clinical setting for each tracer. 64Cu-ATSM showed the highest tumor accumulation and little renal clearance. However, the lack of correlation between 64Cu-ATSM distribution and immunohistochemistry hypoxia markers casts some doubt on the hypoxia selectivity of 64Cu-ATSM.


PLOS ONE | 2009

Real-Time Imaging of HIF-1α Stabilization and Degradation

Ekaterina Moroz; Sean Carlin; Katerina Dyomina; Sean Burke; Howard T. Thaler; Ronald G. Blasberg; Inna Serganova

HIF-1α is overexpressed in many human cancers compared to normal tissues due to the interaction of a multiplicity of factors and pathways that reflect specific genetic alterations and extracellular stimuli. We developed two HIF-1α chimeric reporter systems, HIF-1α/FLuc and HIF-1α(ΔODDD)/FLuc, to investigate the tightly controlled level of HIF-1α protein in normal (NIH3T3 and HEK293) and glioma (U87) cells. These reporter systems provided an opportunity to investigate the degradation of HIF-1α in different cell lines, both in culture and in xenografts. Using immunofluorescence microscopy, we observed different patterns of subcellular localization of HIF-1α/FLuc fusion protein between normal cells and cancer cells; similar differences were observed for HIF-1α in non-transduced, wild-type cells. A dynamic cytoplasmic-nuclear exchange of the fusion protein and HIF-1α was observed in NIH3T3 and HEK293 cells under different conditions (normoxia, CoCl2 treatment and hypoxia). In contrast, U87 cells showed a more persistent nuclear localization pattern that was less affected by different growing conditions. Employing a kinetic model for protein degradation, we were able to distinguish two components of HIF-1α/FLuc protein degradation and quantify the half-life of HIF-1α fusion proteins. The rapid clearance component (t1/2 ∼4–6 min) was abolished by the hypoxia-mimetic CoCl2, MG132 treatment and deletion of ODD domain, and reflects the oxygen/VHL-dependent degradation pathway. The slow clearance component (t1/2 ∼200 min) is consistent with other unidentified non-oxygen/VHL-dependent degradation pathways. Overall, the continuous bioluminescence readout of HIF-1α/FLuc stabilization in vitro and in vivo will facilitate the development and validation of therapeutics that affect the stability and accumulation of HIF-1α.


The Journal of Nuclear Medicine | 2013

Monitoring Afatinib Treatment in HER2-Positive Gastric Cancer with 18F-FDG and 89Zr-Trastuzumab PET

Yelena Y. Janjigian; Nerissa Viola-Villegas; Jason P. Holland; Vadim Divilov; Sean Carlin; Erica M. Gomes-DaGama; Gabriela Chiosis; Gregory Carbonetti; Elisa de Stanchina; Jason S. Lewis

We evaluated the ability of the PET imaging agent 89Zr-trastuzumab to delineate HER2-positive gastric cancer and to monitor the pharmacodynamic effects of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor afatinib. Methods: Using 89Zr-trastuzumab, 18F-FDG, or 3′-deoxy-3′-18F-fluorothymidine (18F-FLT PET), we imaged HER2-positive NCI-N87 and HER2-negative MKN74 gastric cancer xenografts in mice. Next, we examined the pharmacodynamic effects of afatinib in NCI-N87 xenografts using 89Zr-trastuzumab and 18F-FDG PET and comparing imaging results to changes in tumor size and in protein expression as monitored by Western blot and histologic studies. Results: Although 18F-FDG uptake in NCI-N87 tumors did not change, a decrease in 89Zr-trastuzumab uptake was observed in the afatinib-treated versus control groups (3.0 ± 0.0 percentage injected dose per gram (%ID/g) vs. 21.0 ± 3.4 %ID/g, respectively; P < 0.05). 89Zr-trastuzumab PET results corresponded with tumor reduction, apoptosis, and downregulation of HER2 observed on treatment with afatinib. Downregulation of total HER2, phosphorylated (p)-HER2, and p-EGFR occurred within 24 h of the first dose of afatinib, with a sustained effect over 21 d of treatment. Conclusion: Afatinib demonstrated antitumor activity in HER2-positive gastric cancer in vivo. 89Zr-trastuzumab PET specifically delineated HER2-positive gastric cancer and can be used to measure the pharmacodynamic effects of afatinib.


International Journal of Radiation Oncology Biology Physics | 2009

Immunohistochemical Detection of Changes in Tumor Hypoxia

James A. Russell; Sean Carlin; Sean Burke; Bixiu Wen; Kwang Mo Yang; C. Clifton Ling

PURPOSE Although hypoxia is a known prognostic factor, its effect will be modified by the rate of reoxygenation and the extent to which the cells are acutely hypoxic. We tested the ability of exogenous and endogenous markers to detect reoxygenation in a xenograft model. Our technique might be applicable to stored patient samples. METHODS AND MATERIALS The human colorectal carcinoma line, HT29, was grown in nude mice. Changes in tumor hypoxia were examined by injection of pimonidazole, followed 24 hours later by EF5. Cryosections were stained for these markers and for carbonic anhydrase IX (CAIX) and hypoxia-inducible factor 1alpha (HIF1alpha). Tumor hypoxia was artificially manipulated by carbogen exposure. RESULTS In unstressed tumors, all four markers showed very similar spatial distributions. After carbogen treatment, pimonidazole and EF5 could detect decreased hypoxia. HIF1alpha staining was also decreased relative to CAIX, although the effect was less pronounced than for EF5. Control tumors displayed small regions that had undergone spontaneous changes in tumor hypoxia, as judged by pimonidazole relative to EF5; most of these changes were reflected by CAIX and HIF1alpha. CONCLUSION HIF1alpha can be compared with either CAIX or a previously administered nitroimidazole to provide an estimate of reoxygenation.


