41 results on '"Larson, Steven M."'
Search Results
2. Pretargeting: A Path Forward for Radioimmunotherapy.
- Author
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Cheal SM, Chung SK, Vaughn BA, Cheung NV, and Larson SM
- Subjects
- Haptens, Humans, Radioimmunotherapy methods, Radioisotopes, Antibodies, Bispecific, Immunoconjugates therapeutic use, Neoplasms diagnostic imaging, Neoplasms drug therapy, Neoplasms radiotherapy
- Abstract
Pretargeted radioimmunodiagnosis and radioimmunotherapy aim to efficiently combine antitumor antibodies and medicinal radioisotopes for high-contrast imaging and high-therapeutic-index (TI) tumor targeting, respectively. As opposed to conventional radioimmunoconjugates, pretargeted approaches separate the tumor-targeting step from the payload step, thereby amplifying tumor uptake while reducing normal-tissue exposure. Alongside contrast and TI, critical parameters include antibody immunogenicity and specificity, availability of radioisotopes, and ease of use in the clinic. Each of the steps can be optimized separately; as modular systems, they can find broad applications irrespective of tumor target, tumor type, or radioisotopes. Although this versatility presents enormous opportunity, pretargeting is complex and presents unique challenges for clinical translation and optimal use in patients. The purpose of this article is to provide a brief historical perspective on the origins and development of pretargeting strategies in nuclear medicine, emphasizing 2 protein delivery systems that have been extensively evaluated (i.e., biotin-streptavidin and hapten-bispecific monoclonal antibodies), as well as radiohaptens and radioisotopes. We also highlight recent innovations, including pretargeting with bioorthogonal chemistry and novel protein vectors (such as self-assembling and disassembling proteins and Affibody molecules). We caution the reader that this is by no means a comprehensive review of the past 3 decades of pretargeted radioimmunodiagnosis and pretargeted radioimmunotherapy. But we do aim to highlight major developmental milestones and to identify benchmarks for success with regard to TI and toxicity in preclinical models and clinically. We believe this approach will lead to the identification of key obstacles to clinical success, revive interest in the utility of radiotheranostics applications, and guide development of the next generation of pretargeted theranostics., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)
- Published
- 2022
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3. A Self-Assembling and Disassembling (SADA) Bispecific Antibody (BsAb) Platform for Curative Two-step Pretargeted Radioimmunotherapy.
- Author
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Santich BH, Cheal SM, Ahmed M, McDevitt MR, Ouerfelli O, Yang G, Veach DR, Fung EK, Patel M, Burnes Vargas D, Malik AA, Guo HF, Zanzonico PB, Monette S, Michel AO, Rudin CM, Larson SM, and Cheung NK
- Subjects
- Animals, Humans, Mice, Mice, Nude, Molecular Targeted Therapy, Positron Emission Tomography Computed Tomography, Xenograft Model Antitumor Assays, Neoplasms radiotherapy, Radioimmunotherapy
- Abstract
Purpose: Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices. To overcome these challenges we developed a novel multimerization platform that rapidly removes tumor-targeting proteins from the blood to substantially improve therapeutic index., Experimental Design: The platform was designed as a fusion of a self-assembling and disassembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 × anti-DOTA). SADA-BsAbs were assessed with multiple in vivo tumor models using two-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry, and antitumor responses., Results: SADA-BsAbs self-assembled into stable tetramers (220 kDa), but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA-BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, two-step SADA-PRIT safely delivered massive doses of alpha-emitting (
225 Ac, 1.48 MBq/kg) or beta-emitting (177 Lu, 6,660 MBq/kg) S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver., Conclusions: The SADA-BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys, or liver. Because of its modularity, SADA-BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve therapeutic index and maximize the delivered dose. See related commentary by Capala and Kunos, p. 377 ., (©2020 American Association for Cancer Research.)- Published
- 2021
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4. First-in-Humans Trial of Dasatinib-Derivative Tracer for Tumor Kinase-Targeted PET.
- Author
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Krebs S, Veach DR, Carter LM, Grkovski M, Fornier M, Mauro MJ, Voss MH, Danila DC, Burnazi E, Null M, Staton K, Pressl C, Beattie BJ, Zanzonico P, Weber WA, Lyashchenko SK, Lewis JS, Larson SM, and Dunphy MPS
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Pilot Projects, Prospective Studies, Whole Body Imaging, Dasatinib analogs & derivatives, Fluorine Radioisotopes pharmacokinetics, Neoplasms diagnostic imaging, Positron Emission Tomography Computed Tomography methods, Protein-Tyrosine Kinases metabolism, Radiopharmaceuticals pharmacokinetics
- Abstract
We developed a first-of-kind dasatinib-derivative imaging agent,
18 F-SKI-249380 (1 8 F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using18 F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of18 F-SKI (mean, 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney ( n = 2) or three 10-min whole-body PET/CT scans ( n = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of18 F-SKI. In total, 27 tumor lesions were analyzed, with a median SUVpeak of 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 ± 0.81 min; plasma, 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 ± 148.49 min; plasma, 240 ± 84.85 min; n = 2) or a small rise to a plateau ( n = 2). Like dasatinib,18 F-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). Conclusion:18 F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2020
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5. First-in-Human Trial of Epichaperome-Targeted PET in Patients with Cancer.
- Author
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Dunphy MPS, Pressl C, Pillarsetty N, Grkovski M, Modi S, Jhaveri K, Norton L, Beattie BJ, Zanzonico PB, Zatorska D, Taldone T, Ochiana SO, Uddin MM, Burnazi EM, Lyashchenko SK, Hudis CA, Bromberg J, Schöder HM, Fox JJ, Zhang H, Chiosis G, Lewis JS, and Larson SM
- Subjects
- Adult, Aged, Benzodioxoles adverse effects, Cell Line, Tumor, Cell Proliferation drug effects, Female, Humans, Iodine Radioisotopes administration & dosage, Male, Middle Aged, Neoplasms genetics, Neoplasms pathology, Positron Emission Tomography Computed Tomography methods, Purines adverse effects, Tissue Distribution radiation effects, Benzodioxoles administration & dosage, HSP90 Heat-Shock Proteins genetics, Neoplasms diagnostic imaging, Neoplasms drug therapy, Purines administration & dosage
- Abstract
Purpose:
124 I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose124 I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging., Experimental Design: Adult patients with cancer ( n = 30) received124 I-PU-H71 tracer (201±12 MBq, <25 μg) intravenous bolus followed by PET/CT scans and blood radioassays., Results:124 I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas).124 I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects., Conclusions: Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using124 I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics., (©2020 American Association for Cancer Research.)- Published
- 2020
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6. Alpha radioimmunotherapy using 225 Ac-proteus-DOTA for solid tumors - safety at curative doses.
