Menée in vitro, cette étude met en évidence un mécanisme par lequel un nanogel de polyéthylène glycol contenant des nanoparticules d'or sensibilise les cellules tumorales aux rayons X en favorisant la synthèse de protéines de stress au niveau du réticulum endoplasmique

Radiosensitization of tumor cells through endoplasmic reticulum stress induced by PEGylated nanogel containing gold nanoparticles

Yasui, Hironobu ; Takeuchi, Ryo ; Nagane, Masaki ; Meike, Shunsuke ; Nakamura, Yoshinari ; Yamamori, Tohru ; Ikenaka, Yoshinori ; Kon, Yasuhiro ; Murotani, Hiroki ; Oishi, Motoi ; Nagasaki, Yukio ; Inanami, Osamu

High atomic number molecules, such as gold and platinum, are known to enhance the biological effect of X-irradiation. This study was aimed to determine the radiosensitizing potential of PEGylated nanogel containing gold nanoparticles (GNG) and the cellular mechanism involved. GNG pretreatment increased the levels of reproductive cell death and apoptosis induced by X-irradiation. GNG accumulated in cytoplasm and increased the expression of endoplasmic reticulum (ER) stress-related protein. GNG [...]

Cet article fait le point sur le rôle du stress oxydant dans les lésions de l'ADN causées par les effets de proximité induits par les rayonnements ionisants

The role of oxidative DNA damage in radiation induced bystander effect

Havaki, Sophia ; Kotsinas, Athanassios ; Chronopoulos, Efstathios ; Kletsas, Dimitris ; Georgakilas, Alexandros ; Gorgoulis, Vassilis G.

Ionizing radiation (IR) has been described as a double-edged sword, since it is used for diagnostic and therapeutic medical applications, and at the same time it is a well known human mutagen and carcinogen, causing wide-ranging chromosomal aberrations. It is nowadays accepted that the detrimental effects of IR are not restricted only in the irradiated cells, but also to non-irradiated bystander or even distant cells manifesting various biological effects. This review presents the role of [...]

Menée sur des modèles sphéroïdes de carcinome épidermoïde de la tête et du cou, cette étude évalue l'efficacité potentielle d'une immunoradiothérapie à base de cétuximab combinée à une radiothérapie externe

Potential of a Cetuximab-based radioimmunotherapy combined with external irradiation manifests in a 3-D cell assay

Ingargiola, M. ; Runge, R. ; Heldt, J. M. ; Freudenberg, R. ; Steinbach, J. ; Cordes, N. ; Baumann, M. ; Kotzerke, J. ; Brockhoff, G. ; Kunz-Schughart, L. A.

Targeting epidermal growth factor receptor (EGFR)-overexpressing tumors with radiolabeled anti-EGFR antibodies is a promising strategy for combination with external radiotherapy. In this study, we evaluated the potential of external plus internal irradiation by [90Y]Y-CHX-A″-DTPA-C225 (Y-90-C225) in a 3-D environment using FaDu and SAS head and neck squamous cell carcinoma (HNSCC) spheroid models and clinically relevant endpoints such as spheroid control probability (SCP) and spheroid control [...]

Menée sur une cohorte de professionnels de santé comportant 903 hommes atteints d'un cancer de la prostate traité entre 2000 et 2010, cette étude compare, du point de vue de données péri-opératoires, de la survie sans récidive à 3 ou 5 ans et de la qualité de vie, l'efficacité d'une prostatectomie radicale rétropubienne par voie ouverte et d'une prostatectomie radicale laparoscopique assistée par robot

Benchmarks for Operative Outcomes of Robotic and Open Radical Prostatectomy: Results from the Health Professionals Follow-up Study

Mehrdad Alemozaffar a b , Martin Sanda a c , Derek Yecies d , Lorelei A. Mucci e f , Meir J. Stampfer e f and Stacey A. Kenfield e f g

Background : Robot-assisted laparoscopic radical prostatectomy (RALP) has become increasingly common; however, there have been no nationwide, population-based, non–claims-based studies to evaluate differences in outcomes between RALP and open radical retropubic prostatectomy (RRP). Objective : To determine surgical, oncologic, and health-related quality of life (HRQOL) outcomes following RALP and RRP in a nationwide cohort. Design, setting, and participants : We identified 903 men in the Health [...]

