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51. Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

Author

Lia Walcher, Ann-Kathrin Kistenmacher, Huizhen Suo, Reni Kitte, Sarah Dluczek, Alexander Strauß, André-René Blaudszun, Tetyana Yevsa, Stephan Fricke, and Uta Kossatz-Boehlert

Subjects
cancer stem cells, senescence, targeted therapy, CAR cells, biomarkers, precision therapy, Immunologic diseases. Allergy, RC581-607
Abstract

The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.

Published
2020
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52. Discriminating radiation injury from recurrent tumor with [18F]PARPi and amino acid PET in mouse models

Author

Patrick L. Donabedian, Susanne Kossatz, John A. Engelbach, Stephen A. Jannetti, Brandon Carney, Robert J. Young, Wolfgang A. Weber, Joel R. Garbow, and Thomas Reiner

Subjects
PET/CT, PARP1, Radiation necrosis, Radiation injury, Amino acid PET, Biomarkers, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Abstract Background Radiation injury can be indistinguishable from recurrent tumor on standard imaging. Current protocols for this differential diagnosis require one or more follow-up imaging studies, long dynamic acquisitions, or complex image post-processing; despite much research, the inability to confidently distinguish between these two entities continues to pose a significant dilemma for the treating clinician. Using mouse models of both glioblastoma and radiation necrosis, we tested the potential of poly(ADP-ribose) polymerase (PARP)-targeted PET imaging with [18F]PARPi to better discriminate radiation injury from tumor. Results In mice with experimental radiation necrosis, lesion uptake on [18F]PARPi-PET was similar to contralateral uptake (1.02 ± 0.26 lesion/contralateral %IA/ccmax ratio), while [18F]FET-PET clearly delineated the contrast-enhancing region on MR (2.12 ± 0.16 lesion/contralateral %IA/ccmax ratio). In mice with focal intracranial U251 xenografts, tumor visualization on PARPi-PET was superior to FET-PET, and lesion-to-contralateral activity ratios (max/max, p = 0.034) were higher on PARPi-PET than on FET-PET. Conclusions A murine model of radiation necrosis does not demonstrate [18F]PARPi avidity, and [18F]PARPi-PET is better than [18F]FET-PET in distinguishing radiation injury from brain tumor. [18F]PARPi-PET can be used for discrimination between recurrent tumor and radiation injury within a single, static imaging session, which may be of value to resolve a common dilemma in neuro-oncology.

Published
2018
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53. Target engagement imaging of PARP inhibitors in small-cell lung cancer

Author

Brandon Carney, Susanne Kossatz, Benjamin H. Lok, Valentina Schneeberger, Kishore K. Gangangari, Naga Vara Kishore Pillarsetty, Wolfgang A. Weber, Charles M. Rudin, John T. Poirier, and Thomas Reiner

Subjects
Science
Abstract

Treatment of small-cell lung cancer remains a challenge due to multiple mechanisms of resistance to current therapies; measuring patient response is crucial in adapting and choosing adequate treatment. Here the authors develop a strategy to visualise in vivo dynamics of a class of widely used PARP inhibitors.

Published
2018
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55. Cancer vaccines and immunotherapeutic approaches in hepatobiliary and pancreatic cancers

Author

Inga Hochnadel, Uta Kossatz-Boehlert, Nils Jedicke, Henrike Lenzen, Michael P. Manns, and Tetyana Yevsa

Subjects
cancer vaccines, cholangiocarcinoma, gastrointestinal cancer, hepatocellular carcinoma, immunotherapy, pancreatic ductal adenocarcinoma, Immunologic diseases. Allergy, RC581-607, Therapeutics. Pharmacology, RM1-950
Abstract

Hepatobiliary and pancreatic cancers along with other gastrointestinal malignancies remain the leading cause of cancer-related deaths worldwide. Strategies developed in the recent years on immunotherapy and cancer vaccines in the setting of primary liver cancer as well as in pancreatic cancer are the scope of this review. Significance of orthotopic and autochthonous animal models which mimic and/or closely reflect human malignancies allowing for a prompt and trustworthy analysis of new therapeutics is underlined. Combinational approaches that on one hand, specifically target a defined cancer-driving pathway, and on the other hand, restore the functions of immune cells, which effector functions are often suppressed by a tumor milieu, are shown to have the strongest perspectives and future directions. Among combinational immunotherapeutic approaches a personalized- and individual cancer case-based therapy is of special importance.