Molecular Pharmaceutics | 2014

Noninvasive Imaging of PSMA in prostate tumors with (89)Zr-Labeled huJ591 engineered antibody fragments: the faster alternatives.

Nerissa Viola-Villegas; Kuntal K. Sevak; Sean Carlin; Michael G. Doran; Henry W. Evans; Derek Bartlett; Anna M. Wu; Jason S. Lewis

Engineered antibody fragments offer faster delivery with retained tumor specificity and rapid clearance from nontumor tissues. Here, we demonstrate that positron emission tomography (PET) based detection of prostate specific membrane antigen (PSMA) in prostatic tumor models using engineered bivalent antibodies built on single chain fragments (scFv) derived from the intact antibody, huJ591, offers similar tumor delineating properties but with the advantage of rapid targeting and imaging. 89Zr-radiolabeled huJ591 scFv (dimeric scFv-CH3; 89Zr-Mb) and cysteine diabodies (dimeric scFv; 89Zr-Cys-Db) demonstrated internalization and similar Kds (∼2 nM) compared to 89Zr-huJ591 in PSMA(+) cells. Tissue distribution assays established the specificities of both 89Zr-Mb and 89Zr-Cys-Db for PSMA(+) xenografts (6.2 ± 2.5% ID/g and 10.2 ± 3.4% ID/g at 12 h p.i. respectively), while minimal accumulation in PSMA(−) tumors was observed. From the PET images, 89Zr-Mb and 89Zr-Cys-Db exhibited faster blood clearance than the parent huJ591 while tumor-to-muscle ratios for all probes show comparable values across all time points. Ex vivo autoradiography and histology assessed the distribution of the probes within the tumor. Imaging PSMA-expressing prostate tumors with smaller antibody fragments offers rapid tumor accumulation and accelerated clearance; hence, shortened wait periods between tracer administration and high-contrast tumor imaging and lower dose-related toxicity are potentially realized.


The Journal of Nuclear Medicine | 2012

Image-Guided Po2 Probe Measurements Correlated with Parametric Images Derived from 18F-Fluoromisonidazole Small-Animal PET Data in Rats

Rachel Bartlett; Bradley J. Beattie; Naryanan M; Georgi Jc; Qing Chen; Sean Carlin; Roble G; Pat Zanzonico; Mithat Gonen; Joseph O'Donoghue; Fischer A; John L. Humm

18F-fluoromisonidazole PET, a noninvasive means of identifying hypoxia in tumors, has been widely applied but with mixed results, raising concerns about its accuracy. The objective of this study was to determine whether kinetic analysis of dynamic 18F-fluoromisonidazole data provides better discrimination of tumor hypoxia than methods based on a simple tissue-to-plasma ratio. Methods: Eleven Dunning R3327-AT prostate tumor-bearing nude rats were immobilized in custom-fabricated whole-body molds, injected intravenously with 18F-fluoromisonidazole, and imaged dynamically for 105 min. They were then transferred to a robotic system for image-guided measurement of intratumoral partial pressure of oxygen (Po2). The dynamic 18F-fluoromisonidazole uptake data were fitted with 2 variants of a 2-compartment, 3-rate-constant model, one constrained to have K1 equal to k2 and the other unconstrained. Parametric images of the rate constants were generated. The Po2 measurements were compared with spatially registered maps of kinetic rate constants and tumor-to-plasma ratios. Results: The constrained pharmacokinetic model variant was shown to provide fits similar to that of the unconstrained model and did not introduce significant bias in the results. The trapping rate constant, k3, of the constrained model provided a better discrimination of low Po2 than the tissue-to-plasma ratio or the k3 of the unconstrained model. Conclusion: The use of kinetic modeling on a voxelwise basis can identify tumor hypoxia with improved accuracy over simple tumor-to-plasma ratios. An effective means of controlling noise in the trapping rate constant, k3, without introducing significant bias, is to constrain K1 equal to k2 during the fitting process.

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Jason S. Lewis

Memorial Sloan Kettering Cancer Center

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John L. Humm

Memorial Sloan Kettering Cancer Center

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Pat Zanzonico

Memorial Sloan Kettering Cancer Center

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Hanwen Zhang

Memorial Sloan Kettering Cancer Center

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Jason A. Koutcher

Memorial Sloan Kettering Cancer Center

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C. Clifton Ling

Memorial Sloan Kettering Cancer Center

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Dalya Abdel-Atti

Memorial Sloan Kettering Cancer Center

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Ellen Ackerstaff

Memorial Sloan Kettering Cancer Center

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Heiko Schöder

Memorial Sloan Kettering Cancer Center

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Kuntal K. Sevak

Memorial Sloan Kettering Cancer Center

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