- Author
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Cheal SM, McDevitt MR, Santich BH, Patel M, Yang G, Fung EK, Veach DR, Bell M, Ahad A, Vargas DB, Punzalan B, Pillarsetty NVK, Xu H, Guo HF, Monette S, Michel AO, Piersigilli A, Scheinberg DA, Ouerfelli O, Cheung NV, and Larson SM
- Subjects
- Actinium administration & dosage, Actinium pharmacokinetics, Animals, Cell Line, Tumor, Dose-Response Relationship, Radiation, Female, Half-Life, Heterocyclic Compounds, 1-Ring administration & dosage, Heterocyclic Compounds, 1-Ring chemistry, Heterocyclic Compounds, 1-Ring pharmacokinetics, Humans, Indium Radioisotopes administration & dosage, Indium Radioisotopes pharmacokinetics, Mice, Nanoparticles administration & dosage, Nanoparticles chemistry, Neoplasms diagnosis, Neoplasms immunology, Neoplasms pathology, Radioimmunotherapy adverse effects, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Radiotherapy Dosage, Tissue Distribution, Toxicity Tests, Chronic, Xenograft Model Antitumor Assays, Alpha Particles therapeutic use, Neoplasms therapy, Radioimmunotherapy methods, Radiopharmaceuticals administration & dosage, Theranostic Nanomedicine methods
- Abstract
This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using
225 Ac and its theranostic pair,111 In. We call our novel tumor-targeting DOTA-hapten PRIT system "proteus-DOTA" or "Pr." Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Methods: Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that225 Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for177 Lu or90 Y, leading to poor tumor uptake in vivo . Therefore, we synthesized Pr consisting of an empty DOTA-chelate for225 Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with225 Ac and its imaging surrogate,111 In. In vitro studies verified anti-DOTA scFv recognition of [225 Ac]Pr, and in vivo biodistribution and clearance studies were performed to evaluate hapten suitability and in vivo targeting efficiency. Results: Intravenously (i.v.) administered225 Ac- or111 In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. In vivo pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [225 Ac]Pr and [111 In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [225 Ac]Pr alone or pretargeted [225 Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [225 Ac]Pr only ( P < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity. Conclusions: [225 Ac]Pr and its imaging biomarker [111 In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [225 Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [225 Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity., Competing Interests: Competing Interests: N.K.C reports receiving commercial research grants from Y-mAbs Therapeutics, Inc. in 2015 and Abpro-Labs, Inc. in 2017, holding ownership interest/equity in Y-mAbs Therapeutics and in Abpro-Labs, and owning stock options in Eureka Therapeutics, Inc. N.K.C is the inventor and owner of issued patents licensed by MSK to Y-mAbs Therapeutics, Biotec Pharmacon, and Abpro Labs. These include US patents 6451995, 7507724, 7704973, 7740845, 7666424, 9315585, and multiple pending patents. N.K.C is a scientific advisory board member of Abpro Labs and Eureka Therapeutics. N.K.C, S.M.L, and S.M.C were named as one of the inventors in the following patent applications relating to GPA33: SK2014-074, SK2015-091, SK2017-079, SK2018-045, SK2014-116, SK2016-052, and SK2018-068 filed by MSK. S.M.L reports receiving commercial research grants from Genentech, Inc., WILEX AG, Telix Pharmaceuticals Limited, and Regeneron Pharmaceuticals, Inc.; holding ownership interest/equity in Elucida Oncology, Inc. and Y-mAbs Therapeutics, and holding stock in ImaginAb, Inc. S.M.L is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samus Therapeutics, Inc., Elucida Oncology, Inc., and Y-mAbs Therapeutics, Inc. S.M.L serves or has served as a consultant to Cynvec LLC, Eli Lilly & Co., Prescient Therapeutics Limited, Advanced Innovative Partners, LLC, Gerson Lehrman Group, Progenics Pharmaceuticals, Inc., and Janssen Pharmaceuticals, Inc. G.Y and O.O are listed as inventors and receive royalties from patents that were filed by MSK. O.O is an unpaid member of the scientific advisory board of Angiogenex and owns shares in Angiogenex. B.H.S and N.K.C are inventors on US Patent No. 62/502,151. D.A.S is a consultant to, on the board of, and/or has equity in: PGNX, SLS, KLUS, IOVA, PFE, ATNM, Oncopep and Eureka Therapeutics. MSK has filed for patent protection on behalf of D.A.S for technology discussed in this paper. All other authors have no competing interests., (© The author(s).)- Published
- 2020
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7. Paradigms for Precision Medicine in Epichaperome Cancer Therapy.
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Pillarsetty N, Jhaveri K, Taldone T, Caldas-Lopes E, Punzalan B, Joshi S, Bolaender A, Uddin MM, Rodina A, Yan P, Ku A, Ku T, Shah SK, Lyashchenko S, Burnazi E, Wang T, Lecomte N, Janjigian Y, Younes A, Batlevi CW, Guzman ML, Roboz GJ, Koziorowski J, Zanzonico P, Alpaugh ML, Corben A, Modi S, Norton L, Larson SM, Lewis JS, Chiosis G, Gerecitano JF, and Dunphy MPS
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Cell Line, Tumor, Dose-Response Relationship, Drug, Drug Administration Schedule, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Molecular Chaperones metabolism, Molecular Imaging, Neoplasms diagnostic imaging, Neoplasms genetics, Neoplasms pathology, Precision Medicine methods, Protein Interaction Mapping methods, Protein Interaction Maps genetics, Theranostic Nanomedicine methods, Xenograft Model Antitumor Assays, Antineoplastic Agents administration & dosage, Molecular Chaperones antagonists & inhibitors, Neoplasms drug therapy, Protein Interaction Maps drug effects
- Abstract
Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients' tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection. We thus provide preclinical and clinical evidence in the use of this theranostic platform for precision medicine targeting of the aberrant properties of protein networks., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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8. ImmunoPET Imaging of Endogenous and Transfected Prolactin Receptor Tumor Xenografts.
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Cheal SM, Ruan S, Veach DR, Longo VA, Punzalan BJ, Wu J, Fung EK, Kelly MP, Kirshner JR, Giurleo JT, Ehrlich G, Han AQ, Thurston G, Olson WC, Zanzonico PB, Larson SM, and Carrasquillo JA
- Subjects
- Animals, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacokinetics, Cell Line, Tumor, Female, Humans, Immunoconjugates chemistry, Immunoconjugates immunology, Immunoconjugates pharmacokinetics, Mice, Mice, Nude, Molecular Imaging methods, Neoplasms pathology, Radiopharmaceuticals chemistry, Radiopharmaceuticals immunology, Radiopharmaceuticals pharmacokinetics, Receptors, Prolactin immunology, Receptors, Prolactin metabolism, Tissue Distribution, Xenograft Model Antitumor Assays, Antibodies, Monoclonal administration & dosage, Immunoconjugates administration & dosage, Neoplasms diagnostic imaging, Positron-Emission Tomography methods, Radiopharmaceuticals administration & dosage
- Abstract
Antibodies labeled with positron-emitting isotopes have been used for tumor detection, predicting which patients may respond to tumor antigen-directed therapy, and assessing pharmacodynamic effects of drug interventions. Prolactin receptor (PRLR) is overexpressed in breast and prostate cancers and is a new target for cancer therapy. We evaluated REGN2878, an anti-PRLR monoclonal antibody, as an immunoPET reagent. REGN2878 was labeled with Zr-89 after conjugation with desferrioxamine B or labeled with I-131/I-124. In vitro determination of the half-maximal inhibitory concentration (IC50) of parental REGN2878, DFO-REGN2878, and iodinated REGN2878 was performed by examining the effect of the increasing amounts of these on uptake of trace-labeled I-131 REGN2878. REGN1932, a non-PRLR binding antibody, was used as a control. Imaging and biodistribution studies were performed in mice bearing tumor xenografts with various expression levels of PRLR, including MCF-7, transfected MCF-7/PRLR, PC3, and transfected PC3/PRLR and T4D7v11 cell lines. The specificity of uptake in tumors was evaluated by comparing Zr-89 REGN2878 and REGN1932, and in vivo competition compared Zr-89 REGN2878 uptake in tumor xenografts with and without prior injection of 2 mg of nonradioactive REGN2878. The competition binding assay of DFO-REGN2878 at ratios of 3.53-5.77 DFO per antibody showed IC50 values of 0.4917 and 0.7136 nM, respectively, compared to 0.3455 nM for parental REGN2878 and 0.3343 nM for I-124 REGN2878. Imaging and biodistribution studies showed excellent targeting of Zr-89 REGN2878 in PRLR-positive xenografts at delayed times of 189 h (presented as mean ± 1 SD, percent injected activity per mL (%IA/mL) 74.6 ± 33.8%IA/mL). In contrast, MCF-7/PRLR tumor xenografts showed a low uptake (7.0 ± 2.3%IA/mL) of control Zr-89 REGN1932 and a very low uptake and rapid clearance of I-124 REGN2878 (1.4 ± 0.6%IA/mL). Zr-89 REGN2878 has excellent antigen-specific targeting in various PRLR tumor xenograft models. We estimated, using image-based kinetic modeling, that PRLR antigen has a very rapid in vivo turnover half-life of ∼14 min from the cell membrane. Despite relatively modest estimated tumor PRLR expression numbers, PRLR-expressing cells have shown final retention of the Zr-89 REGN2878 antibody, with an uptake that appeared to be related to PRLR expression. This reagent has the potential to be used in clinical trials targeting PRLR.
