title: RGS4, CD95L and B7H3: Targeting evasive resistance and the immune privilege of glioblastoma
creator: Pfenning, Philipp-Niclas
subject: ddc-570
subject: 570 Life sciences
description: Glioblastoma are the most common primary brain tumors in adults with a median survival of one year even with multimodal therapy including surgical resection, radiotherapy, and chemotherapy. Important hallmarks of these tumors are vascular proliferation, diffuse invasion of tumor cells into the surrounding brain tissue and effective suppression of the immune system. The efficacy of resection and current radiochemotherapy treatment regimens are therefore extremely limited. Both the genesis and development as well as the progression of malignant gliomas are highly dependent on angiogenic processes, the formation of new blood vessels from pre-existing vessels. Current treatment strategies tested in clinical trials targeting tumor angiogenesis have so far not been proven to increase survival of the patients. In addition to the insufficiency of clinical trials done, this has been attributed to several potent evasion strategies occurring at disease progression and recurrence, including increasing infiltrative tumor growth, commonly referred to as ‘evasive resistance’. These invasive growth patterns occur in addition as responses to radiotherapy and essentially trigger disease progression and have a strong influence on patients’ survival.   Parts of the work presented here address the challenge of targeting the evasive resistance in glioblastoma in order to develop novel treatment strategies for a clinical application which combine anti-angiogenic with radio-enhanced anti-invasive modalities. Several strategies, focusing on different molecular targets, were undertaken: (1) Activation of the PI3K/AKT/mTOR signaling pathway is relatively common in human glioblastoma and is associated with poor survival. A clinically relevant radiation-enhanced inhibition of this pathway, using the mTOR inhibitor CCI 779, resulted in the dual control of angiogenesis and excessive invasiveness. This is mediated by a combined disrupture of the VEGF/VEGFR-2 angiogenic signaling axis on glioblastoma as well as on endothelial cells and suppression of RGS4, which was identified to be a key driver of glioblastoma invasiveness. (2) Following compelling evidence, proving that invasiveness is mediated in apoptosis-resistant glioblastoma in part by the CD95 death receptor system, antagonism of the receptor-ligand interaction was accomplished by the CD95-ligand inhibitor APG101. Clinically relevant administration of this novel compound resulted in inhibition of invasion-driving effector molecules, reduced unwanted radiotherapy-induced invasiveness, and prolonged survival of glioma-bearing mice. In addition to increased angiogenesis and invasive growth, glioblastoma effectively inhibit antitumor immune responses. Impaired recognition and attack by the immune system is effectively achieved by creating an immunosuppressive microenvironment through expression and secretion of several factors. In order to identify potential immunotherapy related targets, the costimulatory molecule B7H3 was investigated for its role in glioblastoma immunobiology. Expression correlates with grades of glioma malignancy and is associated with poor patients’ survival. Cell-bound and secreted B7H3 was identified to suppress tumor attacks by the immune system as well as to mediate invasiveness of glioblastoma cells. From the findings presented in this thesis, several therapeutic options emerge for targeting unwanted adaptive evasive escape and immunosuppression and should be considered for further clinical investigation in glioblastoma therapy.     
date: 2011
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/11962/1/DISSERTATION_Pfenning_2011.pdf
identifier: DOI:10.11588/heidok.00011962
identifier: urn:nbn:de:bsz:16-opus-119622
identifier:   Pfenning, Philipp-Niclas  (2011) RGS4, CD95L and B7H3: Targeting evasive resistance and the immune privilege of glioblastoma.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/11962/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng