hub highly phosphorylated upon integrin activation, and has long been recognized as promoting cancer cell migration, proliferation, and survival/chemoresistance through downstream activation of Rho-GEF, talin, cortactin, SFKs, PI3K/AKT, Ras/MAPK, or NF-κB pathways ( 303 , 304 ) (Figure 1). More recent studies have described that besides its classical localization at the plasma membrane of tumor cells, FAK can also translocate to the nucleus and act as a transcription factor driving the expression of cytokines and chemokines favoring tumor immune evasion, independently of integrin signaling ( 305 ). In pancreatic cancer, FAK inhibition increases the immune infiltrate within the tumor environment, thereby sensitizing tumors to immune-checkpoint blockade ( 306 ). In addition, FAK inhibition also affect stromal cells. By targeting carcinoma-associated endothelial cells, FAK inhibition enhances vascular permeability, drug delivery, and overcomes chemo-resistance to DNA-damaging agents ( 307 ). Altogether, these data largely support the potential for therapeutic benefits of FAK inhibitors, used alone or in combination therapies, in the arsenal of anti-cancer strategies, illustrated by their success in various preclinical models (Table 1). FAK inhibition mostly relies on small molecule inhibitors working through various mechanisms: ATP competitive kinase inhibition (TAE-226, VS-4718, VS-6062, VS-6063, GSK-2256098, PF-573228), FAK scaffold inhibition (compounds 14, Y11, Y15, C4, INT2-31, M13, R2), or more recently ATP competitive non-kinase inhibition (BI853520) (Table 1). In combination, FAK inhibition was reported to improve the efficacy of chemotherapeutic agents (docetaxel, paclitaxel, temzolomide, 5-FU, gemcitabine, doxorubicin), targeted therapies (EGFR inhibitor, Src inhibitor, sunitinib, BRAF inhibitor, CXCR4 inhibitor, HDAC inhibitor), or immunotherapy (PD1 antagonists, T cell immunotherapy) (Table 1). Acceptable safety profiles were obtained in phase I clinical
TGI of 46% after 11 days of treatment compared to control mice treated with the formulating vehicle. D) DPT-C9h was administered IP at 1, 5, or 25 mg/kg once daily for 5 weeks in mice bearing HBCx-12A tumours (triple negative model). Ten mice were included per group and the control group was treated with the formulating vehicle. E) DPT-sh1 and DPT-C9hM was administered IP at 1.5 mg/kg and 5 mg/Kg respectively, once daily for 5 weeks in mice bearing HBCx-12A tumours generated from the HBCx-12A cell line. Ten mice were included per group. F) DPT-C9h was administered IP at 5 mg/kg in mice bearing HBCx-12A cell line previously infected with a Ds-Red-Luc+ lentivirus. Bioluminescence imaging was shown in two mice (out ten), one receiving control vehicle (right mouse) and the other treated by DPT-C9h (left mouse). G) DPT-C9h was administrated IP at 5 mg/kg in mice bearing HBCx-3 (luminal model) once daily for five weeks. Ten mice were included per group. H) Relative variation of all treated tumours. In all in vivo experiments, mice of the control groups received 0.2 ml of the drug-formulating vehicle with the same schedule as the treated animals. Growth curves were obtained by plotting mean RTV against time. When RTV of all treated mice were considered from positive ration (resistant tumours) to negative ratio (sensitive tumours), we observed that 72% of all 198-treated mice have negative ratio, showing that peptide treatment has a high in vivo anti-tumour effect in BC xenografted models.
De plus, la découverte du VEGF comme facteur crucial dans les mécanismes d'angiogenèse de par sa surexpression dans les tumeurs constitue une cible très intéressante pour le traitement en pathologie tumorale.