- Published
- 2018
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9. Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures.
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Graham NA, Minasyan A, Lomova A, Cass A, Balanis NG, Friedman M, Chan S, Zhao S, Delgado A, Go J, Beck L, Hurtz C, Ng C, Qiao R, Ten Hoeve J, Palaskas N, Wu H, Müschen M, Multani AS, Port E, Larson SM, Schultz N, Braas D, Christofk HR, Mellinghoff IK, and Graeber TG
- Subjects
- Cell Line, Tumor, Evolution, Molecular, Gene Amplification, Gene Deletion, Gene Expression Regulation, Neoplastic, Genomic Instability, Humans, Metabolic Networks and Pathways, Principal Component Analysis, Selection, Genetic, DNA Copy Number Variations, Gene Expression Profiling methods, Glycolysis, Neoplasms genetics
- Abstract
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including
18 F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)- Published
- 2017
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10. The epichaperome is an integrated chaperome network that facilitates tumour survival.
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Rodina A, Wang T, Yan P, Gomes ED, Dunphy MP, Pillarsetty N, Koren J, Gerecitano JF, Taldone T, Zong H, Caldas-Lopes E, Alpaugh M, Corben A, Riolo M, Beattie B, Pressl C, Peter RI, Xu C, Trondl R, Patel HJ, Shimizu F, Bolaender A, Yang C, Panchal P, Farooq MF, Kishinevsky S, Modi S, Lin O, Chu F, Patil S, Erdjument-Bromage H, Zanzonico P, Hudis C, Studer L, Roboz GJ, Cesarman E, Cerchietti L, Levine R, Melnick A, Larson SM, Lewis JS, Guzman ML, and Chiosis G
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Drug Discovery, Female, Genes, myc genetics, HSP70 Heat-Shock Proteins metabolism, HSP90 Heat-Shock Proteins metabolism, Humans, Mice, Molecular Chaperones antagonists & inhibitors, Multiprotein Complexes antagonists & inhibitors, Multiprotein Complexes chemistry, Neoplasms drug therapy, Neoplasms genetics, Organ Specificity, Molecular Chaperones metabolism, Multiprotein Complexes metabolism, Neoplasms metabolism, Neoplasms pathology
- Abstract
Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention., Competing Interests: The authors declare competing financial interests: details are available in the online version of the paper. Readers are welcome to comment on the online version of the paper
- Published
- 2016
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11. Humanized Affinity-matured Monoclonal Antibody 8H9 Has Potent Antitumor Activity and Binds to FG Loop of Tumor Antigen B7-H3.
- Author
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Ahmed M, Cheng M, Zhao Q, Goldgur Y, Cheal SM, Guo HF, Larson SM, and Cheung NK
- Subjects
- Amino Acid Sequence, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal, Murine-Derived, Cell Line, Tumor, Crystallography, X-Ray, Humans, Molecular Sequence Data, Neoplasms immunology, Sequence Homology, Amino Acid, Antibodies, Monoclonal immunology, B7 Antigens immunology, Neoplasms therapy
- Abstract
B7-H3 (CD276) is both an inhibitory ligand for natural killer cells and T cells and a tumor antigen that is widely expressed among human solid tumors. Anti-B7-H3 mouse monoclonal antibody 8H9 has been successfully used for radioimmunotherapy for patients with B7-H3(+) tumors. We present the humanization, affinity maturation, and epitope mapping of 8H9 based on structure determination, modeling, and yeast display methods. The crystal structure of ch8H9 Fab fragment was solved to 2.5-Å resolution and used as a template for humanization. By displaying the humanized 8H9 single chain Fv (scFv) on the surface of yeast, the affinity was matured by sequential random mutagenesis and fluorescence-activated cell sorting. Six mutations (three in the complementarity-determining region and three in the framework regions) were identified and incorporated into an affinity-matured humanized 8H9 construct (hu8H9-6m) and an affinity-matured chimeric 8H9 construct (ch8H9-6m). The hu8H9-6m scFv had a 160-fold improvement in affinity (0.9 nm KD) compared with parental hu8H9 scFv (144 nm KD). The IgG formats of ch8H9-6m and hu8H9-6m (nanomolar to subnanomolar KD) had 2-9-fold enhancements in affinity compared with their parental forms, potent in vitro antibody-dependent cell-mediated cytotoxicity (0.1-0.3 μg/ml EC50), and high tumor uptake in mouse xenografts. Based on in silico docking studies and experimental validation, the molecular epitope of 8H9 was determined to be dependent on the FG loop of B7-H3, a region critical to its function in immunologic blockade and unique among anti-B7-H3 antibodies published to date., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2015
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12. Radioimmunotherapy of human tumours.
- Author
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Larson SM, Carrasquillo JA, Cheung NK, and Press OW
- Subjects
- Actinium administration & dosage, Actinium therapeutic use, Alpha Particles therapeutic use, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal pharmacology, Clinical Trials as Topic, Hematologic Neoplasms radiotherapy, Humans, Molecular Targeted Therapy methods, Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types.
- Published
- 2015
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13. Bone-seeking radiopharmaceuticals for treatment of osseous metastases, Part 1: α therapy with 223Ra-dichloride.
- Author
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Pandit-Taskar N, Larson SM, and Carrasquillo JA
- Subjects
- Alpha Particles, Animals, Bone Neoplasms secondary, Humans, Neoplasm Metastasis, Neoplasms pathology, Organometallic Compounds therapeutic use, Organophosphorus Compounds therapeutic use, Pain Management, Radioisotopes therapeutic use, Radiometry methods, Strontium therapeutic use, Antineoplastic Agents therapeutic use, Bone Neoplasms radiotherapy, Neoplasms radiotherapy, Radiopharmaceuticals therapeutic use, Radium therapeutic use
- Abstract
Metastatic disease to bone is commonly seen in the advanced stages of many cancers. The cardinal symptom, pain, is often the cause of significant morbidity and reduced quality of life. Treatment of bone pain includes nonsteroidal analgesics and opiates; however, long-term use of these drugs is commonly associated with significant side effects, and tolerance is common. External-beam radiation therapy is effective mainly in localized disease sites. Bone-targeting radiopharmaceuticals are beneficial in the management of patients with multiple metastatic lesions. This article focuses on the 3 most commonly used agents: the Food and Drug Administration-approved (89)Sr-chloride, (153)Sm-ethylenediaminetetramethylene phosphonic acid (EDTMP), and (223)Ra-dichloride. We will discuss the physical characteristics, clinical data, dosage, and administration of these agents, including optimal patient selection and toxicity associated with their use. These radioactive agents have proven efficacy in the treatment of painful osseous metastases from prostate cancer and breast cancer. Significant recent advances include use of these agents in combination with chemotherapy and the use of the α emitter (223)Ra-dichloride in prostate cancer, primarily to improve survival and skeletal related events. The review is presented in 2 parts. The first will discuss the characteristics and clinical use of (223)Ra-dichloride, and the second will discuss the β emitters (89)Sr and (153)Sm-EDTMP.
