Publications by authors named "Marija Trajkovic-Arsic"

32 Publications

Administration routes for SSTR- / PSMA- and FAP-directed theranostic radioligands in mice.

J Nucl Med 2022 Jan 6. Epub 2022 Jan 6.

Department of Nuclear Medicine, University Hospital Essen, Germany.

The NETTER-1, VISION, and TheraP trials prove efficacy of repeat intravenous (i.v.) application of small radioligands. Application by subcutaneous (s.c.), intraperitoneal (i.p.), or oral (p.o.) access are important alternatives and may yield comparable or favorable organ and tumor radioligand uptake. Here, we assess organ and tumor biodistribution for various radioligand application routes in healthy mice and models of somatostatin receptor (SSTR)-, prostate-specific membrane antigen (PSMA)-, and fibroblast activation protein (FAP)- expressing cancer. Healthy and tumor-bearing male C57BL/6 or NOD SCID Gamma mice, respectively, were applied with a mean of 6.0±0.5 MBq Ga DOTATOC (RM1-SSTR allograft), 5.3±0.3 MBq Ga-PSMA11 (RM1-PSMA allograft) or 4.8±0.2 MBq Ga-FAPI46 (HT1080 FAP xenograft) i.v., i.p., s.c. or p.o.. In vivo positron emission tomography and ex vivo biodistribution in tumor, organs, and at the injection site were assessed up to 5h post injection (p.i.). Healthy mice were monitored for up to 7 days after the last scan for signs of stress or adverse reactions. After i.v., i.p. and s.c. radioligand administration, average residual activity at the injection site was <17%IA/g (1h p.i.), <10%IA/g (2h p.i.) and ≤4%IA/g (4h p.i.) for all radioligands. Following oral administration ≥50%IA/g remained within the intestines until 4h p.i.. Biodistribution in organs of healthy mice was nearly equivalent following i.v., i.p., and s.c. application at 1h p.i. and all subsequent timepoints (≤1%IA/g for liver, blood and bone marrow; 11.2±1.4%IA/g for kidneys). In models for SSTR-, PSMA- and FAP-expressing cancer, tumor uptake was higher or equivalent for i.p./s.c. versus i.v. injection at 5h p.i. (ex vivo): SSTR: 7.2±1.0%IA/g ( = 0.0197) / 6.5±1.3%IA/g ( = 0.0827) versus 2.9±0.3%IA/g; PSMA: 3.4±0.8%IA/g ( = 0.9954) / 3.9±0.8%IA/g ( = 0.8343) versus 3.3±0.7%IA/g and FAP: 1.1±0.1%IA/g ( = 0.9805) / 1.1±0.1%IA/g ( = 0.7446) versus 1.0±0.2%IA/g. In healthy mice, biodistribution of small theranostic ligands following i.p. or s.c. application is nearly equivalent compared to i.v. injection. S.c. administration resulted in highest absolute SSTR tumor and tumor-to-organ uptake as compared to the i.v. route, warranting further clinical assessment.
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http://dx.doi.org/10.2967/jnumed.121.263453DOI Listing
January 2022

Native glycan fragments detected by MALDI mass spectrometry imaging are independent prognostic factors in pancreatic ductal adenocarcinoma.

EJNMMI Res 2021 Dec 1;11(1):120. Epub 2021 Dec 1.

Research Unit Analytical Pathology, Helmholtz Zentrum Munich, 85764, Neuherberg, Germany.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies to date. The impressively developed stroma that surrounds and modulates the behavior of cancer cells is one of the main factors regulating the PDAC growth, metastasis and therapy resistance. Here, we postulate that stromal and cancer cell compartments differentiate in protein/lipid glycosylation patterns and analyze differences in glycan fragments in those compartments with clinicopathologic correlates.

Results: We analyzed native glycan fragments in 109 human FFPE PDAC samples using high mass resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometric imaging (MALDI-FT-ICR-MSI). Our method allows detection of native glycan fragments without previous digestion with PNGase or any other biochemical reaction. With this method, 8 and 18 native glycans were identified as uniquely expressed in only stromal or only cancer cell compartment, respectively. Kaplan-Meier survival model identified glycan fragments that are expressed in cancer cell or stromal compartment and significantly associated with patient outcome. Among cancer cell region-specific glycans, 10 predicted better and 6 worse patient survival. In the stroma, 1 glycan predicted good and 4 poor patient survival. Using factor analysis as a dimension reduction method, we were able to group the identified glycans in 2 factors. Multivariate analysis revealed that these factors can be used as independent survival prognostic elements with regard to the established Union for International Cancer Control (UICC) classification both in tumor and stroma regions.

Conclusion: Our method allows in situ detection of naturally occurring glycans in FFPE samples of human PDAC tissue and highlights the differences among glycans found in stromal and cancer cell compartment offering a basis for further exploration on the role of specific glycans in cancer-stroma communication.
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http://dx.doi.org/10.1186/s13550-021-00862-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636555PMC
December 2021

The long non-coding RNA HOTAIRM1 promotes tumor aggressiveness and radiotherapy resistance in glioblastoma.

Cell Death Dis 2021 09 28;12(10):885. Epub 2021 Sep 28.

Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt, Frankfurt, Germany.

Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was determined by analyzing HOTAIRM1 in multiple glioblastoma gene expression data sets for associations with prognosis, as well as, IDH mutation and MGMT promoter methylation status. Finally, the role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients, independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, decreased invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses revealed impaired mitochondrial function and determination of reactive oxygen species (ROS) levels confirmed increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2), a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells both in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
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http://dx.doi.org/10.1038/s41419-021-04146-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478910PMC
September 2021

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.

Nat Commun 2021 09 17;12(1):5505. Epub 2021 Sep 17.

Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8 T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.
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http://dx.doi.org/10.1038/s41467-021-25728-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448826PMC
September 2021

Hyperpolarized C Spectroscopy with Simple Slice-and-Frequency-Selective Excitation.

Biomedicines 2021 Jan 27;9(2). Epub 2021 Jan 27.

Department of Nuclear Medicine, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, Germany.

Hyperpolarized C nuclear magnetic resonance spectroscopy can characterize in vivo tissue metabolism, including preclinical models of cancer and inflammatory disease. Broad bandwidth radiofrequency excitation is often paired with free induction decay readout for spectral separation, but quantification of low-signal downstream metabolites using this method can be impeded by spectral peak overlap or when frequency separation of the detected peaks exceeds the excitation bandwidth. In this work, alternating frequency narrow bandwidth (250 Hz) slice-selective excitation was used for C spectroscopy at 7 T in a subcutaneous xenograft rat model of human pancreatic cancer (PSN1) to improve quantification while measuring the dynamics of injected hyperpolarized [1-C]lactate and its metabolite [1-C]pyruvate. This method does not require sophisticated pulse sequences or specialized radiofrequency and gradient pulses, but rather uses nominally spatially offset slices to produce alternating frequency excitation with simpler slice-selective radiofrequency pulses. Additionally, point-resolved spectroscopy was used to calibrate the C frequency from the thermal proton signal in the target region. This excitation scheme isolates the small [1-C]pyruvate peak from the similar-magnitude tail of the much larger injected [1-C]lactate peak, facilitates quantification of the [1-C]pyruvate signal, simplifies data processing, and could be employed for other substrates and preclinical models.
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http://dx.doi.org/10.3390/biomedicines9020121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911979PMC
January 2021

Hyperpolarized C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC.

Sci Rep 2021 01 13;11(1):1191. Epub 2021 Jan 13.

School of Medicine, Institute of Diagnostic and Interventional Radiology, Technical University of Munich, 81675, Munich, Germany.

The in vivo assessment of tissue metabolism represents a novel strategy for the evaluation of oncologic disease. Hepatocellular carcinoma (HCC) is a high-prevalence, high-mortality tumor entity often discovered at a late stage. Recent evidence indicates that survival differences depend on metabolic alterations in tumor tissue, with particular focus on glucose metabolism and lactate production. Here, we present an in vivo imaging technique for metabolic tumor phenotyping in rat models of HCC. Endogenous HCC was induced in Wistar rats by oral diethyl-nitrosamine administration. Peak lactate-to-alanine signal ratios (L/A) were assessed with hyperpolarized magnetic resonance spectroscopic imaging (HPMRSI) after [1-C]pyruvate injection. Cell lines were derived from a subset of primary tumors, re-implanted in nude rats, and assessed in vivo with dynamic hyperpolarized magnetic resonance spectroscopy (HPMRS) after [1-C]pyruvate injection and kinetic modelling of pyruvate metabolism, taking into account systemic lactate production and recirculation. For ex vivo validation, enzyme activity and metabolite concentrations were spectroscopically quantified in cell and tumor tissue extracts. Mean peak L/A was higher in endogenous HCC compared to non-tumorous tissue. Dynamic HPMRS revealed higher pyruvate-to-lactate conversion rates (k) and lactate signal in subcutaneous tumors derived from high L/A tumor cells, consistent with ex vivo measurements of higher lactate dehydrogenase (LDH) levels in these cells. In conclusion, HPMRS and HPMRSI reveal distinct tumor phenotypes corresponding to differences in glycolytic metabolism in HCC tumor tissue.
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http://dx.doi.org/10.1038/s41598-020-80952-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806739PMC
January 2021

Characterization of a dual BET/HDAC inhibitor for treatment of pancreatic ductal adenocarcinoma.

Int J Cancer 2020 11 29;147(10):2847-2861. Epub 2020 Jun 29.

Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Medicine Essen, Essen, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is resistant to virtually all chemo- and targeted therapeutic approaches. Epigenetic regulators represent a novel class of drug targets. Among them, BET and HDAC proteins are central regulators of chromatin structure and transcription, and preclinical evidence suggests effectiveness of combined BET and HDAC inhibition in PDAC. Here, we describe that TW9, a newly generated adduct of the BET inhibitor (+)-JQ1 and class I HDAC inhibitor CI994, is a potent dual inhibitor simultaneously targeting BET and HDAC proteins. TW9 has a similar affinity to BRD4 bromodomains as (+)-JQ1 and shares a conserved binding mode, but is significantly more active in inhibiting HDAC1 compared to the parental HDAC inhibitor CI994. TW9 was more potent in inhibiting tumor cell proliferation compared to (+)-JQ1, CI994 alone or combined treatment of both inhibitors. Sequential administration of gemcitabine and TW9 showed additional synergistic antitumor effects. Microarray analysis revealed that dysregulation of a FOSL1-directed transcriptional program contributed to the antitumor effects of TW9. Our results demonstrate the potential of a dual chromatin-targeting strategy in the treatment of PDAC and provide a rationale for further development of multitarget inhibitors.
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http://dx.doi.org/10.1002/ijc.33137DOI Listing
November 2020

N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma.