Published
2017
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56. DTPA-Receptor – A novel reporter gene system for the specific and sensitive PET imaging of CAR-T cells and AAV transduced cells

Author

Weber, Wolfgang, primary, Morath, Volker, additional, Fritschle, Katja, additional, Warmuth, Linda, additional, Anneser, Markus, additional, Dötsch, Sarah, additional, Zivanic, Milica, additional, Krumwiede, Luisa, additional, Bösl, Philipp, additional, Bozoglu, Tarik, additional, Robu, Stephanie, additional, Libertini, Silvana, additional, Kossatz, Susanne, additional, Kupatt, Christian, additional, Schwaiger, Markus, additional, Steiger, Katja, additional, Busch, Dirk, additional, and Skerra, Arne, additional

Published
2023
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62. Characterization of CD34+ and CD34- cells from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Wolf, Benita, primary, Krieg, Kathrin, primary, Falk, Christine, primary, Breuhahn, Kai, primary, Keppeler, Hildegard, primary, Biedermann, Tilo, primary, Schmid, Evi, primary, Warmann, Steven, primary, Fuchs, Joerg, primary, Vetter, Silvia, primary, Thiele, Dennis, primary, Nieser, Maike, primary, Avci-Adali, Meltem, primary, Skokowa, Yulia, primary, Schöls, Ludger, primary, Hauser, Stefan, primary, Ringelhan, Marc, primary, Yevsa, Tetyana, primary, Heikenwalder, Mathias, primary, and Kossatz-Boehlert, Uta, primary

Published
2023
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63. Supplemental Material and Methods from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Wolf, Benita, primary, Krieg, Kathrin, primary, Falk, Christine, primary, Breuhahn, Kai, primary, Keppeler, Hildegard, primary, Biedermann, Tilo, primary, Schmid, Evi, primary, Warmann, Steven, primary, Fuchs, Joerg, primary, Vetter, Silvia, primary, Thiele, Dennis, primary, Nieser, Maike, primary, Avci-Adali, Meltem, primary, Skokowa, Yulia, primary, Schöls, Ludger, primary, Hauser, Stefan, primary, Ringelhan, Marc, primary, Yevsa, Tetyana, primary, Heikenwalder, Mathias, primary, and Kossatz-Boehlert, Uta, primary

Published
2023
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64. Supplementary Fig. 2 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Kossatz, Susanne, primary, Carney, Brandon, primary, Schweitzer, Melanie, primary, Carlucci, Giuseppe, primary, Miloushev, Vesselin Z., primary, Maachani, Uday B., primary, Rajappa, Prajwal, primary, Keshari, Kayvan R., primary, Pisapia, David, primary, Weber, Wolfgang A., primary, Souweidane, Mark M., primary, and Reiner, Thomas, primary

Published
2023
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65. Supplemental Figure legends from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Wolf, Benita, primary, Krieg, Kathrin, primary, Falk, Christine, primary, Breuhahn, Kai, primary, Keppeler, Hildegard, primary, Biedermann, Tilo, primary, Schmid, Evi, primary, Warmann, Steven, primary, Fuchs, Joerg, primary, Vetter, Silvia, primary, Thiele, Dennis, primary, Nieser, Maike, primary, Avci-Adali, Meltem, primary, Skokowa, Yulia, primary, Schöls, Ludger, primary, Hauser, Stefan, primary, Ringelhan, Marc, primary, Yevsa, Tetyana, primary, Heikenwalder, Mathias, primary, and Kossatz-Boehlert, Uta, primary