C'est grâce à ces découvertes que Folkman émit l'hypothèse que le traitement avec des molécules détruisant les vaisseaux irriguant la tumeur pourrait inhiber la croissance des cellules cancéreuses, ou au moins stabiliser la tumeur. Et c'est seulement à partir des années 90 que les données expérimentales ont véritablement corroboré cette hypothèse. En effet, le rôle de l'angiogenèse dans le développement tumoral et la reconnaissance du VEGF comme un facteur clé dans ce processus ont conduit au développement de molécules anti-angiogéniques dans le traitement du cancer. Parmi elles, les principales sont celles visant à inhiber la voie du VEGF, au premier rang desquelles les anticorps anti-VEGF (bevacizumab) et les inhibiteurs de tyrosine kinase des récepteurs du VEGF (vatalanib, sorafenib, sunitinib … ). D’autres stratégies d’inhibition de l’angiogenèse sont en cours d’évaluation, ciblant la voie du VEGF ou d’autres voies impliquées dans l’angiogenèse.
test (CH50) that revealed a significant activation of the complement system by the nanohybrids. Protein-repellent polymers (e.g. PEG) will be incorporated in the PVOH crown of the nanohybrid to improve its stealthy properties.
Finally, the key characteristic of these nanohybrids is the presence of many hydroxyl functions enabling their post-functionalization by targeting agents and/or anti-tumoral compounds that could increase the selectivity and the efficiency of the therapy.
where they showed a significant increase in the one-year survival rate for carcinoma-bearing
mice treated with gold nanoparticles prior to X-ray therapy. This in vivo study preceded
several other in vitro ones to characterize the radiosensitizing effects of gold. 6 A large variety
of objects has been observed through these studies. For example, nanoparticles (NPs) size has
advancement of oxidative-antioxidative disorders is followed by progression of CRC.  Cancer cells characteristically have a high antioxidant capacity that regulates ROS to levels that are compatible with cellular biological functions but still higher than in normal cells. Targeting these high antioxidant defence mechanisms is a strategy to kill cancer cells but not normal cells. [9-12] However, all antineoplastic agents generate some ROS as they induce apoptosis in cancer cells, because one of the pathways of drug-induced apoptosis involves the release of cytochrome C from mitochondria. When this occurs, electrons are diverted from the electron transfer system to oxygen by NADH dehydrogenase and reduced coenzyme Q10, resulting in the formation of superoxide radicals. 
Keywords: colorectal cancer, chemotherapeutic stress, “stemness”, WNT/beta-catenin signaling, WNT inhibitors
Received: January 05, 2015 Accepted: April 29, 2015 Published: May 11, 2015
Most solid tumors contain a subfraction of cells with stem/progenitor cell features. Stem cells are naturally chemoresistant suggesting that chronic chemotherapeutic stress may select for cells with increased “stemness”. We carried out a comprehensive molecular and functional analysis of six independently selected colorectal cancer (CRC) cell lines with acquired resistance to three different chemotherapeutic agents derived from two distinct parental cell lines. Chronic drug exposure resulted in complex alterations of stem cell markers that could be classified into three categories: 1) one cell line, HT-29/5-FU, showed increased “stemness” and WNT-signaling, 2) three cell lines showed decreased expression of stem cell markers, decreased aldehyde dehydrogenase activity, attenuated WNT-signaling and lost the capacity to form colonospheres and 3) two cell lines displayed prominent expression of ABC transporters with a heterogeneous response for stem cell markers. While WNT- signaling could be attenuated in the HT-29/5-FU cells by the WNT-signaling inhibitors ICG-001 and PKF-118, this was not accompanied by any selective growth inhibitory effect suggesting that the cytotoxic activity of these compounds is not directly linked to WNT-signaling inhibition. We conclude that classical WNT-signaling inhibitors have toxic off-target activities that need to be addressed for clinical development.
