Menée sur une lignée cellulaire humaine de cancer du poumon, cette étude montre que les rayonnements ionisants des grains d'iode 125 peuvent favoriser la mort des cellules tumorales en bloquant leur cycle cellulaire au point de contrôle G2/M

Biological Effects of 125I Seeds Radiation on A549 Lung Cancer Cells: G2/M Arrest and Enhanced Cell Death

Qu, Ang ; Wang, Hao ; Li, Jinna ; Wang, Junjie ; Liu, Jingjia ; Hou, Yuzhu ; Huang, Li ; Zhao, Yong

External beam radiation (EBRT) and 125I seeds continuous low dose rate radiation (CLDR) were used to treat patients with lung cancer. We herein investigated the biological effects of EBRT and CLDR on lung cancer cells. A549 human lung cancer cell line was thus exposed to different doses of EBRT and CLDR. CLDR was more efficient to inhibit cell growth than EBRT. CLDR induced increased DNA damage as evidenced by long-lasting p-H2AX activity. The enhanced inhibitory effects of CLDR on lung cancer [...]

A partir d'une revue systématique de la littérature publiée entre janvier 2003 et juin 2012 (50 articles), cette étude évalue la faisabilité et le bénéfice, en termes de survie globale, d'une métastasectomie hépatique chez les patients atteints d'un cancer colorectal et d'une maladie extra-hépatique

Systematic review of outcomes of patients undergoing resection for colorectal liver metastases in the setting of extra hepatic disease

Hwang, Michael ; Jayakrishnan, Thejus T. ; Green, Danielle E. ; George, Ben ; Thomas, James P. ; Groeschl, Ryan T. ; Erickson, Beth ; Pappas, Sam G. ; Clark Gamblin, T. ; Turaga, Kiran K.

Background : Surgical resection for patients with colorectal liver metastases (CRLM) can offer patients a significant survival benefit. We hypothesised that patients with CRLM and extra hepatic disease (EHD) undergoing metastasectomy had comparable survival and describe outcomes based on the distribution of metastatic disease. Methods : A systematic search using a predefined registered protocol was undertaken between January 2003 and June 2012. Primary exposure was hepatic resection for CRLM [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude suggère l'intérêt d'une stratégie basée sur l'inhibition combinée de MET et de ERK pour le traitement d'un cancer gastrique avec amplification de MET

Dynamic Reprogramming of Signaling Upon Met Inhibition Reveals a Mechanism of Drug Resistance in Gastric Cancer

Lai, Andrea Z. ; Cory, Sean ; Zhao, Hong ; Gigoux, Mathieu ; Monast, Anie ; Guiot, Marie-Christine ; Huang, Sidong ; Tofigh, Ali ; Thompson, Crista ; Naujokas, Monica ; Marcus, Victoria A. ; Bertos, Nicholas ; Sehat, Bita ; Perera, Rushika M. ; Bell, Emily S. ; Page, Brent D. G. ; Gunning, Patrick T. ; Ferri, Lorenzo E. ; Hallett, Michael ; Park, Morag

The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, [...]

Cet article passe en revue les travaux récents dans le développement préclinique d'inhibiteurs sélectifs de l'export de protéines nucléaires pour le traitement des cancers

Clinical Translation of Nuclear Export Inhibitors in Cancer

Senapedis, William T. ; Baloglu, Erkan ; Landesman, Yosef

Clinical targeting of multi-dimensional proteins such as the proteasome has been efficacious in recent years. Inhibitors such as bortezomib and carfilzomib have been used successfully to treat multiple myeloma despite early skepticism surrounding unsubstantiated toxic side effects. Another target of this magnitude is ready to emerge as a clinically viable option for targeting various neoplasias. This target, XPO1 (exportin-1 also known as Chromosome Region Maintenance 1 (CRM1)), is the [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes permettant de rendre compte d'une faible efficacité des inhibiteurs de MEK dans les tumeurs présentant des mutations du gène KRAS

Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors

Lito, Piro ; Saborowski, Anna ; Yue, Jingyin ; Solomon, Martha ; Joseph, Eric ; Gadal, Sunyana ; Saborowski, Michael ; Kastenhuber, Edward ; Fellmann, Christof ; Ohara, Kazuhiro ; Morikami, Kenji ; Miura, Takaaki ; Lukacs, Christine ; Ishii, Nobuya ; Lowe, Scott ; Rosen, Neal

MEK inhibitors are clinically active in BRAFV600E melanomas but only marginally so in KRAS mutant tumors. Here, we found that MEK inhibitors suppress ERK signaling more potently in BRAFV600E, than in KRAS mutant tumors. To understand this, we performed an RNAi screen in a KRAS mutant model and found that CRAF knockdown enhanced MEK inhibition. MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAFV600E. MEK inhibitors induced RAF-MEK complexes in KRAS mutant [...]