Published
2023
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66. Supplementary Fig. 1 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Kossatz, Susanne, primary, Carney, Brandon, primary, Schweitzer, Melanie, primary, Carlucci, Giuseppe, primary, Miloushev, Vesselin Z., primary, Maachani, Uday B., primary, Rajappa, Prajwal, primary, Keshari, Kayvan R., primary, Pisapia, David, primary, Weber, Wolfgang A., primary, Souweidane, Mark M., primary, and Reiner, Thomas, primary

Published
2023
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67. Supplementary Fig. 3 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Kossatz, Susanne, primary, Carney, Brandon, primary, Schweitzer, Melanie, primary, Carlucci, Giuseppe, primary, Miloushev, Vesselin Z., primary, Maachani, Uday B., primary, Rajappa, Prajwal, primary, Keshari, Kayvan R., primary, Pisapia, David, primary, Weber, Wolfgang A., primary, Souweidane, Mark M., primary, and Reiner, Thomas, primary

Published
2023
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68. Supplementary Fig. 6 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Kossatz, Susanne, primary, Carney, Brandon, primary, Schweitzer, Melanie, primary, Carlucci, Giuseppe, primary, Miloushev, Vesselin Z., primary, Maachani, Uday B., primary, Rajappa, Prajwal, primary, Keshari, Kayvan R., primary, Pisapia, David, primary, Weber, Wolfgang A., primary, Souweidane, Mark M., primary, and Reiner, Thomas, primary

Published
2023
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71. Data from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Wolf, Benita, primary, Krieg, Kathrin, primary, Falk, Christine, primary, Breuhahn, Kai, primary, Keppeler, Hildegard, primary, Biedermann, Tilo, primary, Schmid, Evi, primary, Warmann, Steven, primary, Fuchs, Joerg, primary, Vetter, Silvia, primary, Thiele, Dennis, primary, Nieser, Maike, primary, Avci-Adali, Meltem, primary, Skokowa, Yulia, primary, Schöls, Ludger, primary, Hauser, Stefan, primary, Ringelhan, Marc, primary, Yevsa, Tetyana, primary, Heikenwalder, Mathias, primary, and Kossatz-Boehlert, Uta, primary

Published
2023
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72. Supplementary Fig. 7 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Kossatz, Susanne, primary, Carney, Brandon, primary, Schweitzer, Melanie, primary, Carlucci, Giuseppe, primary, Miloushev, Vesselin Z., primary, Maachani, Uday B., primary, Rajappa, Prajwal, primary, Keshari, Kayvan R., primary, Pisapia, David, primary, Weber, Wolfgang A., primary, Souweidane, Mark M., primary, and Reiner, Thomas, primary

Published
2023
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73. Supplementary methods from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Kossatz, Susanne, primary, Carney, Brandon, primary, Schweitzer, Melanie, primary, Carlucci, Giuseppe, primary, Miloushev, Vesselin Z., primary, Maachani, Uday B., primary, Rajappa, Prajwal, primary, Keshari, Kayvan R., primary, Pisapia, David, primary, Weber, Wolfgang A., primary, Souweidane, Mark M., primary, and Reiner, Thomas, primary

Published
2023
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74. The mTORC1 pathway in Cul3/p53 ko cells from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Wolf, Benita, primary, Krieg, Kathrin, primary, Falk, Christine, primary, Breuhahn, Kai, primary, Keppeler, Hildegard, primary, Biedermann, Tilo, primary, Schmid, Evi, primary, Warmann, Steven, primary, Fuchs, Joerg, primary, Vetter, Silvia, primary, Thiele, Dennis, primary, Nieser, Maike, primary, Avci-Adali, Meltem, primary, Skokowa, Yulia, primary, Schöls, Ludger, primary, Hauser, Stefan, primary, Ringelhan, Marc, primary, Yevsa, Tetyana, primary, Heikenwalder, Mathias, primary, and Kossatz-Boehlert, Uta, primary

Published
2023
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75. Differentiation stain using immunofluorescence from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Wolf, Benita, primary, Krieg, Kathrin, primary, Falk, Christine, primary, Breuhahn, Kai, primary, Keppeler, Hildegard, primary, Biedermann, Tilo, primary, Schmid, Evi, primary, Warmann, Steven, primary, Fuchs, Joerg, primary, Vetter, Silvia, primary, Thiele, Dennis, primary, Nieser, Maike, primary, Avci-Adali, Meltem, primary, Skokowa, Yulia, primary, Schöls, Ludger, primary, Hauser, Stefan, primary, Ringelhan, Marc, primary, Yevsa, Tetyana, primary, Heikenwalder, Mathias, primary, and Kossatz-Boehlert, Uta, primary

Published
2023
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76. Effects of single or combinational doxorubicin treatment in Cul3/p53 ko cells from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Wolf, Benita, primary, Krieg, Kathrin, primary, Falk, Christine, primary, Breuhahn, Kai, primary, Keppeler, Hildegard, primary, Biedermann, Tilo, primary, Schmid, Evi, primary, Warmann, Steven, primary, Fuchs, Joerg, primary, Vetter, Silvia, primary, Thiele, Dennis, primary, Nieser, Maike, primary, Avci-Adali, Meltem, primary, Skokowa, Yulia, primary, Schöls, Ludger, primary, Hauser, Stefan, primary, Ringelhan, Marc, primary, Yevsa, Tetyana, primary, Heikenwalder, Mathias, primary, and Kossatz-Boehlert, Uta, primary

Published
2023
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77. Supplementary Fig. 5 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Kossatz, Susanne, primary, Carney, Brandon, primary, Schweitzer, Melanie, primary, Carlucci, Giuseppe, primary, Miloushev, Vesselin Z., primary, Maachani, Uday B., primary, Rajappa, Prajwal, primary, Keshari, Kayvan R., primary, Pisapia, David, primary, Weber, Wolfgang A., primary, Souweidane, Mark M., primary, and Reiner, Thomas, primary

Published
2023
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78. Supplementary Fig. 4 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Kossatz, Susanne, primary, Carney, Brandon, primary, Schweitzer, Melanie, primary, Carlucci, Giuseppe, primary, Miloushev, Vesselin Z., primary, Maachani, Uday B., primary, Rajappa, Prajwal, primary, Keshari, Kayvan R., primary, Pisapia, David, primary, Weber, Wolfgang A., primary, Souweidane, Mark M., primary, and Reiner, Thomas, primary

Published
2023
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79. Effects of doxorubicin and hCXCL8 on stem associated markers in hHCC cell lines from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Wolf, Benita, primary, Krieg, Kathrin, primary, Falk, Christine, primary, Breuhahn, Kai, primary, Keppeler, Hildegard, primary, Biedermann, Tilo, primary, Schmid, Evi, primary, Warmann, Steven, primary, Fuchs, Joerg, primary, Vetter, Silvia, primary, Thiele, Dennis, primary, Nieser, Maike, primary, Avci-Adali, Meltem, primary, Skokowa, Yulia, primary, Schöls, Ludger, primary, Hauser, Stefan, primary, Ringelhan, Marc, primary, Yevsa, Tetyana, primary, Heikenwalder, Mathias, primary, and Kossatz-Boehlert, Uta, primary

Published
2023
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80. Doxorubicin treatments (raw data) in human HCC cell lines from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Wolf, Benita, primary, Krieg, Kathrin, primary, Falk, Christine, primary, Breuhahn, Kai, primary, Keppeler, Hildegard, primary, Biedermann, Tilo, primary, Schmid, Evi, primary, Warmann, Steven, primary, Fuchs, Joerg, primary, Vetter, Silvia, primary, Thiele, Dennis, primary, Nieser, Maike, primary, Avci-Adali, Meltem, primary, Skokowa, Yulia, primary, Schöls, Ludger, primary, Hauser, Stefan, primary, Ringelhan, Marc, primary, Yevsa, Tetyana, primary, Heikenwalder, Mathias, primary, and Kossatz-Boehlert, Uta, primary