Sci Rep 2020 04 28;10(1):7157. Epub 2020 Apr 28.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

N-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of N-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.
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http://dx.doi.org/10.1038/s41598-020-64040-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188804PMC
April 2020

TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer.

Cell Death Discov 2020 11;6:12. Epub 2020 Mar 11.

Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany, Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany, Essen, Germany.

Oncogenic mutations are encountered in more than 90% of pancreatic ductal adenocarcinomas. MEK inhibition has failed to procure any clinical benefits in mutant RAS-driven cancers including pancreatic ductal adenocarcinoma (PDAC). To identify potential resistance mechanisms underlying MEK inhibitor (MEKi) resistance in PDAC, we investigated lysosomal drug accumulation in PDAC models both in vitro and in vivo. Mouse PDAC models and human PDAC cell lines as well as human PDAC xenografts treated with the MEK inhibitor trametinib or refametinib led to an enhanced expression of lysosomal markers and enrichment of lysosomal gene sets. A time-dependent, increase in lysosomal content was observed upon MEK inhibition. Strikingly, there was a strong activation of lysosomal biogenesis in cell lines of the classical compared to the basal-like molecular subtype. Increase in lysosomal content was associated with nuclear translocation of the Transcription Factor EB () and upregulation of target genes. siRNA-mediated depletion of led to a decreased lysosomal biogenesis upon MEK inhibition and potentiated sensitivity. Using LC-MS, we show accumulation of MEKi in the lysosomes of treated cells. Therefore, MEK inhibition triggers lysosomal biogenesis and subsequent drug sequestration. Combined targeting of MEK and lysosomal function may improve sensitivity to MEK inhibition in PDAC.
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http://dx.doi.org/10.1038/s41420-020-0246-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066197PMC
March 2020

The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation.

Int J Cancer 2020 07 7;147(1):189-201. Epub 2020 Jan 7.

Division of Functional Genome Analysis (B070), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Binding of transcription factors to mutated DNA sequences is a likely regulator of cancer progression. Noncoding regulatory mutations such as those on the core promoter of the gene encoding human telomerase reverse transcriptase have been shown to affect gene expression in cancer. Using a protein microarray of 667 transcription factor DNA-binding domains and subsequent functional assays, we looked for transcription factors that preferentially bind the mutant hTERT promoter and characterized their downstream effects. One of them, friend leukemia integration 1 (FLI1), which belongs to the E26 transforming-specific family of transcription factors, exhibited particularly strong effects with respect to regulating hTERT expression, while the even better binding ELK3 did not. Depletion of FLI1 decreased expression of the genes for cyclin D1 (CCND1) and E2F transcription factor 2 (E2F2) resulting in a G1/S cell cycle arrest and in consequence a reduction of cell proliferation. FLI1 also affected CMTM7, another gene involved in G1/S transition, although by another process that suggests a balanced regulation of the tumor suppressor gene's activity via opposing regulation processes. FLI1 expression was found upregulated and correlated with an increase in CCND1 expression in pancreatic cancer and brain tumors. In non-neoplastic lung cells, however, FLI1 depletion led to rapid progression through the cell cycle. This coincides with the fact that FLI1 is downregulated in lung tumors. Taken together, our data indicate a cell cycle regulatory hub involving FLI1, hTERT, CCND1 and E2F2 in a tissue- and context-dependent manner.
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http://dx.doi.org/10.1002/ijc.32831DOI Listing
July 2020

MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells and .

Stem Cells Int 2019 2;2019:8475389. Epub 2019 Jun 2.

Department of Internal Medicine I, Ulm University, Germany.

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a very poor prognosis. At the same time, its incidence is on the rise, and PDAC is expected to become the second leading cause of cancer-related death by 2030. Despite extensive work on new therapeutic approaches, the median overall survival is only 6-12 months after diagnosis and the 5-year survival is less than 7%. While pancreatic cancer is particularly difficult to treat, patients usually succumb not to the growth of the primary tumor, but to extensive metastasis; therefore, strategies to reduce the migratory and metastatic capacity of pancreatic cancer cells merit close attention. The vast majority of pancreatic cancers harbor RAS mutations. The outstanding relevance of the RAS/MEK/ERK pathway in pancreatic cancer biology has been extensively shown previously. Due to their high dependency on Ras mutations, pancreatic cancers might be particularly sensitive to inhibitors acting downstream of Ras. Herein, we use a genetically engineered mouse model of pancreatic cancer and primary pancreatic cancer cells were derived from this model to demonstrate that small-molecule MEK inhibitors functionally abrogate cancer stem cell populations as demonstrated by reduced sphere and organoid formation capacity. Furthermore, we demonstrate that MEK inhibition suppresses TGF-induced epithelial-to-mesenchymal transition and migration and ultimately results in a highly significant reduction in circulating tumor cells in mice.
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http://dx.doi.org/10.1155/2019/8475389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589314PMC
June 2019

Targeting the H3K4 Demethylase KDM5B Reprograms the Metabolome and Phenotype of Melanoma Cells.

J Invest Dermatol 2019 12 21;139(12):2506-2516.e10. Epub 2019 Jun 21.

Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium, University of Duisburg-Essen, Duisburg/Essen, Germany. Electronic address:

Melanoma cells shift between epigenetic-metabolic states to adapt to stress and, particularly, to drugs. Here, we unraveled the metabolome of an H3K4 demethylase (KDM5B/JARID1B)-driven melanoma cell phenotype that is known to be multidrug resistant. We set up a fast protocol for standardized, highly sensitive liquid chromatography-high resolution mass spectrometry analyzing stably controlled KDM5B expression by RNAi or doxycycline-induced overexpression. Within the KDM5B-dependent metabolome, we found significant and highly specific regulation of 11 intracellular metabolites. Functionally, overexpression of KDM5B in melanoma cells led to broadening of their oxidative metabolism from mainly glutamine-dependent to additionally glucose- and fatty acid-utilizing, upregulation of the pentose phosphate pathway as a source of antioxidant NADPH, and maintenance of a high ratio of reduced to oxidized glutathione. Histone lysine demethylase inhibition (GSK-J1, 2,4-PDCA) decreased colony formation and invasion in three-dimensional models. Thus, targeting KDM5B could represent an alternative way of modulating the metabolome and malignant cell behavior in melanoma.
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http://dx.doi.org/10.1016/j.jid.2019.06.124DOI Listing
December 2019

Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib in -Mutant Pancreatic and Colorectal Cancer.

Cancer Res 2019 05 11;79(9):2367-2378. Epub 2019 Mar 11.

German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Aberrations within the PI3K/AKT signaling axis are frequently observed in numerous cancer types, highlighting the relevance of these pathways in cancer physiology and pathology. However, therapeutic interventions employing AKT inhibitors often suffer from limitations associated with target selectivity, efficacy, or dose-limiting effects. Here we present the first crystal structure of autoinhibited AKT1 in complex with the covalent-allosteric inhibitor borussertib, providing critical insights into the structural basis of AKT1 inhibition by this unique class of compounds. Comprehensive biological and preclinical evaluation of borussertib in cancer-related model systems demonstrated a strong antiproliferative activity in cancer cell lines harboring genetic alterations within the PTEN, PI3K, and RAS signaling pathways. Furthermore, borussertib displayed antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models of mutant pancreatic and colon cancer. SIGNIFICANCE: Borussertib, a first-in-class covalent-allosteric AKT inhibitor, displays antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models and provides a starting point for further pharmacokinetic/dynamic optimization.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2861DOI Listing
May 2019

A Novel Approach for Image-Guided I Therapy of Pancreatic Ductal Adenocarcinoma Using Mesenchymal Stem Cell-Mediated NIS Gene Delivery.

Mol Cancer Res 2019 01 17;17(1):310-320. Epub 2018 Sep 17.

Department of Internal Medicine IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany.

The sodium iodide symporter () as theranostic gene would allow for non-invasive imaging of functional NIS expression and therapeutic radioiodine application. Genetically engineered mesenchymal stem cells (MSC), based on their tumor-homing abilities, show great promise as tumor-selective gene delivery vehicles for non-thyroidal tumors. As a next step towards clinical application, tumor specificity and efficacy of MSCs were investigated in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC). Syngeneic murine MSCs were stably transfected with a -expressing plasmid driven by the -promoter (NIS-MSC). I-scintigraphy and I-PET revealed significant perchlorate-sensitive NIS-mediated radioiodide accumulation in PDAC after systemic injection of NIS-MSCs. Active MSC recruitment into the tumor stroma was confirmed using NIS immunohistochemistry (IHC). A therapeutic strategy, consisting of three cycles of systemic MSC-mediated delivery, followed by I application, resulted in a significant delay and reduction in tumor growth as compared to controls. Furthermore, IHC analysis of α-SMA and Ki67 revealed differences in the amount and behavior of activated fibroblasts in tumors of mice injected with NIS-MSCs as compared with saline-treated mice. Taken together, MSCs as gene delivery vehicles in this advanced endogenous PDAC mouse model demonstrated high stromal targeting of NIS by selective recruitment of NIS-MSCs after systemic application resulting in an impressive I therapeutic effect. IMPLICATIONS: These data expand the prospect of MSC-mediated radioiodine imaging-guided therapy of pancreatic cancer using the sodium iodide symporter as a theranostic gene in a clinical setting.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0185DOI Listing
January 2019

Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting.

Cancer Res 2018 09 29;78(17):4997-5010. Epub 2018 May 29.

Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.

Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multilayered tumor microenvironment. In this study, we employed a dual recombinase-based strategy to modulate Notch signaling specifically in myeloid cells to dissect the tumorigenic role of Notch in PDAC stroma. Pancreas-specific KrasG12D activation and loss of Tp53 was induced using a Pdx1-Flp transgene, whereas Notch signaling was genetically targeted using a myeloid-targeting Lyz2-Cre strain for either activation of Notch2-IC or deletion of Rbpj. Myeloid-specific Notch activation significantly decreased tumor infiltration by protumorigenic M2 macrophages in spontaneous endogenous PDAC, which translated into significant survival benefit. Further characterization revealed upregulated antigen presentation and cytotoxic T effector phenotype upon Notch-induced M2 reduction. This approach is the first proof of concept for genetic targeting and reprogramming of myeloid cells in a complex disease model of PDAC and provides evidence for a regulatory role of Notch signaling in intratumoral immune phenotypes. This study provides insight into the role of myeloid-dependent NOTCH signaling in PDAC and accentuates the need to dissect differential roles of signaling pathways in different cellular components within the tumor microenvironment. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0052DOI Listing
September 2018

Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene.