Cet article passe en revue les travaux récents sur les mécanismes d'action de la trabectédine dans les cellules tumorales et leur micro-environnement

Trabectedin, a drug acting on both cancer cells and the tumour microenvironment

D'Incalci, M. ; Badri, N. ; Galmarini, C. M. ; Allavena, P.

Trabectedin is the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of patients with relapsed platinum-sensitive ovarian cancer. From the beginning of its development, trabectedin showed some peculiar properties that clearly distinguished it from other anti-cancer drugs. In this mini-review, we will outline the current state of knowledge regarding the mode of action of [...]

Cet article passe en revue les travaux récents sur le développement d'inhibiteurs de la signalisation PI3K/AKT/mTOR pour le traitement des cancers

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

Dienstmann, Rodrigo ; Rodon, Jordi ; Serra, Violeta ; Tabernero, Josep

The frequent activation of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival, has made it a much desired target for pharmacologic intervention. Following the regulatory approval of the rapamycin analogs everolimus and temsirolimus, recent years have seen an explosion in the number of phosphoinositide 3-kinase (PI3K) pathway inhibitors under clinical investigation. These include: ATP-competitive, dual inhibitors of class I PI3K and mTORC1/2; “pan-PI3K” [...]

Menée sur des lignées cellulaires de leucémie lymphocytaire chronique, cette étude évalue les mécanismes d'action d'un traitement combinant fludarabine et bendamustine

Evaluation of bendamustine in combination with fludarabine in primary chronic lymphocytic leukemia cells

El-Mabhouh, Amal A. ; Ayres, Mary L. ; Shpall, Elizabeth J. ; Baladandayuthapani, Veerabhadran ; Keating, Michael J. ; Wierda, William G. ; Gandhi, Varsha

The fludarabine and cyclophosphamide couplet has become the backbone of CLL standard of care. While this is an effective treatment, it results in untoward toxicity. Bendamustine is a newly approved and better-tolerated alkylating agent. We hypothesized that similar to cyclophosphamide, bendamustine-induced DNA damage will be inhibited by fludarabine, resulting in increased cytotoxicity. To test this hypothesis and the role of stromal microenvironment in this process, we treated CLL lymphocytes [...]

Cet article passe en revue les travaux récents sur les inhibiteurs d'EGFR pour le traitement de première ligne d'un cancer avancé du poumon non à petites cellules présentant des mutations du gène EGFR

Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients: Main challenges still to be overcome

Remon, J. ; Morán, T. ; Reguart, N. ; Majem, M. ; Carcereny, E. ; Lianes, P.

First line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is the standard treatment in advanced EGFR-mutant Non Small Cell Lung Cancer (NSCLC) patients, with an improvement in response rate, progression free survival, and quality of life compared with upfront chemotherapy. However, in the real world, EGFR mutation results often return positive once chemotherapy has been started. Different clinical strategies have been tested in this situation: reserve the EGFR TKI until [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes de cancer de la prostate résistant à la castration, cette étude évalue l'efficacité d'une stratégie basée sur l'inhibition des protéines BET à bromodomaine

Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer

Asangani, Irfan A. ; Dommeti, Vijaya L. ; Wang, Xiaoju ; Malik, Rohit ; Cieslik, Marcin ; Yang, Rendong ; Escara-Wilke, June ; Wilder-Romans, Kari ; Dhanireddy, Sudheer ; Engelke, Carl ; Iyer, Mathew K. ; Jing, Xiaojun ; Wu, Yi-Mi ; Cao, Xuhong ; Qin, Zhaohui S. ; Wang, Shaomeng ; Feng, Felix Y. ; Chinnaiyan, Arul M.

Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 [...]

Menée in vitro et in vivo, cette étude évalue les mécanismes d'action d'un anticorps monoclonal anti HER3 en combinaison avec le cetuximab pour le traitement de patients atteints d'un carcinome épidermoïde de la tête et du cou

Combination of Anti-HER3 Antibody MM-121/SAR256212 and Cetuximab Inhibits Tumor Growth in Preclinical Models of Head and Neck Squamous Cell Carcinoma (HNSCC)

Jiang, Ning ; Wang, Dongsheng ; Hu, Zhongliang ; Shin, Hyung Ju C. ; Qian, Guoqing ; Rahman, Mohammad Aminur ; Zhang, Hongzheng ; Amin, A.R.M. Ruhul ; Nannapaneni, Sreenivas ; Wang, Xiaojing ; Chen, Zhengjia ; Garcia, Gabriela ; MacBeath, Gavin ; Shin, Dong M. ; Khuri, Fadlo R. ; Ma, Jun ; Chen, Zhuo G. ; Saba, Nabil

The EGFR monoclonal antibody cetuximab is the only approved targeted agent for treating head and neck squamous cell carcinoma (HNSCC). Yet resistance to cetuximab has hindered its activity in this disease. Intrinsic or compensatory HER3 signaling may contribute to cetuximab resistance. To investigate the therapeutic benefit of combining MM-121/SAR256212, an anti-HER3 monoclonal antibody, with cetuximab in HNSCC, we initially screened twelve HNSCC cell lines for total and phosphorylated levels [...]

Mené sur 45 patients atteints d'un cancer avancé réfractaire aux traitements disponibles, cet essai de phase I évalue la toxicité et l'activité clinique d'une immunothérapie ciblant un récepteur des cellules dendritiques

Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205

Dhodapkar, Madhav V. ; Sznol, Mario ; Zhao, Biwei ; Wang, Ding ; Carvajal, Richard D. ; Keohan, Mary L. ; Chuang, Ellen ; Sanborn, Rachel E. ; Lutzky, Jose ; Powderly, John ; Kluger, Harriet ; Tejwani, Sheela ; Green, Jennifer ; Ramakrishna, Venky ; Crocker, Andrea ; Vitale, Laura ; Yellin, Michael ; Davis, Thomas ; Keler, Tibor

Immune-based therapies for cancer are generating substantial interest because of the success of immune checkpoint inhibitors. This study aimed to enhance anticancer immunity by exploiting the capacity of dendritic cells (DCs) to initiate T cell immunity by efficient uptake and presentation of endocytosed material. Delivery of tumor-associated antigens to DCs using receptor-specific monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits robust antigen-specific immune [...]

Mené sur 50 patients atteints d'une tumeur neuroendocrine de stade avancé (âge médian : 60,5 ans), cet essai italien de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité de l'évérolimus en combinaison avec l'octréotide

Everolimus in combination with octreotide long-acting repeatable in a first-line setting for patients with neuroendocrine tumors: An ITMO group study

Bajetta, Emilio ; Catena, Laura ; Fazio, Nicola ; Pusceddu, Sara ; Biondani, Pamela ; Blanco, Giusi ; Ricci, Sergio ; Aieta, Michele ; Pucci, Francesca ; Valente, Monica ; Bianco, Nadia ; Mauri, Chiara Maria ; Spada, Francesca

BACKGROUND Preclinical and clinical studies suggest synergistic activity between somatostatin analogues and mammalian target of rapamycin inhibitors. The activity and safety of everolimus was assessed in combination with octreotide long-acting repeatable (LAR) in patients with neuroendocrine tumors (NETs) of gastroenteropancreatic and lung origin. METHODS This was a phase 2, multicenter trial using a Simon's 2-stage minimax design. Treatment-naive patients with advanced well-differentiated NETs [...]