Published
2023
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81. Der Multigentest EndoPredict® als prognostischer Biomarker in der klinischen Routine beim frühen Östrogenrezeptor-positiven, Her2-negativen Mammakarzinom

Author

Kiechle, Marion B. (Prof. Dr.), Kiechle, Marion B. (Prof. Dr.);Kossatz, Susanne (Prof. Dr.), Anders, Sophie-Isabelle, Kiechle, Marion B. (Prof. Dr.), Kiechle, Marion B. (Prof. Dr.);Kossatz, Susanne (Prof. Dr.), and Anders, Sophie-Isabelle

Abstract

Multigentests sollen in der klinischen Routine zur Stratifizierung des Metastasierungsrisikos beim Mammakarzinom helfen. In dieser Dissertation wurde prospektiv Outcome und Compliance von Patienten mit ÖR-pos/Her2-neg Mammakarzinom erhoben, deren Entscheidung bezüglich einer Chemotherapie mithilfe des EndoPredict-Tests getroffen wurde: Der EndoPredict ist hier im klinischen Alltag den klassisch klinisch-pathologischen Parametern überlegen. Hochrisikopatienten profitieren von einer Chemotherapie., In clinical routine, multigene tests should help to stratify the risk of metastasis in breast cancer. In this dissertation, outcome and compliance of patients with ER receptor-pos/ Her2-neg breast cancer, whose decision regarding chemotherapy was made using the EndoPredict multigen test, was analysed: In everyday clinical practice, the EndoPredict test is superior to the classic clinical-pathological parameters concerning risk strafication. High-risk patients benefit from chemotherapy.

Published
2023

83. Doxorubicin treatments (raw data) in human HCC cell lines from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Uta Kossatz-Boehlert, Mathias Heikenwalder, Tetyana Yevsa, Marc Ringelhan, Stefan Hauser, Ludger Schöls, Yulia Skokowa, Meltem Avci-Adali, Maike Nieser, Dennis Thiele, Silvia Vetter, Joerg Fuchs, Steven Warmann, Evi Schmid, Tilo Biedermann, Hildegard Keppeler, Kai Breuhahn, Christine Falk, Kathrin Krieg, and Benita Wolf

Abstract

Supplemental Figure 5 data file

Published
2023

84. Supplemental Material and Methods from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Uta Kossatz-Boehlert, Mathias Heikenwalder, Tetyana Yevsa, Marc Ringelhan, Stefan Hauser, Ludger Schöls, Yulia Skokowa, Meltem Avci-Adali, Maike Nieser, Dennis Thiele, Silvia Vetter, Joerg Fuchs, Steven Warmann, Evi Schmid, Tilo Biedermann, Hildegard Keppeler, Kai Breuhahn, Christine Falk, Kathrin Krieg, and Benita Wolf

Abstract

detailed information to material and Methods

Published
2023

85. Data from Specific Targeting of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

Author

Ali Azhdarinia, William E. Fisher, Sadhna Dhingra, Thomas Reiner, Jo Simien, Hop S. Tran Cao, Sukhen C. Ghosh, Julie Voss, Susanne Kossatz, and Servando Hernandez Vargas