- Published
- 2014
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14. Split-dose technique for FDG PET/CT-guided percutaneous ablation: a method to facilitate lesion targeting and to provide immediate assessment of treatment effectiveness.
- Author
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Ryan ER, Sofocleous CT, Schöder H, Carrasquillo JA, Nehmeh S, Larson SM, Thornton R, Siegelbaum RH, Erinjeri JP, and Solomon SB
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Fluorodeoxyglucose F18, Humans, Male, Middle Aged, Radiopharmaceuticals, Retrospective Studies, Catheter Ablation methods, Multimodal Imaging, Neoplasms diagnostic imaging, Neoplasms surgery, Positron-Emission Tomography, Tomography, X-Ray Computed
- Abstract
Purpose: To describe a split-dose technique for fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-guided ablation that permits both target localization and evaluation of treatment effectiveness., Materials and Methods: Institutional review board approved the study with a waiver of consent. From July to December 2011, 23 patients (13 women, 10 men; mean age, 59 years; range, 35-87 years) with 29 FDG-avid tumors (median size, 1.4 cm; range, 0.6-4.4 cm) were targeted for ablation. The location of the lesion was the liver (n = 23), lung (n = 4), adrenal gland (n = 1), and thigh (n = 1). Radiofrequency ablation was performed in 17 lesions; microwave ablation, in six; irreversible electroporation, in five; and cryoablation, in one. The pathologic condition of the tumor was metastatic colorectal adenocarcinoma in 18 lesions, primary hepatocellular carcinoma in one lesion, and a variety of metastatic tumors in the remaining 10 lesions. A total of 4 mCi (148 MBq) of FDG was administered before the procedure for localization and imaging guidance. At completion of the ablation, an additional 8 mCi (296 MBq) of FDG was administered to assess ablation adequacy. Results of subsequent imaging follow-up were used to determine if postablation imaging after the second dose of FDG reliably helped predict complete tumor ablation. Descriptive statistics were used to summarize the results., Results: Twenty-eight of 29 (97%) ablated lesions showed no residual FDG activity after the second intraprocedural FDG dose. One patient with residual activity underwent immediate biopsy that revealed residual viable tumor and was immediately re-treated. Follow-up imaging at a median of 155 days (range, 92-257 days) after ablation showed local recurrences in two (7%) lesions that were originally negative at postablation PET., Conclusion: Split-dose FDG PET/CT may be a useful tool to provide both guidance and endpoint evaluation, allowing an opportunity for repeat intervention if necessary. Further work is necessary to validate these concepts.
- Published
- 2013
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15. A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors.
- Author
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Iyer G, Morris MJ, Rathkopf D, Slovin SF, Steers M, Larson SM, Schwartz LH, Curley T, DeLaCruz A, Ye Q, Heller G, Egorin MJ, Ivy SP, Rosen N, Scher HI, and Solit DB
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Benzoquinones administration & dosage, Benzoquinones adverse effects, Docetaxel, Drug Administration Schedule, Female, Humans, Lactams, Macrocyclic administration & dosage, Lactams, Macrocyclic adverse effects, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms metabolism, Neoplasms pathology, Taxoids administration & dosage, Taxoids adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, HSP90 Heat-Shock Proteins antagonists & inhibitors, Neoplasms drug therapy
- Abstract
Purpose: To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies., Experimental Design: Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m(2). 17-AAG was administered over 1-2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m(2) in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot., Results: Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m(2)-17-AAG 650 mg/m(2) due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed., Conclusions: The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m(2) and 17-AAG 500 mg/m(2).
- Published
- 2012
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16. Molecular imaging for personalized cancer care.
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Kircher MF, Hricak H, and Larson SM
- Subjects
- Humans, Neoplasm Staging, Neoplasms pathology, Neoplasms therapy, Molecular Imaging, Neoplasms diagnosis, Precision Medicine
- Abstract
Molecular imaging is rapidly gaining recognition as a tool with the capacity to improve every facet of cancer care. Molecular imaging in oncology can be defined as in vivo characterization and measurement of the key biomolecules and molecularly based events that are fundamental to the malignant state. This article outlines the basic principles of molecular imaging as applied in oncology with both established and emerging techniques. It provides examples of the advantages that current molecular imaging techniques offer for improving clinical cancer care as well as drug development. It also discusses the importance of molecular imaging for the emerging field of theranostics and offers a vision of how molecular imaging may one day be integrated with other diagnostic techniques to dramatically increase the efficiency and effectiveness of cancer care., (Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
- Published
- 2012
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17. Oncology.
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Larson SM
- Subjects
- Biomarkers, Tumor metabolism, Fluorodeoxyglucose F18, Humans, Molecular Imaging, Molecular Probes metabolism, Molecular Targeted Therapy, Multimodal Imaging, Positron-Emission Tomography, Radioimmunotherapy, Tomography, X-Ray Computed, Neoplasms diagnostic imaging, Neoplasms metabolism, Neoplasms radiotherapy
- Published
- 2011
18. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90.
- Author
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Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DaGama EM, Caldas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, and Chiosis G
- Subjects
- Animals, Antineoplastic Agents pharmacology, Benzodioxoles pharmacology, Cell Line, Tumor, Computational Biology, Drug Discovery, Gene Expression Regulation, Neoplastic drug effects, HSP90 Heat-Shock Proteins genetics, Humans, Neoplasms genetics, Purines pharmacology, Signal Transduction, Gene Expression Regulation, Neoplastic physiology, HSP90 Heat-Shock Proteins metabolism, Neoplasms metabolism, Proteomics methods
- Abstract
Most cancers are characterized by multiple molecular alterations, but identification of the key proteins involved in these signaling pathways is currently beyond reach. We show that the inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes and affinity captures Hsp90-dependent oncogenic client proteins. We have used PU-H71 affinity capture to design a proteomic approach that, when combined with bioinformatic pathway analysis, identifies dysregulated signaling networks and key oncoproteins in chronic myeloid leukemia. The identified interactome overlaps with the well-characterized altered proteome in this cancer, indicating that this method can provide global insights into the biology of individual tumors, including primary patient specimens. In addition, we show that this approach can be used to identify previously uncharacterized oncoproteins and mechanisms, potentially leading to new targeted therapies. We further show that the abundance of the PU-H71-enriched Hsp90 species, which is not dictated by Hsp90 expression alone, is predictive of the cell's sensitivity to Hsp90 inhibition.
- Published
- 2011
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19. Optimizing tumor targeting of the lipophilic EGFR-binding radiotracer SKI 243 using a liposomal nanoparticle delivery system.
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Medina OP, Pillarsetty N, Glekas A, Punzalan B, Longo V, Gönen M, Zanzonico P, Smith-Jones P, and Larson SM
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Cell Line, Tumor, Humans, Liposomes, Mice, Mice, Nude, Neoplasms drug therapy, Radiopharmaceuticals pharmacokinetics, Antineoplastic Agents administration & dosage, ErbB Receptors antagonists & inhibitors, ErbB Receptors metabolism, Neoplasms diagnostic imaging, Positron-Emission Tomography, Radiopharmaceuticals administration & dosage
- Abstract
Positron emission tomography (PET) of epidermal growth factor receptor (EGFR) kinase-specific radiolabeled tracers could provide a means for non-invasively characterizing EGFR expression and signaling activity in patients' tumors before, during, and after therapy with EGFR inhibitors. Towards this goal, our group has developed PET tracers which irreversibly bind to EGFR. However, tumor uptake is relatively low because of both the lipophilicity of such tracers (e.g. the morpholino-[124I]-IPQA [SKI 212243]), with octanol-to-water partition coefficients of up to 4, and a short dwell time in the blood and significant hepatobiliary clearance and intestinal reuptake. Liposomal nanoparticle delivery systems may favorably alter the pharmacokinetic profile and improve tumor targeting of highly lipophilic but otherwise promising cancer imaging tracers, such as the EGFR inhibitor SKI 243. SKI 243 is therefore an interesting model molecule for incorporation into lipid-based nanoparticles, as it would not only improve their solubility but also increase the circulation time, availability and, potentially, targeting of tumors. In the current study, we compared the pharmacokinetics and tumor targeting of the bare EGFR kinase-targeting radiotracer SKI 212243 (SKI 243) with that of the same tracer embedded in liposomes. SKI 243 and liposomal SKI 243 are both taken up by tumor xenografts but liposomal SKI 243 remained in the blood longer and consequently exhibited a 3- to 6-fold increase in uptake in the tumor among several other organs., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2011
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20. Oncology.
- Author
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Larson SM
- Subjects
- Adult, Animals, Diagnostic Imaging, Female, Humans, Male, Mice, Middle Aged, Nuclear Medicine, Medical Oncology statistics & numerical data, Medical Oncology trends, Neoplasms diagnosis, Neoplasms pathology, Neoplasms physiopathology, Neoplasms therapy
- Published
- 2010
21. Doctor, what does my future hold? The prognostic value of FDG-PET in solid tumours.
- Author
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Lucignani G and Larson SM
- Subjects
- Humans, Neoplasms diagnostic imaging, Neoplasms therapy, Prognosis, Survival Analysis, Fluorodeoxyglucose F18, Neoplasms diagnosis, Positron-Emission Tomography
- Published
- 2010
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22. (124)I-iodopyridopyrimidinone for PET of Abl kinase-expressing tumors in vivo.
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Doubrovin M, Kochetkova T, Santos E, Veach DR, Smith-Jones P, Pillarsetty N, Balatoni J, Bornmann W, Gelovani J, and Larson SM
- Subjects
- Binding, Competitive drug effects, Blotting, Western, Cell Line, Tumor, Humans, Isotope Labeling, K562 Cells, Positron-Emission Tomography, Protein Binding, RNA, Small Interfering, Enzyme Inhibitors pharmacokinetics, Neoplasms diagnostic imaging, Neoplasms enzymology, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases metabolism, Pyridones pharmacokinetics, Pyrimidines pharmacokinetics, Radiopharmaceuticals pharmacokinetics
- Abstract
Unlabelled: Because of the recent development of an iodopyridopyrimidinone Abl protein kinase inhibitor (PKI), (124)I-SKI-212230 ((124)I-SKI230), we investigated the feasibility of a PET-based molecular imaging method for the direct visualization of Abl kinase expression and PKI treatment., Methods: In vitro pharmacokinetic properties, including specific and nonspecific binding of (124)I-SKI230 to its Abl kinase target and interaction with other PKIs, were assessed in cell-free medium and chronic myelogenous leukemia (CML) cells overexpressing BCR-Abl (K562), in comparison with BT-474 cells that are low in Abl expression. In a xenograft tumor model, we assessed the in vivo pharmacokinetics of (124)I-SKI230 using PET and postmortem tissue sampling. We also tested a paradigm of (124)I-SKI230 PET after treatment of the animal with a dose of Abl-specific PKI for the monitoring of the tumor response., Results: In vitro studies confirmed that SKI230 binds to Abl kinase with nanomolar affinity, that selective uptake occurs in cell lines known to express Abl kinase, that RNAi knock-down supports specificity of cellular uptake due to Abl kinase, and that imatinib, an archetype Abl PKI, completely displaces SKI230. With SKI230, we obtained successful in vivo PET of Abl-expressing human tumors in a nude rat. We were also able to demonstrate evidence of substrate inhibition of in vivo radiotracer uptake in the xenograft tumor after treatment of the animal as a model of PKI treatment monitoring., Conclusion: These results support the hypothesis that molecular imaging using PET will be useful for the study of in vivo pharmacodynamics of Abl PKI molecular therapy in humans.
- Published
- 2010
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23. Practice-based evidence of the beneficial impact of positron emission tomography in clinical oncology.
- Author
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Larson SM
- Subjects
- Benchmarking, Centers for Medicare and Medicaid Services, U.S., Cooperative Behavior, Evidence-Based Medicine, Humans, Insurance, Health, Reimbursement, Interdisciplinary Communication, Medicare, Neoplasm Staging, Neoplasms therapy, Odds Ratio, Registries, Surveys and Questionnaires, United States, Neoplasms diagnostic imaging, Outcome and Process Assessment, Health Care, Patient Care Planning, Patient Selection, Positron-Emission Tomography, Tomography, X-Ray Computed
- Published
- 2008
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24. Improved tumor imaging and therapy via i.v. IgG-mediated time-sequential modulation of neonatal Fc receptor.
- Author
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Jaggi JS, Carrasquillo JA, Seshan SV, Zanzonico P, Henke E, Nagel A, Schwartz J, Beattie B, Kappel BJ, Chattopadhyay D, Xiao J, Sgouros G, Larson SM, and Scheinberg DA
- Subjects
- Actinium chemistry, Animals, Female, Humans, Immunoglobulin G administration & dosage, Immunoglobulin G adverse effects, Immunotherapy, Indium Radioisotopes chemistry, Injections, Intravenous, Iodine Radioisotopes, Mice, Neoplasms immunology, Neoplasms metabolism, Positron-Emission Tomography, Time Factors, Histocompatibility Antigens Class I metabolism, Immunoglobulin G immunology, Immunoglobulin G therapeutic use, Neoplasms pathology, Neoplasms therapy, Receptors, Fc metabolism
- Abstract
The long plasma half-life of IgG, while allowing for enhanced tumor uptake of tumor-targeted IgG conjugates, also results in increased background activity and normal-tissue toxicity. Therefore, successful therapeutic uses of conjugated antibodies have been limited to the highly sensitive and readily accessible hematopoietic tumors. We report a therapeutic strategy to beneficially alter the pharmacokinetics of IgG antibodies via pharmacological inhibition of the neonatal Fc receptor (FcRn) using high-dose IgG therapy. IgG-treated mice displayed enhanced blood and whole-body clearance of radioactivity, resulting in better tumor-to-blood image contrast and protection of normal tissue from radiation. Tumor uptake and the resultant therapeutic response was unaltered. Furthermore, we demonstrated the use of this approach for imaging of tumors in humans and discuss its potential applications in cancer imaging and therapy. The ability to reduce the serum persistence of conjugated IgG antibodies after their infusion can enhance their therapeutic index, resulting in improved therapeutic and diagnostic efficacy.
- Published
- 2007
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25. NCCN task force report: positron emission tomography (PET)/computed tomography (CT) scanning in cancer.