Menée sur 352 patients atteints d'un cancer primitif du poumon non à petites cellules, cette étude japonaise identifie les facteurs associés à l'utilisation d'un traitement chirurgical de sauvetage et analyse son efficacité en fonction des caractéristiques clinicopathologiques des patients

Salvage thoracic surgery in patients with primary lung cancer

Uramoto, Hidetaka ; Tanaka, Fumihiro

Background : Patients with advanced non-small cell lung cancer (NSCLC) continue to have a poor prognosis. The majority of patients are not indicated for surgery for a radical cure, and systemic chemotherapy is the mainstay of treatment. However, long-term survival is rare due to the resistance to therapy. On the other hand, surgery is performed only under certain conditions for colon cancer and esophageal cancer. Few reports are available about salvage thoracic surgery in patients with primary [...]

Menée sur 250 patients atteints d'un cancer du poumon de stade pT1-3N2 traité par résection complète entre 2005 et 2011 (durée médiane de suivi : 24 mois), cette étude chinoise évalue le taux de récidive loco-régionale et identifie les sites anatomiques impliqués afin de déterminer le volume tissulaire à traiter dans le cadre d'une radiothérapie post-opératoire

Patterns of Local-Regional Failure in Completely Resected Stage IIIA(N2) Non-Small Cell Lung Cancer Cases: Implications for Postoperative Radiation Therapy Clinical Target Volume Design

Feng, Wen ; Fu, Xiao-Long ; Cai, Xu-Wei ; Yang, Huan-Jun ; Wu, Kai-Liang ; Fan, Min ; Xiang, Jia-Qing ; Zhang, Ya-Wei ; Chen, Hai-Quan

Purpose : To analyze patterns of local-regional failure (LRF) for completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) patients treated in our hospital and to propose a clinical target volume (CTV) for postoperative radiation therapy (PORT) in these patients. Methods and Materials : From 2005 to 2011, consecutive patients with pT1-3N2 NSCLC who underwent complete resection in our hospital but who did not receive PORT were identified. The patterns of first LRF were assessed and [...]

Menée à partir des données des registres américains du cancer portant sur 4 914 patients atteints d'un carcinome rénal métastatique non à cellules claires diagnostiqué entre 2000 et 2009 (durée médiane de suivi : 20 mois), cette étude évalue la proportion de patients ayant subi une néphrectomie cytoréductive ainsi que le benéfice, en termes de survie, associé à ce traitement

Cytoreductive nephrectomy in patients with metastatic non-clear-cell renal cell carcinoma (RCC)

Aizer, Ayal A. ; Urun, Yuksel ; McKay, Rana R. ; Kibel, Adam S. ; Nguyen, Paul L. ; Choueiri, Toni K.

Objective : To determine whether patients with metastatic non-clear-cell renal cell carcinoma (RCC) benefit from cytoreductive nephrectomy (CN). Patients and Methods : We used the Surveillance, Epidemiology, and End Results (SEER) programme to identify a population-based sample of 4914 patients diagnosed with metastatic RCC between 2000 and 2009. Of the 4914 patients, 591 had non-clear-cell histology. The median follow-up was 20 months. The primary outcome measure was RCC-specific mortality. [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé MPT0E028, un inhibiteur d'histone désacétylase, en combinaison avec le sorafenib pour le traitement d'un carcinome hépatocellulaire

Synergistic Interaction between the HDAC Inhibitor, MPT0E028, and Sorafenib in Liver Cancer Cells In Vitro and In Vivo

Chen, Chun-Han ; Chen, Mei-Chuan ; Wang, Jing-Chi ; Tsai, An-Chi ; Chen, Ching-Shih ; Liou, Jing-Ping ; Pan, Shiow-Lin ; Teng, Che-Ming

Purpose: To investigate the antitumor activities of a histone deacetylase (HDAC) inhibitor, MPT0E028, plus sorafenib in liver cancer cells in vitro and in vivo. Experimental Design: Different liver cancer cell lines were exposed to sorafenib in the presence or absence of MPT0E028, and cell viability was determined by MTT assay. Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and Western blot analysis. The Hep3B xenograft model was [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par une surexpression du gène SYK dans la résistance aux inhibiteurs de FLT3 chez les patients atteints d'une leucémie myéloïde aiguë

SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia

Puissant, Alexandre ; Fenouille, Nina ; Alexe, Gabriela ; Pikman, Yana ; Bassil, Christopher F ; Mehta, Swapnil ; Du, Jinyan ; Kazi, Julhash U ; Luciano, Frédéric ; Rönnstrand, Lars ; Kung, Andrew L ; Aster, Jon C ; Galinsky, Ilene ; Stone, Richard M ; DeAngelo, Daniel J ; Hemann, Michael T ; Stegmaier, Kimberly

Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD [...]