Abstract

Purpose:Clinically available intraoperative imaging tools to assist surgeons in identifying occult lesions are limited and partially responsible for the high rate of disease recurrence in patients with neuroendocrine tumors (NET). Using the established clinical efficacy of radiolabeled somatostatin analogs as a model, we demonstrate the ability of a fluorescent somatostatin analog to selectively target tumors that overexpress somatostatin receptor subtype-2 (SSTR2) and demonstrate utility for fluorescence-guided surgery (FGS).Experimental Design:A multimodality chelator (MMC) was used as a “radioactive linker” to synthesize the fluorescently labeled somatostatin analog, 67/68Ga-MMC(IR800)-TOC. In vivo studies were performed to determine the pharmacokinetic profile, optimal imaging time point, and specificity for SSTR2-expressing tissues. Meso- and microscopic imaging of resected tissues and frozen sections were also performed to further assess specific binding, and binding to human NETs was examined using surgical biospecimens from patients with pancreatic NETs.Results:Direct labeling with 67Ga/68Ga provided quantitative biodistribution analysis that was in agreement with fluorescence data. Receptor-mediated uptake was observed in vivo and ex vivo at the macro-, meso-, and microscopic scales. Surgical biospecimens from patients with pancreatic NETs also displayed receptor-specific agent binding, allowing clear delineation of tumor boundaries that matched pathology findings.Conclusions:The radioactive utility of the MMC allowed us to validate the binding properties of a novel FGS agent that could have a broad impact on cancer outcomes by equipping surgeons with real-time intraoperative imaging capabilities.

Published
2023

86. Data from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Uta Kossatz-Boehlert, Mathias Heikenwalder, Tetyana Yevsa, Marc Ringelhan, Stefan Hauser, Ludger Schöls, Yulia Skokowa, Meltem Avci-Adali, Maike Nieser, Dennis Thiele, Silvia Vetter, Joerg Fuchs, Steven Warmann, Evi Schmid, Tilo Biedermann, Hildegard Keppeler, Kai Breuhahn, Christine Falk, Kathrin Krieg, and Benita Wolf

Abstract

Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related deaths and is reported to be resistant to chemotherapy caused by tumor-initiating cells. These tumor-initiating cells express stem cell markers. An accumulation of tumor-initiating cells can be found in 2% to 50% of all HCC and is correlated with a poor prognosis. Mechanisms that mediate chemoresistance include drug export, increased metabolism, and quiescence. Importantly, the mechanisms that regulate quiescence in tumor-initiating cells have not been analyzed in detail so far. In this research we have developed a single cell tracking method to follow up the fate of tumor-initiating cells during chemotherapy. Thereby, we were able to demonstrate that mCXCL1 exerts cellular state-specific effects regulating the resistance to chemotherapeutics. mCXCL1 is the mouse homolog of the human IL8, a chemokine that correlates with poor prognosis in HCC patients. We found that mCXCL1 blocks differentiation of premalignant cells and activates quiescence in tumor-initiating cells. This process depends on the activation of the mTORC1 kinase. Blocking of the mTORC1 kinase induces differentiation of tumor-initiating cells and allows their subsequent depletion using the chemotherapeutic drug doxorubicin. Our work deciphers the mCXCL1–mTORC1 pathway as crucial in liver cancer stem cell maintenance and highlights it as a novel target in combination with conventional chemotherapy. Cancer Res; 76(18); 5550–61. ©2016 AACR.

Published
2023

87. Supplemental Figure legends from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Uta Kossatz-Boehlert, Mathias Heikenwalder, Tetyana Yevsa, Marc Ringelhan, Stefan Hauser, Ludger Schöls, Yulia Skokowa, Meltem Avci-Adali, Maike Nieser, Dennis Thiele, Silvia Vetter, Joerg Fuchs, Steven Warmann, Evi Schmid, Tilo Biedermann, Hildegard Keppeler, Kai Breuhahn, Christine Falk, Kathrin Krieg, and Benita Wolf

Abstract

Figure legends

Published
2023

88. Effects of doxorubicin and hCXCL8 on stem associated markers in hHCC cell lines from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Uta Kossatz-Boehlert, Mathias Heikenwalder, Tetyana Yevsa, Marc Ringelhan, Stefan Hauser, Ludger Schöls, Yulia Skokowa, Meltem Avci-Adali, Maike Nieser, Dennis Thiele, Silvia Vetter, Joerg Fuchs, Steven Warmann, Evi Schmid, Tilo Biedermann, Hildegard Keppeler, Kai Breuhahn, Christine Falk, Kathrin Krieg, and Benita Wolf

