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Novel approach for glioblastoma therapy by simultaneous targeting of Notch cancer stem cell signaling and angiogenesis

NOVEL APPROACH FOR GLIOBLASTOMA THERAPY BY SIMULTANEOUS TARGETING OF NOTCH CANCER STEM CELL SIGNALING AND ANGIOGENESIS

 

Project ID: PN-III-P1-1.1-PD-2016-2093 

Contract number: 121 ⁄ 2018 

Acronim: GLIOCASTENO

Funding source: State Bugdet through Romanian National Authority for Scientific Research and Innovation CNCS- UEFISCDI

Funding amount:  250.000 lei 

Period: 24 months

Project start: 02/05/2018

Project end: 30/04/2020 

Contractor: Victor Babes National Institute of Pathology

 

Project title: Novel approach for glioblastoma therapy by simultaneous targeting of Notch cancer stem cell signaling and angiogenesis

 

Team: 

Project Director: Maria Linda POPA, MD, PhD, Assistant Professor

Mentor: Cristiana TANASE, Prof. Habil. Dr. CS I

 

Summary: Glioblastoma multiforme (GBM) represent some of the most lethal forms of cancer, with a survival rate of 12-18 months from diagnosis and a 5 year survival rate which does not exceed 3%. Despite advances in understanding the molecular biology of glioblastoma multiforme, WHO grade IV, these aggressive tumors are still incurable. These statistics emphasize the need to develop new effective therapeutic strategies against this disease. 
The presence of cancer stem cells in brain tumors has been suggested in the recent years, extrapolating from other types of malignancies. The Notch signaling is a important pathway for survival of cancer stem cells. Increased Notch signaling promotes tumor development, while blockage of Notch pathway suppresses proliferation and/or survival. When considering the cross-talk between Notch signaling and the RAS/MEK/ERK and PI-3K/Akt pathways downstream of EGFR and their roles in experimental gliomas, it is tempting to speculate that simultaneous inhibition of several of these pathways could lead to improved treatment of glioma patients.

In light of recent molecular treatment resistance or inefficacy, the concomitant inhibition of Notch pathway and angiogenesis proposed in the present project could offer a promising strategy to surpass the cross talk between various pathways and to emerge as alternative therapies. 
The main objective of the present project is Evaluation of synergic effects of multiple signaling pathway inhibition (cancer stem cell signaling – Notch, angiogenesis, PI3K signaling) as potential novel therapeutical approaches for glioblastoma treatment. 

 

Project Objectives:

The main objective of the present project is Evaluation of synergic effects of multiple signaling pathway inhibition (cancer stem cell signaling – Notch, angiogenesis, PI3K signaling) as potential novel therapeutical approaches for glioblastoma treatment. 

The specific objectives
are: 

· Generation and characterization of primary patient-derived glioblastoma cell cultures; 
· Modulation of glioblastoma cell behavior trough individual and combinatorial inhibition of Notch and PI3K/ angiogenesis; 
· Evaluation of synergic combinatorial effects of Notch/ PI3K /angiogenic inhibitors as potential novel therapeutical approaches for glioblastoma treatment.

 

Estimated results:

One method/protocol: “Glioblastoma primary cell culture generation, subsequent propagation and characterization “.

Two papers published in prestigious ISI journals.

Two communications at renowned scientific congresses.

Two scientific studyies: “Modulation of glioblastoma cell behavior trough individual and combinatorial inhibition of Notch and PI3K/ angiogenesis “ and “Evaluation of synergic combinatorial effects of Notch/ PI3K /angiogenic inhibitors as potential novel therapeutical approaches for glioblastoma treatment“.

 

Results:

Phase 1 summary 

Protocol for generation, propagation and characterization of primary glioblastoma cell cultures

Phase 2 summary 

Papers:

Multiplex Assay for Multiomics Advances in Personalized-Precision Medicine, J Immunoassay Immunochem. 2019;40(1):3-25. doi: 10.1080/15321819.2018.1562940

Posters:

CANCER STEM CELL MARKERS CORRELATED WITH ANGIOGENIC FACTOR AND CYTOKINE LEVEL IN GLIOMA, The Third Conference of Immuno-Dermathology Association; The 48th Conference of Romanian Immunology Society, 18-21 September 2019, Bucharest, Romania

Abstract                                             Poster

 

Proliferation and migration hindering by selective inhibition of signaling pathways in glioblastoma cell cultures, International Conference “Cancer Metastasis”, EORTC, , 11-14 December 2019, Seefeld-in-Tirol, Austria