Oncotarget 2017 May;8(20):33393-33404

Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany.

The theranostic sodium iodide symporter (NIS) gene allows detailed molecular imaging of transgene expression and application of therapeutic radionuclides. As a crucial step towards clinical application, we investigated tumor specificity and transfection efficiency of epidermal growth factor receptor (EGFR)-targeted polyplexes as systemic NIS gene delivery vehicles in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) that closely reflects human disease. PDAC was induced in mice by pancreas-specific activation of constitutively active KrasG12D and deletion of Trp53. We used tumor-targeted polyplexes (LPEI-PEG-GE11/NIS) based on linear polyethylenimine, shielded by polyethylene glycol and coupled with the EGFR-specific peptide ligand GE11, to target a NIS-expressing plasmid to high EGFR-expressing PDAC. In vitro iodide uptake studies in cell explants from murine EGFR-positive and EGFR-ablated PDAC lesions demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS. In vivo 123I gamma camera imaging and three-dimensional high-resolution 124I PET showed significant tumor-specific accumulation of radioiodide after systemic LPEI-PEG-GE11/NIS injection. Administration of 131I in LPEI-PEG-GE11/NIS-treated mice resulted in significantly reduced tumor growth compared to controls as determined by magnetic resonance imaging, though survival was not significantly prolonged. This study opens the exciting prospect of NIS-mediated radionuclide imaging and therapy of PDAC after systemic non-viral NIS gene delivery.
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http://dx.doi.org/10.18632/oncotarget.16499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464876PMC
May 2017

Hes1 Controls Exocrine Cell Plasticity and Restricts Development of Pancreatic Ductal Adenocarcinoma in a Mouse Model.

Am J Pathol 2016 11 14;186(11):2934-2944. Epub 2016 Sep 14.

II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. Electronic address:

Perturbation of pancreatic acinar cell state can lead to acinar-to-ductal metaplasia (ADM), a precursor lesion to the development of pancreatic ductal adenocarcinoma (PDAC). In the pancreas, Notch signaling is active both during development and in adult cellular differentiation processes. Hes1, a key downstream target of the Notch signaling pathway, is expressed in the centroacinar compartment of the adult pancreas as well as in both preneoplastic and malignant lesions. In this study, we used a murine genetic in vivo approach to ablate Hes1 in pancreatic progenitor cells (Ptf1a; Hes1). Using this model, we studied the role of Hes1 in both acinar cell plasticity and pancreatic regeneration after caerulein-induced pancreatitis and in Kras-driven PDAC development. We show that, although pancreatic development is not perturbed on the deletion of Hes1, terminal acinar differentiation in the adult pancreas is compromised. Moreover, the loss of Hes1 leads to the impaired regeneration of the exocrine compartment, accelerated fatty metaplasia, and persistent ADM after acute caerulein-induced pancreatitis. In Kras-driven carcinogenesis, Hes1 ablation resulted in increased ADM, decreased formation of high-grade pancreatic intraepithelial neoplasias, and accelerated development of PDAC with shortened survival time. In conclusion, Hes1 plays a key role in acinar cell integrity and plasticity on cellular insults. Furthermore, Hes1 is an essential component of the pancreatic intraepithelial neoplasias-to-PDAC route in Kras-driven mouse pancreatic carcinogenesis.
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http://dx.doi.org/10.1016/j.ajpath.2016.07.025DOI Listing
November 2016

Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer.

Clin Cancer Res 2017 Mar 23;23(6):1461-1470. Epub 2016 Sep 23.

Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Germany.

Tumor heterogeneity is a hallmark of pancreatic ductal adenocarcinoma (PDAC). It determines tumor biology including tumor cellularity (i.e., amount of neoplastic cells and arrangement into clusters), which is related to the proliferative capacity and differentiation and the degree of desmoplasia among others. Given the close relation of tumor differentiation with differences in progression and therapy response or, e.g., the recently reported protective role of tumor stroma, we aimed at the noninvasive detection of PDAC groups, relevant for future personalized approaches. We hypothesized that histologic differences in PDAC tissue composition are detectable by the noninvasive diffusion weighted- (DW-) MRI-derived apparent diffusion coefficient (ADC) parameter. PDAC cellularity was quantified histologically and correlated with the ADC parameter and survival in genetically engineered mouse models and human patients. Histologic analysis showed an inverse relationship of tumor cellularity and stroma content. Low tumor cellularity correlated with a significantly prolonged mean survival time (PDAC = 21.93 months vs. PDAC = 12.7 months; log-rank < 0.001; HR = 2.23; CI, 1.41-3.53). Multivariate analysis using the Cox regression method confirmed tumor cellularity as an independent prognostic marker ( = 0.034; HR = 1.73; CI, 1.04-2.89). Tumor cellularity showed a strong negative correlation with the ADC parameter in murine ( = -0.84; CI, -0.90- -0.75) and human ( = -0.79; CI, -0.90 to -0.56) PDAC and high preoperative ADC values correlated with prolonged survival (ADC = 41.7 months; ADC = 14.77 months; log rank, = 0.040) in PDAC patients. This study identifies high tumor cellularity as a negative prognostic factor in PDAC and supports the ADC parameter for the noninvasive identification of PDAC groups. .
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2432DOI Listing
March 2017

Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.

Nat Med 2015 Oct 21;21(10):1163-71. Epub 2015 Sep 21.

Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.
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http://dx.doi.org/10.1038/nm.3952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959788PMC
October 2015

Selective in vivo imaging of syngeneic, spontaneous, and xenograft tumors using a novel tumor cell-specific hsp70 peptide-based probe.

Cancer Res 2014 Dec 9;74(23):6903-12. Epub 2014 Oct 9.

Department of Radiation Oncology, Klinikum rechts der Isar, TU München and CCG - "Innate Immunity in Tumor Biology", Helmholtz Zentrum München (HMGU), Munich, Germany.

Although in vivo targeting of tumors using fluorescently labeled probes has greatly gained in importance over the last few years, most of the clinically applied reagents lack tumor cell specificity. Our novel tumor cell-penetrating peptide-based probe (TPP) recognizes an epitope of Hsp70 that is exclusively present on the cell surface of a broad variety of human and mouse tumors and metastases, but not on normal tissues. Because of the rapid turnover rate of membrane Hsp70, fluorescently labeled TPP is continuously internalized into syngeneic, spontaneous, chemically/genetically induced and xenograft tumors following intravenous administration, thereby enabling site-specific labeling of primary tumors and metastases. In contrast with the commercially available nonpeptide small molecule αvβ3-integrin antagonist IntegriSense, TPP exhibits a significantly higher tumor-to-background contrast and stronger tumor-specific signal intensity in all tested tumor models. Moreover, in contrast with IntegriSense, TPP reliably differentiates between tumor cells and cells of the tumor microenvironment, such as tumor-associated macrophages and fibroblasts, which were found to be membrane-Hsp70 negative. Therefore, TPP provides a useful tool for multimodal imaging of tumors and metastases that might help to improve our understanding of tumorigenesis and allow the establishment of improved diagnostic procedures and more accurate therapeutic monitoring. TPP might also be a promising platform for tumor-specific drug delivery and other Hsp70-based targeted therapies.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-0413DOI Listing
December 2014

FMT-PCCT: hybrid fluorescence molecular tomography-x-ray phase-contrast CT imaging of mouse models.

IEEE Trans Med Imaging 2014 Jul 24;33(7):1434-46. Epub 2014 Mar 24.

The implementation of hybrid fluorescence molecular tomography (FMT) and X-ray computed tomography (CT) has been shown to be a necessary development, not only for combining anatomical with functional and molecular contrast, but also for generating optical images of high accuracy. FMT affords highly sensitive 3-D imaging of fluorescence bio-distribution, but in stand-alone form it offers images of low resolution. It was shown that FMT accuracy significantly improves by considering anatomical priors from CT. Conversely, CT generally suffers from low soft tissue contrast. Therefore utilization of CT data as prior information in FMT inversion is challenging when different internal organs are not clearly differentiated. Instead, we combined herein FMT with emerging X-ray phase-contrast CT (PCCT). PCCT relies on phase shift differences in tissue to achieve soft tissue contrast superior to conventional CT. We demonstrate for the first time FMT-PCCT imaging of different animal models, where FMT and PCCT scans were performed in vivo and ex vivo, respectively. The results show that FMT-PCCT expands the potential of FMT in imaging lesions with otherwise low or no CT contrast, while retaining the cost benefits of CT and simplicity of hybrid device realizations. The results point to the most accurate FMT performance to date.
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http://dx.doi.org/10.1109/TMI.2014.2313405DOI Listing
July 2014

Multimodal molecular imaging of integrin αvβ3 for in vivo detection of pancreatic cancer.

J Nucl Med 2014 Mar 18;55(3):446-51. Epub 2014 Feb 18.

II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Unlabelled: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Late detection of then nonresectable or metastasized tumors emphasizes the need for novel imaging approaches. Here, we report on so far nonexploited potentials of αvβ3 integrin-targeted molecular imaging technologies for detection of PDAC using genetically engineered mouse models.

Methods: Immunohistochemistry and Western blot were used for characterization of αvβ3 expression in murine and human PDAC. We applied IntegriSense 680 fluorescence molecular tomography, intraoperative fluorescence imaging, and (68)Ga-NODAGA-RGD PET for αvβ3 integrin molecular in vivo imaging of spontaneous PDAC occurring in Ptf1a(+/Cre);Kras(+/LSL-G12D);p53(LoxP/LoxP) mice. (NODAGA is 1,4,7-triazacyclononane-1,4-bis[acetic acid]-7-[2-glutaric acid] and RGD is arginine-glycine-aspartic acid.)

Results: αvβ3 integrin is expressed in tumor cells of human and murine PDAC. IntegriSense fluorescence molecular tomography and (68)Ga-NODAGA-RGD PET enabled faithful visualization of PDAC. Furthermore, intraoperative optical imaging with IntegriSense 680 allowed good delineation of tumor borders.

Conclusion: Imaging approaches targeting αvβ3 integrin expand the potential of molecular imaging for identification of αvβ3-positive PDAC with potential implications in early detection, fluorescence-guided surgery, and therapy monitoring.
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http://dx.doi.org/10.2967/jnumed.113.129619DOI Listing
March 2014

Validation of heat shock protein 70 as a tumor-specific biomarker for monitoring the outcome of radiation therapy in tumor mouse models.