Abstract

Supplemental Figure 6 data file

Published
2023

89. Supplementary Fig. 7 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Thomas Reiner, Mark M. Souweidane, Wolfgang A. Weber, David Pisapia, Kayvan R. Keshari, Prajwal Rajappa, Uday B. Maachani, Vesselin Z. Miloushev, Giuseppe Carlucci, Melanie Schweitzer, Brandon Carney, and Susanne Kossatz

Abstract

Monitoring tumor growth using [18F]PARPi. Display of weekly imaging of tumor development in adult ntv-a;p53fl/fl mice at the indicated time after DF1 cell injection. PET/CT imaging was always conducted 2 h p.i. of [18F]PARPi. Animals were sacrificed after week 6 and tumor presence was confirmed histologically. (b) One animal showed no increase in [18F]PARPi uptake over the weeks and we confirmed histologically that tumor development was absent in this case.

Published
2023

90. Data from Targeted Brain Tumor Radiotherapy Using an Auger Emitter

Author

Thomas Reiner, John L. Humm, Jason S. Lewis, Brian M. Zeglis, Masatomo Maeda, Paula Demétrio De Souza França, Navjot Guru, Susanne Kossatz, Ahmad Sadique, Lukas M. Carter, Stephen A. Jannetti, and Giacomo Pirovano

Abstract

Purpose:Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades.Experimental Design:123I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA.Results:The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of 123I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small-molecule radiotheranostic in a complex preclinical model. In vitro and in vivo studies demonstrate high tumor uptake and a prolonged survival in mice treated with 123I-MAPi when compared with vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery and intrathecal injection.Conclusions:Taken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of 123I-MAPi for clinical translation.

Published
2023

91. Supplementary Fig. 2 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Thomas Reiner, Mark M. Souweidane, Wolfgang A. Weber, David Pisapia, Kayvan R. Keshari, Prajwal Rajappa, Uday B. Maachani, Vesselin Z. Miloushev, Giuseppe Carlucci, Melanie Schweitzer, Brandon Carney, and Susanne Kossatz

Abstract

Chemical structures of PARPi-FL and [18F]PARPi. We developed a fluorescent ("PARPi-FL") (a) and 18F-labelled ("[18F]PARPi") (b) version of a PARP1 targeted small molecule, based on the structure of Olaparib23, 26, 27. Mouse and human PARP1 are orthologs, therefore PARP1 inhibitors bind to both with the same affinity.

Published
2023

92. Supplementary Fig. 6 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Thomas Reiner, Mark M. Souweidane, Wolfgang A. Weber, David Pisapia, Kayvan R. Keshari, Prajwal Rajappa, Uday B. Maachani, Vesselin Z. Miloushev, Giuseppe Carlucci, Melanie Schweitzer, Brandon Carney, and Susanne Kossatz

Abstract

Biodistribution of [18F]PARPi in healthy ntv-a;p53fl/fl mice 2 h p.i.. Animals were injected with [18F]PARPi 2 hours prior to the biodistribution study (n=4). To control for uptake specificity, one group (n=4) was injected with 1 mg Olaparib 30min prior to the [18F]PARPi injection. The biodistribution shows specific (=blockable) uptake of [18F]PARPi in several organs (e.g. lymph nodes, spleen, pancreas, bone, indicating the presence of PARP1 expressing cells, whereas the uptake in liver and kidney cannot be blocked and is therefore due to excretion processes. N=4 per group, 1 mg Olaparib 30 min prior for blocking. Bl-blood, Br-brain, SG-salivary gland, LN-lymph node, He-heart, Sp-spleen, Pa-pancreas, Li-liver, Ki-kidney, St-stomach, SI-small intestine, LI-large intestine, Mu-muscle, Bo-bone.