Cell plasticity is one of the main cancer features and leads to the rapid therapeutic escape of tumor cells following the initial response. The Human Epidermal Receptor (HER) family includes four distinct receptors [EGFR (HER1 or ErbB1), HER2, HER3 and HER4] and eleven ligands [e.g., Epidermal Growth Factor and Neuregulins (NRGs)] and is one of the most extensively studied plasticity network . The HER3 receptor retains low level of kinase activity, sufficient to trans-autophosphorylate its intracellular region . After binding to NRG, HER3 is mainly activated through heterodimerization with other tyrosine kinase receptors, and the level of expression and composition of such heterodimers play a role in the diversification of downstream signaling and oncogenic effects. Such plasticity depends on the level of stimulation, nature of the ligand, cell type, receptor density and can be affected by exposure to antibodies  (Abs) that might thus contribute to HER3 regulation . A specific feature of HER3 signaling activity is its unique ability to directly activate the PI3K/AKT axis, which is at the crossroad of many downstream pathways that involve the apoptosis-related proteins MDM2, FoxO1 and X-linked Inhibitor of Apoptosis (XIAP), the proliferation-related proteins p27 Kip1 and GSK-3 and the ribosomal protein S6 . Consequently, the PI3K/AKT pathway controls different biological processes, such as cell growth, survival and apoptosis, nutrient sensing and metabolic regulation, and is implicated in tumor initiation and progression. Indeed, HER3 genetic ablation impairs in vivo PI3K/AKT-dependent mammary tumorigenesis .
Because treatment with factors that activate death receptor signaling in cancer cells may be an effective anticancer strategy it has been investigated whether PDT can affect this pro-apoptotic pathway.
The early evidence comes from the study designed by Ahmad et al.  where the involvement of the cell surface receptor Fas (CD95) pathway in A431 cells in Pc4 mediated PDT was investigated. It was observed that a significant time-dependent increase in the protein expression of Fas at 5, 15, 30 and 60 min post PDT occurred. In an immunoblot, Fas protein was observed as a doublet, which may indicate the insoluble and soluble forms of Fas. By using immunoprecipitation it was determined that Pc4-PDT resulted in a multimerization of Fas protein leading to its activation. To confirm that PDT induced apoptosis is due to Fas activation the involvement of Fas associated death domain level (FADD) was examined by using immunoblot analysis. It confirmed a time-dependent increase, for up to 1 h post-PDT in Fas protein levels. Pc4-PDT also caused activation of FADD-like interleukin-1 beta-converting enzyme (FLICE), which was evident from the appearance of cleaved products of pro- casapase-8.
Since CDK1/2 inhibitor-resistant cells are sensitised to CDK4/6 inhibitors, combining both inhibitors could be an advantaegous strategy, exploiting a double-bind whereby cells might be unable to evolve resistance to both inhibitors of CDK1/CDK2 and CDK4/CDK6 without drastic reductions in ﬁtness. This need not involve sequential administration of two drugs, as a recent study 44 determined that simultaneous treatment is more effective provided there is no cross-resistance to both drugs. Collateral sensitivity of resistant cells to alternative drugs has recently been validated in experimental models of acute lymphoblastic leukemia and shown by modelling to exploit evolutionary trajectories, much like AT 45 . CDKi-resistant cells were also sensitive to hypoxia and low serum, suggesting other collateral sensitivities that could be exploited by an additional double-bind 38 , poten- tially aiming for cure rather than long-term tumour maintenance. While empirical therapeutic approaches avoid making untested assumptions and will continue to be the mainstay of cancertherapy for the immediate future, mathematical modelling of evolutionary trajectories will take on increasing importance 46 .
families physically, psychologically, and socially. Malnutri- tion also alters disease outcome with increased morbidity, mortality, length of hospital stay, and healthcare costs [ 2 , 3 ]. Unfortunately, malnutrition is often unrecognized [ 4 ]. This may have deleterious consequences, in particular for cancer patients treated by radiotherapy, where the treatment itself is known to enhance weight loss. Thus, there is an imperative need for adequate nutritional assessment tools that provide early detection of malnutrition in patients scheduled to undergo radiotherapy. Several nutritional screening tools have been proposed in the literature but none of them gives entire satisfaction [ 5 , 6 ].
Ciblage de l’EGFR et HER2 en clinique
Les deux stratégies actuellement vali- dées en clinique sont les inhibiteurs de tyrosine kinase (TKI) qui agissent au niveau intracellulaire et les AcM dirigés contre le domaine extracellulaire de l’un ou l’autre de ces récepteurs  . Plusieurs Ac dirigés contre l’EGFR ou HER2 ont été approuvés par la FDA et l’EMEA (European Agency for the Eva- luation of Medicinal Products) et sont utilisés quotidiennement en clinique, comme le trastuzumab, dirigé contre HER2, pour le traitement du cancer du sein métastatique, ou le cetuximab, dirigé contre EGFR, utilisé en association avec une chimiothérapie dans le cancer du côlon. D’autres AcM sont en cours d’évaluation, comme le matuzumab et le panituzumab (anti-EGFR) ou le pertuzu- mab (anti-HER2).