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Podoloff DA, Advani RH, Allred C, Benson AB 3rd, Brown E, Burstein HJ, Carlson RW, Coleman RE, Czuczman MS, Delbeke D, Edge SB, Ettinger DS, Grannis FW Jr, Hillner BE, Hoffman JM, Kiel K, Komaki R, Larson SM, Mankoff DA, Rosenzweig KE, Skibber JM, Yahalom J, Yu JM, and Zelenetz AD
- Subjects
- Breast Neoplasms diagnosis, Breast Neoplasms therapy, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung therapy, Colorectal Neoplasms diagnosis, Colorectal Neoplasms therapy, Fluorodeoxyglucose F18, Humans, Lymphoma diagnosis, Lymphoma pathology, Lymphoma therapy, Neoplasm Staging, Prognosis, Neoplasms diagnosis, Positron-Emission Tomography, Tomography, X-Ray Computed
- Abstract
The use of positron emission tomography (PET) is increasing rapidly in the United States, with the most common use of PET scanning related to oncology. It is especially useful in the staging and management of lymphoma, lung cancer, and colorectal cancer, according to a panel of expert radiologists, surgeons, radiation oncologists, nuclear medicine physicians, medical oncologists, and general internists convened in November 2006 by the National Comprehensive Cancer Network. The Task Force was charged with reviewing existing data and developing clinical recommendations for the use of PET scans in the evaluation and management of breast cancer, colon cancer, non-small cell lung cancer, and lymphoma. This report summarizes the proceedings of this meeting, including discussions of the background of PET, possible future developments, and the role of PET in oncology.
- Published
- 2007
26. Molecular targeting of the lymphovascular system for imaging and therapy.
- Author
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Schöder H, Glass EC, Pecking AP, Harness JK, Wallace AM, Hirnle P, Alberini JL, Vilain D, Larson SM, Hoh CK, and Vera DR
- Subjects
- Animals, Clinical Trials, Phase I as Topic, Glucose-6-Phosphate analogs & derivatives, Humans, Lymph Nodes diagnostic imaging, Lymph Nodes drug effects, Lymph Nodes pathology, Lymph Nodes surgery, Lymphatic System diagnostic imaging, Lymphography, Lymphoscintigraphy, Positron-Emission Tomography methods, Tomography, Emission-Computed, Single-Photon methods, Ultrasonography, Diagnostic Imaging methods, Lymphatic Metastasis diagnosis, Lymphatic System pathology, Neoplasms diagnosis, Neoplasms therapy
- Abstract
Progress toward targeting cancer cells is a multi-disciplinary endeavor. In addition to the surgical and oncology specialties, radiologists collaborate with mathematicians, computer scientists, and physicists, in a constant effort to incrementally improve upon the current imaging modalities. Recently, radiologists have formed collaborations with molecular biologists and chemists in order to develop molecular agents that target cancer cells via receptor-substrate or specific physiochemical interactions. In this review, we summarize selected efforts toward molecular targeting of the lymphovascular system. Standard imaging modalities, positron emission tomography, single photon emission tomography, and ultrasound, are reviewed as well as, the targeted introduction of substances for endolymphatic therapy. We also review the current status of sentinel lymph node mapping with radiocolloids and the application of molecular targeting for the development of a radiopharmaceutical specifically designed for sentinel lymph node mapping.
- Published
- 2006
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27. 18F-FDG PET as a candidate for "qualified biomarker": functional assessment of treatment response in oncology.
- Author
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Larson SM and Schwartz LH
- Subjects
- Biomarkers, Tumor analysis, Humans, Practice Patterns, Physicians' standards, Prognosis, Radiopharmaceuticals, Treatment Outcome, United States, Fluorodeoxyglucose F18, Neoplasms diagnostic imaging, Neoplasms therapy, Outcome Assessment, Health Care methods, Positron-Emission Tomography methods, Positron-Emission Tomography standards, Practice Guidelines as Topic
- Published
- 2006
28. The progress and promise of molecular imaging probes in oncologic drug development.
- Author
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Kelloff GJ, Krohn KA, Larson SM, Weissleder R, Mankoff DA, Hoffman JM, Link JM, Guyton KZ, Eckelman WC, Scher HI, O'Shaughnessy J, Cheson BD, Sigman CC, Tatum JL, Mills GQ, Sullivan DC, and Woodcock J
- Subjects
- Diagnostic Imaging trends, Humans, Neoplasms diagnosis, Technology, Pharmaceutical methods, Technology, Pharmaceutical trends, Antineoplastic Agents therapeutic use, Diagnostic Imaging methods, Drug Design, Neoplasms drug therapy, Radiopharmaceuticals
- Abstract
As addressed by the recent Food and Drug Administration Critical Path Initiative, tools are urgently needed to increase the speed, efficiency, and cost-effectiveness of drug development for cancer and other diseases. Molecular imaging probes developed based on recent scientific advances have great potential as oncologic drug development tools. Basic science studies using molecular imaging probes can help to identify and characterize disease-specific targets for oncologic drug therapy. Imaging end points, based on these disease-specific biomarkers, hold great promise to better define, stratify, and enrich study groups and to provide direct biological measures of response. Imaging-based biomarkers also have promise for speeding drug evaluation by supplementing or replacing preclinical and clinical pharmacokinetic and pharmacodynamic evaluations, including target interaction and modulation. Such analyses may be particularly valuable in early comparative studies among candidates designed to interact with the same molecular target. Finally, as response biomarkers, imaging end points that characterize tumor vitality, growth, or apoptosis can also serve as early surrogates of therapy success. This article outlines the scientific basis of oncology imaging probes and presents examples of probes that could facilitate progress. The current regulatory opportunities for new and existing probe development and testing are also reviewed, with a focus on recent Food and Drug Administration guidance to facilitate early clinical development of promising probes.
- Published
- 2005
- Full Text
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29. JNM supplement on molecular radiotherapy.
- Author
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Wong CO, Pandit-Taskar N, and Larson SM
- Subjects
- Drug Approval, Humans, Microspheres, Radiopharmaceuticals therapeutic use, Drug Delivery Systems methods, Drug Delivery Systems trends, Molecular Biology methods, Molecular Biology trends, Neoplasms radiotherapy, Radioimmunotherapy methods, Radioimmunotherapy trends, Yttrium Radioisotopes therapeutic use
- Published
- 2005
30. CT in PET/CT: essential features of interpretation.
- Author
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Schöder H, Yeung HW, and Larson SM
- Subjects
- Clinical Trials as Topic, Humans, Incidental Findings, Observer Variation, Quality Assurance, Health Care methods, Reproducibility of Results, Sensitivity and Specificity, Image Enhancement methods, Image Interpretation, Computer-Assisted methods, Neoplasms diagnosis, Positron-Emission Tomography methods, Subtraction Technique, Tomography, X-Ray Computed methods
- Published
- 2005
31. Dependence of FDG uptake on tumor microenvironment.
- Author
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Pugachev A, Ruan S, Carlin S, Larson SM, Campa J, Ling CC, and Humm JL
- Subjects
- Animals, Autoradiography, Benzimidazoles pharmacokinetics, Bromodeoxyuridine pharmacokinetics, Coloring Agents pharmacokinetics, Glucose metabolism, Male, Mice, Mice, Nude, Neoplasms blood supply, Neoplasms pathology, Nitroimidazoles pharmacokinetics, Prostatic Neoplasms blood supply, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Cell Hypoxia, Cell Proliferation, Fluorodeoxyglucose F18 pharmacokinetics, Neoplasms metabolism, Radiopharmaceuticals pharmacokinetics
- Abstract
Purpose: To investigate the factors affecting the (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in tumors at a microscopic level, by correlating it with tumor hypoxia, cellular proliferation, and blood perfusion., Methods and Materials: Nude mice bearing Dunning prostate tumors (R3327-AT) were injected with (18)F-FDG and pimonidazole, bromodeoxyuridine, and, 1 min before sacrifice, with Hoechst 33342. Selected tumor sections were imaged by phosphor plate autoradiography, while adjacent sections were used to obtain the images of the spatial distribution of Hoechst 33342, pimonidazole, and bromodeoxyuridine. The images were co-registered and analyzed on a pixel-by-pixel basis., Results: Statistical analysis of the data obtained from these tumors demonstrated that (18)F-FDG uptake was positively correlated with pimonidazole staining intensity in each data set studied. Correlation of FDG uptake with bromodeoxyuridine staining intensity was always negative. In addition, FDG uptake was always negatively correlated with the staining intensity of Hoechst 33342., Conclusions: For the Dunning prostate tumors studied, FDG uptake was always positively correlated with hypoxia and negatively correlated with both cellular proliferation and blood flow. Therefore, for the tumor model studied, higher FDG uptake is indicative of tumor hypoxia, but neither blood flow nor cellular proliferation.