Int J Radiat Oncol Biol Phys 2014 Mar;88(3):694-700

Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Clinical Kooperation Group, Innate Immunity in Tumor Biology, HelmholtzZentrum München, Munich, Germany. Electronic address:

Purpose: Tumor cells, in contrast to normal cells, frequently overexpress heat shock protein 70 (Hsp70) in the cytosol, present it on their cell surface, and actively release it. Therefore, soluble Hsp70 (sHsp70) was investigated as a potential tumor biomarker for monitoring the outcome of radiation therapy.

Methods And Materials: Plasma from mice bearing membrane Hsp70 (mHsp70)-positive FaDu human squamous cell carcinoma of the head and neck and spontaneous pancreatic ductal adenocarcinoma (PDAC) was investigated. A cohort of mice with FaDu tumors (0.32 cm(3)) was irradiated with 30 Gy, and plasma was collected 24 hours after irradiation, after the tumors had shrunk to 50% of their starting volume and after complete remission. sHsp70 levels in the plasma were quantified by enzyme-linked immunosorbent assay.

Results: sHsp70 levels were significantly higher in the blood of tumor-bearing mice than that of control animals. A correlation between increasing sHsp70 plasma levels and tumor volume in the range of 0.01 cm(3) to 0.66 cm(3) was observed. Radiation-induced regression of the tumors was associated with significantly decreased sHsp70 levels, which returned to the level of control animals after complete remission.

Conclusion: We propose sHsp70 as an innovative biomarker for detecting tumors and for monitoring the clinical outcome of radiation therapy in cancer patients.
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http://dx.doi.org/10.1016/j.ijrobp.2013.11.008DOI Listing
March 2014

Monocarboxylate transporter 8 modulates the viability and invasive capacity of human placental cells and fetoplacental growth in mice.

PLoS One 2013 12;8(6):e65402. Epub 2013 Jun 12.

School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Monocarboxylate transporter 8 (MCT8) is a well-established thyroid hormone (TH) transporter. In humans, MCT8 mutations result in changes in circulating TH concentrations and X-linked severe global neurodevelopmental delay. MCT8 is expressed in the human placenta throughout gestation, with increased expression in trophoblast cells from growth-restricted pregnancies. We postulate that MCT8 plays an important role in placental development and transplacental TH transport. We investigated the effect of altering MCT8 expression in human trophoblast in vitro and in a Mct8 knockout mouse model. Silencing of endogenous MCT8 reduced T3 uptake into human extravillous trophoblast-like cells (SGHPL-4; 40%, P<0.05) and primary cytotrophoblast (15%, P<0.05). MCT8 over-expression transiently increased T3 uptake (SGHPL-4∶30%, P<0.05; cytotrophoblast: 15%, P<0.05). Silencing MCT8 did not significantly affect SGHPL-4 invasion, but with MCT8 over-expression T3 treatment promoted invasion compared with no T3 (3.3-fold; P<0.05). Furthermore, MCT8 silencing increased cytotrophoblast viability (∼20%, P<0.05) and MCT8 over-expression reduced cytotrophoblast viability independently of T3 (∼20%, P<0.05). In vivo, Mct8 knockout reduced fetal:placental weight ratios compared with wild-type controls at gestational day 18 (25%, P<0.05) but absolute fetal and placental weights were not significantly different. The volume fraction of the labyrinthine zone of the placenta, which facilitates maternal-fetal exchange, was reduced in Mct8 knockout placentae (10%, P<0.05). However, there was no effect on mouse placental cell proliferation in vivo. We conclude that MCT8 makes a significant contribution to T3 uptake into human trophoblast cells and has a role in modulating human trophoblast cell invasion and viability. In mice, Mct8 knockout has subtle effects upon fetoplacental growth and does not significantly affect placental cell viability probably due to compensatory mechanisms in vivo.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065402PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680392PMC
January 2014

X-ray phase-contrast CT of a pancreatic ductal adenocarcinoma mouse model.

PLoS One 2013 11;8(3):e58439. Epub 2013 Mar 11.

Department of Physics and Institute of Medical Engineering, Technische Universität München, Garching, Germany.

To explore the potential of grating-based x-ray phase-contrast computed tomography (CT) for preclinical research, a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) was investigated. One ex-vivo mouse specimen was scanned with different grating-based phase-contrast CT imaging setups covering two different settings: i) high-resolution synchrotron radiation (SR) imaging and ii) dose-reduced imaging using either synchrotron radiation or a conventional x-ray tube source. These experimental settings were chosen to assess the potential of phase-contrast imaging for two different types of application: i) high-performance imaging for virtual microscopy applications and ii) biomedical imaging with increased soft-tissue contrast for in-vivo applications. For validation and as a reference, histological slicing and magnetic resonance imaging (MRI) were performed on the same mouse specimen. For each x-ray imaging setup, attenuation and phase-contrast images were compared visually with regard to contrast in general, and specifically concerning the recognizability of lesions and cancerous tissue. To quantitatively assess contrast, the contrast-to-noise ratios (CNR) of selected regions of interest (ROI) in the attenuation images and the phase images were analyzed and compared. It was found that both for virtual microscopy and for in-vivo applications, there is great potential for phase-contrast imaging: in the SR-based benchmarking data, fine details about tissue composition are accessible in the phase images and the visibility of solid tumor tissue under dose-reduced conditions is markedly superior in the phase images. The present study hence demonstrates improved diagnostic value with phase-contrast CT in a mouse model of a complex endogenous cancer, promoting the use and further development of grating-based phase-contrast CT for biomedical imaging applications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594292PMC
December 2013

The role of insulin and IGF system in pancreatic cancer.

