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Sant'Ambrogio di Torino, Italy

Sangiolo D.,University of Turin | Sangiolo D.,Candiolo Cancer Institute FPO IRCCS
Expert Opinion on Biological Therapy | Year: 2015

Genetic engineering of T lymphocytes is an appealing strategy to confer and enhance new antitumor specificities to generate effective anticancer cell products for adoptive immunotherapy. The two main approaches are based either on transgenic tumor-antigen specific T cell receptors (TCR) or chimeric antigen receptors (CAR). Initial clinical trials reported important results against selected diseases, along with relevant warnings. Ongoing research challenges are directed toward a widespread application of this approach enhancing the range of possible target antigens, antitumor activity and safety, but also addressing logistic issues regarding cost/effectiveness, up-scaled/automated production and compliance with regulations. © 2015 Taylor & Francis Source


Bertotti A.,University of Turin | Bertotti A.,Candiolo Cancer Institute FPO IRCCS | Bertotti A.,Italian National Institute of Biosystems and Biostructures | Sassi F.,Candiolo Cancer Institute FPO IRCCS
Clinical Cancer Research | Year: 2015

Monoclonal antibodies targeting the EGF receptor (EGFR) tyrosine kinase, such as cetuximab and panitumumab, achieve clinically meaningful responses in patients affected by head and neck and colorectal cancers. Despite this evidence of efficacy, no genomic abnormalities that robustly predict sensitivity to EGFR blockade have been yet identified. This suggests that, in some tumor contexts, EGFR dependency is not acquired during neoplastic transformation and rather reflects an aberrant declination of physiologic traits typical of normal tissue counterparts. Indeed, EGFR signals are crucial for the reconstitution of damaged mucosa in the context of acute inflammation, and their sustained activation is likely to turn into a pro-oncogenic cue during chronic inflammation. Although positive predictors of response to anti-EGFR antibodies remain unknown, multiple determinants of resistance have been described, including alterations interfering with antibody-receptor interaction, deregulation of parallel signaling pathways, and mutations in downstream transducers. These findings provide new opportunities for the optimization of therapeutic strategies based on drug combinations. However, the emerging notion that genetic interactions and compensatory mechanisms may affect - both positively and negatively - the efficacy of targeted therapies complicates the rational design of combinatorial approaches and implies a rethinking of the criteria required to prioritize laboratory findings for clinical validation in investigational trials. © 2015 American Association for Cancer Research. Source


Boccaccio C.,Candiolo Cancer Institute FPO IRCCS | Boccaccio C.,University of Turin | Comoglio P.M.,Candiolo Cancer Institute FPO IRCCS | Comoglio P.M.,University of Turin
Current Opinion in Cell Biology | Year: 2014

The MET oncogene, encoding the hepatocyte growth factor receptor, drives invasive growth, a genetic program largely overlapping with epithelial-mesenchymal transition, and governing physiological and pathological processes such as tissue development and regeneration, as well as cancer dissemination. Recent studies show that MET enables cells to overcome damages inflicted by cancer anti-proliferative targeted therapies, radiotherapy or anti-angiogenic agents. After exposure to such therapies, clones of MET-amplified cancer cells arise within the context of genetically heterogeneous tumors and.. exploiting an ample platform of signaling pathways.. drive recurrence. In cancer stem cells, not only amplification, but also MET physiological expression, inherited from the cell of origin (a stem/progenitor), can contribute to tumorigenesis and therapeutic resistance, by sustaining the inherent self-renewing, self-preserving and invasive growth phenotype. © 2014 Elsevier Ltd. Source


Olivero M.,University of Turin | Olivero M.,Candiolo Cancer Institute FPO IRCCS | Dettori D.,University of Turin | Dettori D.,Candiolo Cancer Institute FPO IRCCS | And 10 more authors.
Oncotarget | Year: 2014

CDT2/L2DTL/RAMP is one of the substrate receptors of the Cullin Ring Ubiquitin Ligase 4 that targets for ubiquitin mediated degradation a number of substrates, such as CDT1, p21 and CHK1, involved in the regulation of cell cycle and survival. Here we show that CDT2 depletion was alone able to induce the apoptotic death in 12/12 human cancer cell lines from different tissues, regardless of the mutation profile and CDT2 expression level. Cell death was associated to rereplication and to loss of CDT1 degradation. Conversely, CDT2 depletion did not affect non-transformed human cells, such as immortalized kidney, lung and breast cell lines, and primary cultures of endothelial cells and osteoblasts. The ectopic over-expression of an activated oncogene, such as the mutation-activated RAS or the amplified MET in non-transformed immortalized breast cell lines and primary human osteoblasts, respectively, made cells transformed in vitro, tumorigenic in vivo, and susceptible to CDT2 loss. The widespread effect of CDT2 depletion in different cancer cells suggests that CDT2 is not in a synthetic lethal interaction to a single specific pathway. CDT2 likely is a non-oncogene to which transformed cells become addicted because of their enhanced cellular stress, such as replicative stress and DNA damage. Source


di Blasio L.,Candiolo Cancer Institute FPO IRCCS | di Blasio L.,University of Turin | Gagliardi P.A.,Candiolo Cancer Institute FPO IRCCS | Gagliardi P.A.,University of Turin | And 12 more authors.
Journal of Cell Science | Year: 2015

Non-amoeboid cell migration is characterised by dynamic competition among multiple protrusions to establish new adhesion sites at the cell's leading edge. However, the mechanisms that regulate the decision to disassemble or to grow nascent adhesions are not fully understood. Here we show that, in endothelial cells, 3- phosphoinositide-dependent protein kinase 1 (PDK1) promotes focal adhesion (FA) turnover by controlling endocytosis of integrin αvβ3 in a PI3K-dependent manner. We demonstrate that PDK1 binds and phosphorylates integrin αvβ3. Downregulation of PDK1 increases FA size and slows down their disassembly. This process requires both PDK1 kinase activity and PI3K activation but does not involve Akt. Moreover, PDK1 silencing stabilises FA in membrane protrusions decreasing migration of endothelial cells on vitronectin. These results indicate that modulation of integrin endocytosis by PDK1 hampers endothelial cell adhesion and migration on extracellular matrix, thus unveiling a novel role for this kinase. © 2015. Published by The Company of Biologists Ltd. Source

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