Mot clés : Anticorps monoclonaux, EGFR, HER2, cancer, pancréas
Abstract. Unresectable pancreatic cancer is still an extremely dismal prognosis. The
conventional therapy using chemotherapy has no real effect on survival and new treatments are needed. EGFR and HER2 have been reported to be implicated and upregulated in pancreatic cancer tumorigenesis. The use of monoclonal antibodies (mAb) targeting these two receptors seems a relevant strategy for a new therapy. In a pre-clinical study, we demonstrated the therapeutic effect of the combination of two humanized Ab used in clinic, trastuzumab (Ab anti-HER2) and matuzumab (Ab anti-EGFR) in vivo in different carcinoma types. This Ab combination induced an important tumoral growth delay associated with some complete responses in two pancreatic carcinoma models expressing low HER2 level and in an ovarian model. Following all these results, a clinical trial is planned in pancreatic cancer.
Each year, breast cancer accounts for more than 400.000 new cancer cases and more than 130.000 cancer deaths in Europe. Prognosis of non metastatic breast cancer patients is directly related to extend of the disease, mainly nodal spreading and tumor size, and to molecular profile, particularly HER2 overexpression. In patients with HER2-overexpressing tumors, different studies have shown cellular and/or humoral immune responses against HER2 associated with a lower tumor development at early stages of the disease. These findings have so led to the hypothesis that the generation of an anti-HER2 immune response should protect patients from HER2-overexpressing tumor growth. Taken together with the clinical efficiency of trastuzumab-based anti- HER2 passive immunotherapy these observations allowed to envisage various vaccinal strategies against HER2. The induction of a stable and strong immunity by cancer vaccines is expected to lead to establishment of immune memory, thereby preventing tumor recurrence. However, an immunological tolerance against HER2 antigen exists representing a barrier to effective vaccination against this oncoprotein. As a consequence, the current challenge for vaccines is to find the best conditions to break this immunological tolerance. In this review, we will discuss the different anti-HER2 vaccine strategies currently developed; considering the strategies having reached the clinical phases as well as those still in preclinical development. The used antigen can be either composed of tumoral allogenic cells or autologous cells or specific of HER2. It can be delivered by dendritic cells or in a DNA, peptidic or proteic form. Another area of the research concerns the use of anti-idiotypic antibodies mimicking HER2.
Par ailleurs, la réduction du risque liée à la ménopause est plus importante pour les cancers localisés au sein que pour les cancers plus étendus, c’est à dire avec envahissement ganglionnaire ou métastases.
Il y a une relation étroite entre ménopause et risque de cancer du sein, et cette relation dépend de la corpulence. Comme l’utilisation d’un traitement substitutif est liée au nombre d’années écoulées depuis la ménopause, il est particulièrement important d’en tenir compte dans l’analyse, afin de pouvoir étudier l’effet propre de l’un et de l’autre. Pour cette raison, l’analyse des effets du traitement substitutif qui suit porte uniquement sur les femmes ménopausées dont l’âge à la ménopause est connu. Cette analyse est, par ailleurs, stratifiée sur le délai depuis la ménopause et sur l’indice de masse corporelle, aussi bien que sur l’âge, la parité et l’âge au premier enfant.