J Mol Endocrinol 2013 Jun 23;50(3):R67-74. Epub 2013 Apr 23.

II Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr 22, 81675 Munich, Germany.

The importance of the IGF system in carcinogenesis has been established for many solid cancers. It is well known that individuals with higher circulating levels of the IGF1 ligand present an increased risk of cancer. However, therapies with monoclonal antibodies targeting the IGF1 receptor (IGF1R) have been largely unsuccessful. One of the potential reasons for this failure is the existence of the highly homologous insulin receptor (IR), which appears to be at least equally efficient as the IGF1R in the transition of mitogenic signals to the nucleus and promotion of cell growth. Furthermore, IGF1 and insulin receptors can form hybrid receptors sensitive to stimulation of all three ligands of the system: insulin, IGF1, and IGF2. Although the connection between insulin, diabetes, and cancer has been established for years now, clear evidence that demonstrate the redundancy of insulin and insulin receptors and insulin-like growth factors and their receptors in cancer is missing. In this review, we focus on the contribution of insulin and IGFs to carcinogenesis in the insulin-producing organ, the pancreas. We give a short summary on the complexity of insulin and the IGF system in the pancreas and their potential roles in pancreatic cancer, especially pancreatic ductal adenocarcinoma. Finally, we discuss drug-targeting options of this system and the rationale of simultaneous targeting of both the insulin and the IGF systems.
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http://dx.doi.org/10.1530/JME-12-0259DOI Listing
June 2013

Tetrac can replace thyroid hormone during brain development in mouse mutants deficient in the thyroid hormone transporter mct8.

Endocrinology 2013 Feb 10;154(2):968-79. Epub 2013 Jan 10.

Leibniz Institute for Age Research/Fritz Lipmann Institute, D-07745 Jena, Germany.

The monocarboxylate transporter 8 (MCT8) plays a critical role in mediating the uptake of thyroid hormones (THs) into the brain. In patients, inactivating mutations in the MCT8 gene are associated with a severe form of psychomotor retardation and abnormal serum TH levels. Here, we evaluate the therapeutic potential of the TH analog 3,5,3',5'-tetraiodothyroacetic acid (tetrac) as a replacement for T(4) in brain development. Using COS1 cells transfected with TH transporter and deiodinase constructs, we could show that tetrac, albeit not being transported by MCT8, can be metabolized to the TH receptor active compound 3,3',5-triiodothyroacetic acid (triac) by type 2 deiodinase and inactivated by type 3 deiodinase. Triac in turn is capable of replacing T(3) in primary murine cerebellar cultures where it potently stimulates Purkinje cell development. In vivo effects of tetrac were assessed in congenital hypothyroid Pax8-knockout (KO) and Mct8/Pax8 double-KO mice as well as in Mct8-KO and wild-type animals after daily injection of tetrac (400 ng/g body weight) during the first postnatal weeks. This treatment was sufficient to promote TH-dependent neuronal differentiation in the cerebellum, cerebral cortex, and striatum but was ineffective in suppressing hypothalamic TRH expression. In contrast, TSH transcript levels in the pituitary were strongly down-regulated in response to tetrac. Based on our findings we propose that tetrac administration offers the opportunity to provide neurons during the postnatal stage with a potent TH receptor agonist, thereby eventually reducing the neurological damage in patients with MCT8 mutations without deteriorating the thyrotoxic situation in peripheral tissues.
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http://dx.doi.org/10.1210/en.2012-1628DOI Listing
February 2013

EGF receptor is required for KRAS-induced pancreatic tumorigenesis.

Cancer Cell 2012 Sep;22(3):304-17

Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.

Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.
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http://dx.doi.org/10.1016/j.ccr.2012.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443395PMC
September 2012

MALDI imaging mass spectrometry for in situ proteomic analysis of preneoplastic lesions in pancreatic cancer.

PLoS One 2012 26;7(6):e39424. Epub 2012 Jun 26.

II Medizinische Klinik, Technische Universität München, Munich, Germany.

The identification of new biomarkers for preneoplastic pancreatic lesions (PanINs, IPMNs) and early pancreatic ductal adenocarcinoma (PDAC) is crucial due to the diseases high mortality rate upon late detection. To address this task we used the novel technique of matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) on genetically engineered mouse models (GEM) of pancreatic cancer. Various GEM were analyzed with MALDI IMS to investigate the peptide/protein-expression pattern of precursor lesions in comparison to normal pancreas and PDAC with cellular resolution. Statistical analysis revealed several discriminative m/z-species between normal and diseased tissue. Intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) could be distinguished from normal pancreatic tissue and PDAC by 26 significant m/z-species. Among these m/z-species, we identified Albumin and Thymosin-beta 4 by liquid chromatography and tandem mass spectrometry (LC-MS/MS), which were further validated by immunohistochemistry, western blot, quantitative RT-PCR and ELISA in both murine and human tissue. Thymosin-beta 4 was found significantly increased in sera of mice with PanIN lesions. Upregulated PanIN expression of Albumin was accompanied by increased expression of liver-restricted genes suggesting a hepatic transdifferentiation program of preneoplastic cells. In conclusion we show that GEM of endogenous PDAC are a suitable model system for MALDI-IMS and subsequent LC-MS/MS analysis, allowing in situ analysis of small precursor lesions and identification of differentially expressed peptides and proteins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039424PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383687PMC
March 2013
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