Pellegatta S.,Fondazione tituto Neurologico C. Besta
Expert review of anticancer therapy | Year: 2011
A number of studies in murine models have suggested that the immune system may edit different tumors by forcing their expression profiles so that they escape immune reactions and proliferate. Glioblastoma (GB), the most frequent and aggressive primary brain tumor, provides a good example of this, thanks to the production of numerous immunosuppressive molecules (with TGF-β being of paramount importance), downregulation of the MHC complex and deregulation of the potential for antigen presentation by the surrounding microglia. Given that surgery, radiotherapy and chemotherapy with available protocols have limited effects on the survival of GB patients, different immunotherapy strategies have been developed, based on the use of dendritic cells, antibodies and peptide vaccination. Presently, bevacizumab, a humanized anti-VEGF antibody, provides the most successful example for immune-based treatment of GB, however, its action is limited in time, as the often tumor relapses due to still undefined immunoediting mechanisms. Altered function of EGF receptor-driven pathways is common in GB and is most frequently due to the presence of a deleted form named EGFRvIII, providing a unique cancer epitope that has been targeted by immunotherapy. A recent trial of GB immunotherapy based on vaccination with the EGFRvIII peptide has shown clinical benefit: interestingly most GBs at relapse were negative for EGFRvIII expression, a relevant, direct example of cancer immunoediting. Investigations on the mechanisms of GB immunoediting will lead to an increased understanding of the biology of this malignancy and hopefully provide novel therapeutic targets. Source
Di Stefano A.L.,French Institute of Health and Medical Research |
Di Stefano A.L.,University of Pavia |
Fucci A.,Columbia University |
Frattini V.,Columbia University |
And 29 more authors.
Clinical Cancer Research | Year: 2015
Purpose: Oncogenic fusions consisting of fibroblast growth factor receptor (FGFR) and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic targets. We analyzed frequency and molecular features of FGFR-TACC fusions and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade II and III glioma. Experimental Design: Overall, 795 gliomas (584 GBM, 85 grades II and III with wild-type and 126 with IDH1/2 mutation) were screened for FGFR-TACC breakpoints and associated molecular profile.Wealso analyzed expression of the FGFR3 and TACC3 components of the fusions. The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3-TACC3-positive glioma were determined in preclinical experiments. Two patients with advanced FGFR3-TACC3-positive GBM received JNJ-42756493 and were assessed for therapeutic response. Results: Three of 85 IDH1/2 wild-type (3.5%) but none of 126 IDH1/2-mutant grade II and III gliomas harbored FGFR3-TACC3 fusions. FGFR-TACC rearrangements were present in 17 of 584 GBM (2.9%). FGFR3-TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. They are mutually exclusive with IDH1/2 mutations and EGFR amplification, whereas they co-occur with CDK4 amplification. JNJ-42756493 inhibited growth of glioma cells harboring FGFR3-TACC3 in vitro and in vivo. The two patients with FGFR3-TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively. Conclusions: RT-PCR sequencing is a sensitive and specific method to identify FGFR-TACC-positive patients. FGFR3-TACC3 fusions are associated with uniform intratumor expression of the fusion protein. The clinical response observed in the FGFR3-TACC3-positive patients treated with an FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR-TACC-positive patients. © 2015 American Association for Cancer Research. Source
Brescia P.,Italian National Cancer Institute |
Ortensi B.,Italian National Cancer Institute |
Fornasari L.,Italian National Cancer Institute |
Levi D.,Fondazione tituto Neurologico C. Besta |
And 2 more authors.
Stem Cells | Year: 2013
The role of the cell surface CD133 as a cancer stem cell marker in glioblastoma (GBM) has been widely investigated, since it identifies cells that are able to initiate neurosphere growth and form heterogeneous tumors when transplanted in immune-compromised mice. However, evidences of CD133-negative cells exhibiting similar properties have also been reported. Moreover, the functional role ofa CD133 in cancer stem/progenitor cells remains poorly understood. We studied the biological effects of CD133 downregulation in GBM patient-derived neurospheres. Our results indicate that there is not a hierarchical relation between CD133-positive and CD133-negative cells composing the neurospheres. Indeed, CD133 appears in an interconvertible state, changing its subcellular localization between the cytoplasm and the plasmamembrane of neurosphere cells. Silencing of CD133 in human GBM neurospheres using lentivirus-mediated short hairpin RNA impairs the self-renewal and tumorigenic capacity of neurosphere cells. These results imply that CD133 could be used as a therapeutic target in GBMs. © AlphaMed Press. Source
Schneider L.,IFOM Foundation The FIRC Institute of Molecular Oncology Foundation |
Schneider L.,TU Darmstadt |
Pellegatta S.,Fondazione tituto Neurologico C. Besta |
Pellegatta S.,Italian National Cancer Institute |
And 9 more authors.
Stem Cell Reports | Year: 2013
The consequences of DNA damage generation in mammalian somatic stem cells, including neural stem cells (NSCs), are poorly understood despite their potential relevance for tissue homeostasis. Here, we show that, following ionizing radiation-induced DNA damage, NSCs enter irreversible proliferative arrest with features of cellular senescence. This is characterized by increased cytokine secretion, loss of stem cell markers, and astrocytic differentiation. We demonstrate that BMP2 is necessary to induce expression of the astrocyte marker GFAP in irradiated NSCs via a noncanonical signaling pathway engaging JAK-STAT. This is promoted by ATM and antagonized by p53. Using a SOX2-Cre reporter mouse model for cell-lineage tracing, we demonstrate irradiation-induced NSC differentiation in vivo. Furthermore, glioblastoma assays reveal that irradiation therapy affects the tumorigenic potential of cancer stem cells by ablating self-renewal and inducing astroglial differentiation. © 2013 The Authors. Source