Fig. 6 zPDX reveal different response pro ﬁles to bevacizumab. Human breast cancer or CRC surgical resected samples were injected into the PVS of 2 dpf Tg( ﬂi1:eGFP) zebraﬁsh larvae. zPDXs were treated in vivo with bevacizumab and compared with untreated controls. At 4 dpi, zebraﬁsh xenografts were imaged by confocal microscopy. The percentage of apoptosis (a, zPDX#3 *P = 0.0159, g = 1.75 and zPDX#5 *P = 0.0101, g = 1.51) and tumor size (b, *P = 0.0381, g = 1.08) were quantiﬁed. In parallel, zebraﬁsh xenografts were analyzed in a ﬂuorescent stereoscope to detect micrometastasis in the CHT region, followed by confocal con ﬁrmation (c). The outcomes are expressed as AVG ± SEM. The number of xenografts analyzed are indicated below the graphs. Results are from 1 independent experiment. Statistical analysis was performed using an unpaired t-test for apoptosis and tumor size and a Fisher ’s exact test for micrometastasis. Statistical results: (ns) > 0.05, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. Cohen’s D 1988 scale of effect size with Hedges ’ g correction (g): g = 0,2 low; g = 0.5 moderate; g = 0.8 high.
c, Surface plasmon resonance measurements of the interaction of 6F6 or of an irrelevant mAb (Irr) with membrane extracts from SW620 cells that express CLDN1. d, Cross-reactivity analysis of the 6F6 mAb towards other CLDN proteins. Top: The expression of the various CLDN proteins (as indicated) in cell lysates from parental or CLDN-transfected SW480 cells was tested by western blotting using the relevant antibodies; Bottom: FACS histograms of 6 F6 binding (10 μg/mL) to parental or CLDN-transfected SW480 cells. Gray, 6 F6 mAb; dotted line, no antibody; black line, irrelevant mAb. Figure S3. CLDN1 is expressed in various cancer cell lines a, FACS histograms of the 6F6 mAb binding (gray histogram) to different cancer cell lines (pancreatic cancer: PANC-1, BXPC-3; ovarian cancer: SKOV-3, IGROV-1; hepatocarcinoma: HUH7). b, Quantification of total CLDN1 expression in the cell lines used in a by western blotting using the anti-CLDN1 polyclonal antibody JAY-8. c, CLDN1 mRNA expression in cell lines from the Cancer Cell Line Encyclopedia (http://www.broadinstitute.org/ccle). Figure S4. Detection of apoptosis in Difi spheroids using the Celigo ™ imaging system and the NucView ™ 488 cell membrane-permeable fluorogenic caspase-3 substrate. Difi cells were seeded at a density of 10 4 /ml in FluoroBrite ™ DMEM supplemented with 10% fetal bovine serum and incubated or not (NT) with 100 μg/ml of the 6 F6 mAb, the anti-EGFR cetuximab (cetux) or an irrelevant mAb (IRR). The caspase-3 substrate was added (5 μM) at the same time. Images were acquired at day 5. The bright-field and caspase 3 (green) images were merged (top panels) and the histogram (lower panel) represents the mean fluorescence intensity; * = p < 0.05 (t-test). Figure S5. Effects of the 6F6 mAb on cancer cell migration in vitro. a, Wound healing assay: confluent SW620 cell monolayers were scratched and then grown in the presence or not (NT) of 100 μg/ml of the 6 F6 mAb or irrelevant antibody (IRR). Images were captured at day 0 (D0) and day 5 (D5) after wounding. b, Cell migration assay in Boyden chambers. Caco2 cells were pre-incubated or not (NT) with 100 μg/ml of 6F6 or irrelevant (IRR) mAb. Data used for statistical analysis were from at least three independent experiments; **p < 0.01 (Kruskall Wallis/Dunn ’s test). (PPTX 2370 kb) Additional file 3: Supplementary methods: Flow cytometry experiments. Immunofluorescence studies. Surface plasmon resonance measurements. Cell migration assays. Apoptosis assay. (DOCX 37 kb) Acknowledgments
The clinical and biological aggressiveness of lung malignancies clearly does not allow for anticancer therapy to be withheld or postponed. Thus, while awaiting specific evidence-based guidelines, the comprehensive management of patients with lung cancer during the COVID-19 pandemic should involve specific and careful attention to their clinical and radiological pulmonary signs, more so than for patients with other types of tumour. From a practical viewpoint, it seems reasonable to suggest that patients with lung cancer undergo systematic testing for SARS-CoV-2 at the beginning of treatment and whenever it is deemed necessary by the treating physician in the course of therapy. This strategy might become more feasible with the increasing availability and progressive use of real-time PCR assays that can provide COVID-19