Published
2023

93. The mTORC1 pathway in Cul3/p53 ko cells from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Uta Kossatz-Boehlert, Mathias Heikenwalder, Tetyana Yevsa, Marc Ringelhan, Stefan Hauser, Ludger Schöls, Yulia Skokowa, Meltem Avci-Adali, Maike Nieser, Dennis Thiele, Silvia Vetter, Joerg Fuchs, Steven Warmann, Evi Schmid, Tilo Biedermann, Hildegard Keppeler, Kai Breuhahn, Christine Falk, Kathrin Krieg, and Benita Wolf

Abstract

Supplemental Figure 3 data file

Published
2023

95. Supplementary Fig. 3 from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Thomas Reiner, Mark M. Souweidane, Wolfgang A. Weber, David Pisapia, Kayvan R. Keshari, Prajwal Rajappa, Uday B. Maachani, Vesselin Z. Miloushev, Giuseppe Carlucci, Melanie Schweitzer, Brandon Carney, and Susanne Kossatz

Abstract

Histological characterization of GEMM tumor model and PARPi-FL localization. (a) The GEMM model showed heterogenous morphological characteristics, representing high grade areas (with necrotic features, high cellularity, microvascular proliferation) and lower grade areas (less cellular, no necrosis). PARP1 expression was more pronounced in high grade areas compared to low grade areas and very low in normal pons. (b) Immunofluorescent characterization of high grade and low grade tumor areas and healthy brain. Tissues were stained for Ki67, CD31 and PARP1 expression. This was compared to the localization of intravenously in vivo injected PARPi-FL.

Published
2023

96. Characterization of CD34+ and CD34- cells from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Uta Kossatz-Boehlert, Mathias Heikenwalder, Tetyana Yevsa, Marc Ringelhan, Stefan Hauser, Ludger Schöls, Yulia Skokowa, Meltem Avci-Adali, Maike Nieser, Dennis Thiele, Silvia Vetter, Joerg Fuchs, Steven Warmann, Evi Schmid, Tilo Biedermann, Hildegard Keppeler, Kai Breuhahn, Christine Falk, Kathrin Krieg, and Benita Wolf

Abstract

Supplemental Figure 1 data file

Published
2023

97. Data from Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models

Author

Thomas Reiner, Mark M. Souweidane, Wolfgang A. Weber, David Pisapia, Kayvan R. Keshari, Prajwal Rajappa, Uday B. Maachani, Vesselin Z. Miloushev, Giuseppe Carlucci, Melanie Schweitzer, Brandon Carney, and Susanne Kossatz

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a universally poor prognosis. Here, we characterize a positron emission tomography (PET) probe for imaging DIPG in vivo. In human histological tissues, the probes target, PARP1, was highly expressed in DIPG compared to normal brain. PET imaging allowed for the sensitive detection of DIPG in a genetically engineered mouse model, and probe uptake correlated to histologically determined tumor infiltration. Imaging with the sister fluorescence agent revealed that uptake was confined to proliferating, PARP1-expressing cells. Comparison with other imaging technologies revealed remarkable accuracy of our biomarker approach. We subsequently demonstrated that serial imaging of DIPG in mouse models enables monitoring of tumor growth, as shown in modeling of tumor progression. Overall, this validated method for quantifying DIPG burden would serve useful in monitoring treatment response in early phase clinical trials. Cancer Res; 77(8); 2112–23. ©2017 AACR.

Published
2023

98. Effects of single or combinational doxorubicin treatment in Cul3/p53 ko cells from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

Author

Uta Kossatz-Boehlert, Mathias Heikenwalder, Tetyana Yevsa, Marc Ringelhan, Stefan Hauser, Ludger Schöls, Yulia Skokowa, Meltem Avci-Adali, Maike Nieser, Dennis Thiele, Silvia Vetter, Joerg Fuchs, Steven Warmann, Evi Schmid, Tilo Biedermann, Hildegard Keppeler, Kai Breuhahn, Christine Falk, Kathrin Krieg, and Benita Wolf

Abstract

Supplemental Figure 4 data file

Published
2023

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