Reppingen, Norman (2018)
Pharmacological Augmentation of Heavy Ion Cancer Therapy.
Technische Universität Darmstadt
Dissertation, Erstveröffentlichung
Kurzbeschreibung (Abstract)
Tremendous progress is currently achieved in treating cancer, including the fields of radiother- apy, immunotherapy and pharmacology. Mechanisms of therapy methods on the one hand and treatment resistance mechanisms are increasingly elaborated, allowing to design combined treatment approaches which address the tremendous therapeutic challenges still imposed by many cancerous diseases. This also applies to heavy ion cancer therapy, which is very effec- tive as a single modality treatment, but remains a localized treatment with unclear systemic effects. On the cellular level, changes of phenotype could render tumor cells more visible to the immune system, as part of the response to radiation and by pharmacological mechanisms. In this thesis, we are looking at phenotype changes of murine tumor cell lines CT26.WT, 4T1 following x-ray and carbon ion irradiation as well as specific inhibition of c-Met, MEK and Akt, in order to gain mechanistic insights. Three pharmacological agents are evaluated, which did already show beneficial immune modulatory effects: Chloroquine, CDDO-Me and XL-184 (cabozantinib). Therefore, it is hypothesized here that the immune stimulatory properties seen in different models by others could act synergistically, as the mechanism(s) of activity of each compound are different and therefore most likely non redundant. In combination with carbon ion irradiation and x-ray an increase in apoptotic cell death was found in apoptotic cells, while carbon ion irradiation alone did rather lead to a necrotic (annexin-V negative) cell death. In an in vivo model for metastatic breast cancer (4T1) it is shown that XL184 does vastly reduce tumor growth. Conclusively, also heavy ion cancer therapy could potentially draw benefit from the pharmacological approach presented in this thesis, as the cell death mechanism and therefore the immunogenicity are potentially different.
| Typ des Eintrags: | Dissertation | ||||
|---|---|---|---|---|---|
| Erschienen: | 2018 | ||||
| Autor(en): | Reppingen, Norman | ||||
| Art des Eintrags: | Erstveröffentlichung | ||||
| Titel: | Pharmacological Augmentation of Heavy Ion Cancer Therapy | ||||
| Sprache: | Englisch | ||||
| Referenten: | Durante, Prof. Dr. Marco ; Thiel, Prof. Dr. Gerhard | ||||
| Publikationsjahr: | 2018 | ||||
| Ort: | Darmstadt | ||||
| Verlag: | TUprints | ||||
| Datum der mündlichen Prüfung: | 6 September 2017 | ||||
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/7713 | ||||
| Kurzbeschreibung (Abstract): | Tremendous progress is currently achieved in treating cancer, including the fields of radiother- apy, immunotherapy and pharmacology. Mechanisms of therapy methods on the one hand and treatment resistance mechanisms are increasingly elaborated, allowing to design combined treatment approaches which address the tremendous therapeutic challenges still imposed by many cancerous diseases. This also applies to heavy ion cancer therapy, which is very effec- tive as a single modality treatment, but remains a localized treatment with unclear systemic effects. On the cellular level, changes of phenotype could render tumor cells more visible to the immune system, as part of the response to radiation and by pharmacological mechanisms. In this thesis, we are looking at phenotype changes of murine tumor cell lines CT26.WT, 4T1 following x-ray and carbon ion irradiation as well as specific inhibition of c-Met, MEK and Akt, in order to gain mechanistic insights. Three pharmacological agents are evaluated, which did already show beneficial immune modulatory effects: Chloroquine, CDDO-Me and XL-184 (cabozantinib). Therefore, it is hypothesized here that the immune stimulatory properties seen in different models by others could act synergistically, as the mechanism(s) of activity of each compound are different and therefore most likely non redundant. In combination with carbon ion irradiation and x-ray an increase in apoptotic cell death was found in apoptotic cells, while carbon ion irradiation alone did rather lead to a necrotic (annexin-V negative) cell death. In an in vivo model for metastatic breast cancer (4T1) it is shown that XL184 does vastly reduce tumor growth. Conclusively, also heavy ion cancer therapy could potentially draw benefit from the pharmacological approach presented in this thesis, as the cell death mechanism and therefore the immunogenicity are potentially different. |
||||
| Alternatives oder übersetztes Abstract: |
|
||||
| URN: | urn:nbn:de:tuda-tuprints-77133 | ||||
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 500 Naturwissenschaften 500 Naturwissenschaften und Mathematik > 530 Physik 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 500 Naturwissenschaften und Mathematik > 590 Tiere (Zoologie) 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin, Gesundheit |
||||
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie | ||||
| Hinterlegungsdatum: | 26 Aug 2018 19:55 | ||||
| Letzte Änderung: | 26 Aug 2018 19:55 | ||||
| PPN: | |||||
| Referenten: | Durante, Prof. Dr. Marco ; Thiel, Prof. Dr. Gerhard | ||||
| Datum der mündlichen Prüfung / Verteidigung / mdl. Prüfung: | 6 September 2017 | ||||
| Export: | |||||
| Suche nach Titel in: | TUfind oder in Google | ||||
 |
Frage zum Eintrag |
Optionen (nur für Redakteure)
 |
Redaktionelle Details anzeigen |
Drucken
Impressum