Mené sur 46 patients atteints d'un mélanome métastatique, cet essai évalue la toxicité et l'activité clinique d'un traitement combinant bévacizumab et ipilimumab (durée médiane de survie : 25,1 mois)

Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma

Hodi, F. Stephen ; Lawrence, Donald P ; Lezcano, Cecilia ; Wu, Xinqi ; Zhou, Jun ; Sasada, Tetsuro ; Zeng, WanYong ; Giobbie-Hurder, Anita ; Atkins, Michael B. ; Ibrahim, Nageatte ; Friedlander, Philip ; Flaherty, Keith T ; Murphy, George ; Rodig, Scott J. ; Velazquez, Elsa ; MIHM, MARTIN C ; Russell, Sara ; Dipiro, Pamela ; Yap, Jeff ; Ramaiya, Nikhil ; Van den Abbeele, Annick D ; Gargano, Maria ; McDermott, David F

Ipilimumab improves survival in advanced melanoma and can induce immune mediated tumor vasculopathy. Besides promoting angiogenesis, VEGF suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA-4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) every 3 weeks for four doses then every 12 weeks, and [...]

Cet article passe en revue les travaux récents sur les traitements d'un cancer de l'ovaire de stade avancé

Ovarian cancer

Jayson, Gordon C. ; Kohn, Elise C. ; Kitchener, Henry C. ; Ledermann, Jonathan A.

Epithelial ovarian cancer is the commonest cause of gynaecological cancer-associated death. The disease typically presents in postmenopausal women, with a few months of abdominal pain and distension. Most women have advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stage III), for which the standard of care remains surgery and platinum-based cytotoxic chemotherapy. Although this treatment can be curative for most patients with early stage disease, most women with [...]

Cet article fait le point sur les indications et les limites de chimiothérapies et de thérapies ciblées pour traiter des métastases cérébrales ayant pour origine un cancer du poumon non à petites cellules

Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases

Zimmermann, Stefan ; Dziadziuszko, Rafal ; Peters, Solange

Lung cancer is characterized by the highest incidence of solid tumor-related brain metastases, which are reported with a growing incidence during the last decade. Prognostic assessment may help to identify subgroups of patients that could benefit from more aggressive therapy of metastatic disease, in particular when central nervous system is involved. The recent sub-classification of non-small cell lung cancer (NSCLC) into molecularly-defined “oncogene-addicted” tumors, the emergence of [...]

Menée sur 10 patients atteints d'un cancer de l'œsophage de stade localement avancé (âge : 49-75 ans ; durée médiane de suivi : 14 mois), cette étude rétrospective évalue la faisabilité d'une radiothérapie guidée par l'image et conjuguée à la modulation d’intensité en combinaison avec une chimiothérapie concomitante par 5-fluorouracile

Feasibility of intensity-modulated and image-guided radiotherapy for locally advanced esophageal cancer

Nguyen, Nam ; Jang, Siyoung ; Vock, Jacqueline ; Vinh-Hung, Vincent ; Chi, Alexander ; Vos, Paul ; Pugh, Judith ; Vo, Richard ; Ceizyk, Misty ; Desai, Anand ; Smith-Raymond, Lexie

Background : In this study the feasibility of intensity-modulated radiotherapy (IMRT) and tomotherapy-based image-guided radiotherapy (IGRT) for locally advanced esophageal cancer was assessed. Methods : A retrospective study of ten patients with locally advanced esophageal cancer who underwent concurrent chemotherapy with IMRT (1) and IGRT (9) was conducted. The gross tumor volume was treated to a median dose of 70 Gy (62.4-75 Gy). Results : At a median follow-up of 14 months (1-39 months), [...]

Menée dans 24 centres hospitaliers britanniques sur 322 patients atteints d'un cancer colorectal de stade avancé, cette étude évalue la faisabilité d'un processus impliquant l'analyse génomique rapide d'échantillons tumoraux pour réaliser des essais randomisés de thérapies ciblées associées à des biomarqueurs

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Maughan, T. S. ; Meade, A. M. ; Adams, R. A. ; Richman, S. D. ; Butler, R. ; Fisher, D. ; Wilson, R. H. ; Jasani, B. ; Taylor, G. R. ; Williams, G. T. ; Sampson, J. R. ; Seymour, M. T. ; Nichols, L. L. ; Kenny, S. L. ; Nelson, A. ; Sampson, C. M. ; Hodgkinson, E. ; Bridgewater, J. A. ; Furniss, D. L. ; Roy, R. ; Pope, M. J. ; Pope, J. K. ; Parmar, M. ; Quirke, P. ; Kaplan, R.

Background: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. Patients and Methods: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, [...]