- Published
- 2005
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32. Clinical value of combined positron emission tomography/computed tomography imaging in the interpretation of 2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography studies in cancer patients.
- Author
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Yeung HW, Schöder H, Smith A, Gonen M, and Larson SM
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Humans, Male, Middle Aged, Neoplasms pathology, Tomography, X-Ray Computed, Fluorodeoxyglucose F18, Neoplasms diagnostic imaging, Positron-Emission Tomography
- Abstract
Background: Positron emission tomography (PET)/computed tomography (CT) is a new imaging modality that provides exact coregistration of anatomic and metabolic data. We have investigated to what degree this new technique might affect the interpretation of PET images in a nonselected group of consecutive cancer patients, reflecting routine condition in a busy cancer center., Methods: Whole-body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-PET and PET/CT fusion image sets were compared in 100 consecutive, nonselected patients: 21 with head and neck cancer, 39 with chest malignancies, and 40 with malignancies of the abdomen and pelvis. All studies were performed for primary staging or evaluation of therapy and were interpreted by two nuclear medicine physicians also trained in radiology. Areas of abnormal FDG uptake were identified on PET and graded as likely benign, equivocal, or likely malignant. Positron emission tomography/computed tomography fusion images were then made available, and the initial findings were amended if necessary., Results: One hundred sixty-six areas with abnormal FDG uptake were identified. Based on PET alone, 51 sites were considered equivocal for malignancy. With PET/CT, the number of equivocal lesions decreased to 24. This difference is more marked in the head and neck as well as the abdomen and pelvis. When the equivocal sites were included in the analysis and grouped with the malignant sites, positive predictive value (PPV) of PET/CT was 89% compared with 75% for PET (p = 0.04)., Conclusion: Combined PET/CT results in increased reader confidence and 53% fewer equivocal readings, as well as improved PPV compared with PET alone.
- Published
- 2005
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33. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development.
- Author
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Kelloff GJ, Hoffman JM, Johnson B, Scher HI, Siegel BA, Cheng EY, Cheson BD, O'shaughnessy J, Guyton KZ, Mankoff DA, Shankar L, Larson SM, Sigman CC, Schilsky RL, and Sullivan DC
- Subjects
- Neoplasm Staging, Neoplasms diagnosis, Neoplasms drug therapy, Reproducibility of Results, Sensitivity and Specificity, Survival Analysis, Fluorodeoxyglucose F18, Neoplasms diagnostic imaging, Positron-Emission Tomography methods
- Abstract
2-[(18)F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) assesses a fundamental property of neoplasia, the Warburg effect. This molecular imaging technique offers a complementary approach to anatomic imaging that is more sensitive and specific in certain cancers. FDG-PET has been widely applied in oncology primarily as a staging and restaging tool that can guide patient care. However, because it accurately detects recurrent or residual disease, FDG-PET also has significant potential for assessing therapy response. In this regard, it can improve patient management by identifying responders early, before tumor size is reduced; nonresponders could discontinue futile therapy. Moreover, a reduction in the FDG-PET signal within days or weeks of initiating therapy (e.g., in lymphoma, non-small cell lung, and esophageal cancer) significantly correlates with prolonged survival and other clinical end points now used in drug approvals. These findings suggest that FDG-PET could facilitate drug development as an early surrogate of clinical benefit. This article reviews the scientific basis of FDG-PET and its development and application as a valuable oncology imaging tool. Its potential to facilitate drug development in seven oncologic settings (lung, lymphoma, breast, prostate, sarcoma, colorectal, and ovary) is addressed. Recommendations include initial validation against approved therapies, retrospective analyses to define the magnitude of change indicative of response, further prospective validation as a surrogate of clinical benefit, and application as a phase II/III trial end point to accelerate evaluation and approval of novel regimens and therapies.
- Published
- 2005
- Full Text
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34. A pragmatic perspective on molecular targeted radionuclide therapy.
- Author
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Larson SM and Krenning EP
- Subjects
- Drug Approval, Humans, Radiopharmaceuticals therapeutic use, Drug Delivery Systems methods, Drug Delivery Systems trends, Molecular Biology methods, Molecular Biology trends, Neoplasms radiotherapy, Radioimmunotherapy methods, Radioimmunotherapy trends, Radioisotopes therapeutic use
- Published
- 2005
35. Clinical significance of unexplained abnormal focal FDG uptake in the abdomen during whole-body PET.
- Author
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Pandit-Taskar N, Schöder H, Gonen M, Larson SM, and Yeung HW
- Subjects
- Aged, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Abdomen physiopathology, Fluorodeoxyglucose F18 pharmacokinetics, Neoplasms diagnostic imaging, Radiopharmaceuticals pharmacokinetics, Tomography, Emission-Computed
- Abstract
Objective: FDG PET is frequently used as part of the diagnostic workup in cancer patients. Visualization of radiotracer-avid foci suggests the presence of malignant disease. Unexplained focal FDG accumulation in the abdomen is sometimes noted, but the clinical significance of this finding is unknown. Therefore, we followed cases with unexplained focal abdominal FDG uptake found incidentally on whole-body scans to define the cause and clinical significance of this finding., Conclusion: Unexplained focal abdominal FDG uptake is an unusual finding with causes that include malignant and benign processes. Among the 14 cases with definitive diagnoses, seven were adenomas, which is a premalignant condition, and five (35.7%) were malignant. Therefore, although rare, unexplained focal abdominal FDG uptake should not be ignored and further diagnostic workup is warranted.
- Published
- 2004
- Full Text
- View/download PDF
36. Clinical implications of different image reconstruction parameters for interpretation of whole-body PET studies in cancer patients.
- Author
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Schöder H, Erdi YE, Chao K, Gonen M, Larson SM, and Yeung HW
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Phantoms, Imaging, Radiopharmaceuticals, Reproducibility of Results, Sensitivity and Specificity, Tomography, Emission-Computed instrumentation, Whole-Body Counting instrumentation, Algorithms, Fluorodeoxyglucose F18, Image Enhancement methods, Image Interpretation, Computer-Assisted methods, Neoplasms diagnostic imaging, Tomography, Emission-Computed methods, Whole-Body Counting methods
- Abstract
Unlabelled: The standardized uptake value (SUV) is the most commonly used parameter to quantify the intensity of radiotracer uptake in tumors. Previous studies suggested that measurements of (18)F-FDG accumulation in tissue might be affected by the image reconstruction method, but the clinical relevance of these findings has not been assessed., Methods: Phantom studies were performed and clinical whole-body (18)F-FDG PET images of 85 cancer patients were analyzed. All images were reconstructed using either filtered backprojection (FBP) with measured attenuation correction (MAC) or iterative reconstruction (IR) with segmented attenuation correction (SAC). In a subset of 15 patients, images were reconstructed using all 4 combinations of IR+SAC, IR+MAC, FBP+SAC, and FBP+MAC. For phantom studies, a sphere containing (18)F-FDG was placed in a water-filled cylinder and the activity concentration of that sphere was measured in FBP and IR reconstructed images using all 4 combinations. Clinical studies were displayed simultaneously and identical regions of interest (ROIs, 50 pixels) were placed in liver, urinary bladder, and tumor tissue in both image sets. SUV max (maximal counts per pixel in ROI) and SUV avg (average counts per pixel) were measured., Results: In phantom studies, measurements from FBP images underestimated the true activity concentration to a greater degree than those from IR images (20% vs. 5% underestimation). In patient studies, SUV derived from FBP images were consistently lower than those from IR images in both normal and tumor tissue: Tumor SUV max with IR+SAC was 9.6 +/- 4.5, with IR+MAC it was 7.7 +/- 3.5, with FBP+MAC it was 6.9 +/- 3.0, and with FBP+SAC it was 8.6 +/- 4.1 (all P < 0.01 vs. IR+SAC). Compared with IR+SAC, SUV from FBP+MAC images were 25%-30% lower. Similar discrepancies were noted for liver and bladder. Discrepancies between measurements became more apparent with increasing (18)F-FDG concentration in tissue., Conclusion: SUV measurements in whole-body PET studies are affected by the applied methods for both image reconstruction and attenuation correction. This should be considered when serial PET studies are done in cancer patients. Moreover, if SUV is used for tissue characterization, different cutoff values should be applied, depending on the chosen method for image reconstruction and attenuation correction.
- Published
- 2004
37. Positron emission tomography-based molecular imaging in human cancer: exploring the link between hypoxia and accelerated glucose metabolism.
- Author
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Larson SM
- Subjects
- DNA metabolism, Glycolysis, Humans, Image Processing, Computer-Assisted, Glucose metabolism, Hypoxia, Neoplasms diagnosis, Neoplasms pathology, Positron-Emission Tomography methods
- Published
- 2004
- Full Text
- View/download PDF
38. Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy
- Author
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Bicak, Mesude, Lückerath, Katharina, Kalidindi, Teja, Phelps, Michael E, Strand, Sven-Erik, Morris, Michael J, Radu, Caius G, Damoiseaux, Robert, Peltola, Mari T, Peekhaus, Norbert, Ho, Austin, Veach, Darren, Malmborg Hager, Ann-Christin, Larson, Steven M, Lilja, Hans, McDevitt, Michael R, Klein, Robert J, and Ulmert, David
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Genetics ,Urologic Diseases ,Prostate Cancer ,Biotechnology ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Actinium ,Alpha Particles ,Animals ,Biomarkers ,Tumor ,Humans ,Immunoconjugates ,Male ,Mice ,Mice ,Nude ,Neoplasms ,Experimental ,Prostate-Specific Antigen ,Prostatic Neoplasms ,Tissue Kallikreins ,hu11B6 ,225Ac ,radiommunotherapy ,prostate cancer ,hK2 - Abstract
Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen ) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.
- Published
- 2020
39. First-in-Human Trial of Epichaperome-Targeted Positron Emission Tomography in Cancer Patients
- Author
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Dunphy, Mark P., Pressl, Christina, Pillarsetty, Nagavarakishore, Grkovski, Milan, Modi, Shanu, Jhaveri, Komal, Norton, Larry, Beattie, Bradley J., Zanzonico, Pat B., Zatorska, Danuta, Taldone, Tony, Ochiana, Stefan O., Uddin, Mohammad M., Burnazi, Eva M., Lyashchenko, Serge K., Hudis, Clifford A., Bromberg, Jacqueline F., Schöder, Heiko M., Fox, Josef J., Zhang, Hanwen, Chiosis, Gabriela, Lewis, Jason S., and Larson, Steven M.
- Subjects
Adult ,Male ,Middle Aged ,Article ,Iodine Radioisotopes ,Purines ,Cell Line, Tumor ,Neoplasms ,Positron Emission Tomography Computed Tomography ,Humans ,Female ,Tissue Distribution ,Benzodioxoles ,HSP90 Heat-Shock Proteins ,Aged ,Cell Proliferation - Abstract
PURPOSE: (124)I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose (124)I-PU-H71 for positron emission tomography (PET) to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging. EXPERIMENTAL DESIGN: Adult patients with cancer (n=30) received (124)I-PU-H71 tracer (201±12 MBq
- Published
- 2020
40. Population pharmacokinetics of antifibroblast activation protein monoclonal antibody F19 in cancer patients
- Author
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Tanswell, Paul, Garin-Chesa, Pilar, Rettig, Wolfgang J, Welt, Sydney, Divgi, Chaitanya R, Casper, Ephraim S, Finn, Ronald D, Larson, Steven M, Old, Lloyd J, and Scott, Andrew M
- Subjects
Adult ,Male ,Serine Endopeptidases ,Antibodies, Monoclonal ,Membrane Proteins ,Antineoplastic Agents ,Middle Aged ,Short Reports ,Antigens, Neoplasm ,Gelatinases ,Neoplasms ,Endopeptidases ,Biomarkers, Tumor ,Humans ,Female ,Growth Substances ,Aged - Abstract
The population pharmacokinetics of 131I-mAbF19, a radiolabelled murine monoclonal antibody against fibroblast activation protein and a potential antitumour stroma agent, were investigated during two phase I studies in cancer patients.131I-mAbF19 serum concentration-time data were obtained in 16 patients from two studies involving imaging and dosimetry in colorectal carcinoma and soft tissue sarcoma. Doses of 0.2, 1 and 2 mg antibody were administered as 60 min intravenous infusions. The data were analysed by nonlinear mixed effect modelling.The data were described by a two-compartment model. Population mean values were 109 ml h(-1) for total serum clearance, 3.1 l for the volume of distribution of the central compartment, and 4.9 l for the volume of distribution at steady state. Mean terminal half-life was 38 h. Intersubject variability was high, but no patient covariates could be identified that further explained this variability. In particular, there was no influence of tumour type or mAbF19 dose.The pharmacokinetics of antistromal mAbF19 were well defined in these two studies with different solid tumour types, and were comparable with those of other murine monoclonal antibodies that do not bind to normal tissue antigens or blood cells.
- Published
- 2001
41. In vivo microcartography and subcellular imaging of tumor angiogenesis: A novel platform for translational angiogenesis research
- Author
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Dunphy, Mark P.S., Entenberg, David, Toledo-Crow, Ricardo, and Larson, Steven M.
- Subjects
- *
NEOVASCULARIZATION , *BIOMOLECULES , *GREEN fluorescent protein , *CONFOCAL microscopy - Abstract
Abstract: Purpose: To eliminate the variable of tumor heterogeneity from a novel in vivo model of tumor angiogenesis. Experimental design: We developed a method to navigate tumor neovasculature in a living tissue microenvironment, enabling relocation of a cell- or microregion-of-interest, for serial in vivo imaging. Orthotopic melanoma was grown, in immunocompetent Tie2GFP mice. Intravital multiphoton fluorescence and confocal reflectance imaging was performed, on a custom microscope with motorized stage and coordinate navigation software. A point within a Tie2GFP+ microvessel was selected for relocation. Custom software predicted target coordinates based upon reference points (tissue-embedded polystyrene beads) and baseline target coordinates. Mice were removed from the stage to make previously-obtained target coordinates invalid in subsequent imaging. Results: Coordinate predictions always relocated target points, in vivo, to within 10–200 μm (within a single 40× field-of-view). The model system provided a virtual living histology of tumor neovascularization and microenvironment, with subcellular spatial resolution and hemodynamic information. Conclusions: The navigation procedure, termed in vivo microcartography, permits control of tissue heterogeneity, as a variable. Tie2 may be the best reporter gene identified, to-date, for intravital microscopy of tumor angiogenesis. This novel model system should strengthen intravital microscopy in its historical role as a vital tool in oncology, angiogenesis research, and angiotherapeutic drug development. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
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