Menée à l'aide de modèles murins, cette étude évalue l'activité antitumorale d'un composé appelé G-749, un inhibiteur de FLT3, pour le traitement des patients atteints d'une leucémie myéloïde aiguë récidivante et réfractaire

G-749, a novel FLT3 kinase inhibitor can overcome drug resistance for the treatment of Acute Myeloid Leukemia

Lee, Hee Kyu ; Kim, Hong Woo ; Lee, In Yong ; Lee, Jungmi ; Lee, Jaekyoo ; Jung, Dong Sik ; Lee, Sang Yeop ; Park, Sung Ho ; Hwang, Haejun ; Choi, Jang-Sik ; Kim, Jung-Ho ; Kim, Se Won ; Kim, Jung Keun ; Cools, Jan ; Koh, Jong Sung ; Song, Ho-Juhn

Aberrant activations of the receptor tyrosine kinase FLT3 are implicated in the pathogenesis of 20–30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore [...]

Menée à l'aide d'un modèle murin transgénique, cette étude met en évidence des mécanismes par lesquels le vemurafenib favorise la formation d'un carcinome épidermoïde cutané dans les tissus infectés par le papillomavirus humain

Vemurafenib cooperates with HPV to promote initiation of cutaneous tumors

Holderfield, Matthew ; Lorenzana, Edward ; Weisburd, Ben ; Lomovasky, Lisa ; Boussemart, Lise ; Lacroix, Ludovic ; Tomasic, Gorana ; Favre, Michel ; Vagner, Stephan ; Robert, Caroline ; Ghoddusi, Majid ; Daniel, Dylan ; Pryer, Nancy ; McCormick, Frank ; Stuart, Darrin

Treatment with RAF inhibitors such as vemurafenib cause the development of cutaneous squamous cell carcinomas (cSCC) or keratoacanthomas (KA) as a side-effect in 18-30% of patients. It is known that RAF inhibitors activate the MAPK pathway and stimulate growth of RAS mutated cells, possibly accounting for up to 60% of cSCC or KA lesions with RAS mutations, but other contributing events are obscure. To identify such events, we evaluated tumors from patients treated with vemurafenib for the [...]

Menée in vitro, in vivo et sur des échantillons prélevés sur des patients atteints d'un adénocarcinome du poumon, cette étude identifie une association entre un faible niveau d'expression du gène NF1 et la résistance à l'erlotinib

Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer

de Bruin, Elza C ; Cowell, Catherine F ; Warne, Patricia H ; Jiang, Ming ; Saunders, Rebecca E ; Melnick, Mary Ann ; Gettinger, Scott N ; Walther, Zenta ; Wurtz, Anna ; Heynen, Guus J ; Heideman, Daniëlle A.M ; Gomez-Roman, Jose Javier ; García-Castaño, Almudena ; Gong, Yixuan ; Ladanyi, Marc ; Varmus, Harold ; Bernards, Rene ; Smit, Egbert F ; Politi, Katerina ; Downward, Julian

Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels un traitement ciblé sur les intégrines

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Truong, Hoa H. ; Xiong, Jiangling ; Ghotra, Veerander P. S. ; Nirmala, Ella ; Haazen, Lizette ; Le Dévédec, Sylvia E. ; Balcio ; #x011F ; lu, Hayri E. ; He, Shuning ; Snaar-Jagalska, B. Ewa ; Vreugdenhil, Erno ; Meerman, John H. N. ; van de Water, Bob ; Danen, Erik H. J.

Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act together with growth factors to support survival and proliferation. Antagonists that target integrins containing the

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé CB-839, un inhibiteur de glutaminase, pour le traitement des cancers du sein triplement négatifs

Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer

Gross, Matthew I. ; Demo, Susan D. ; Dennison, Jennifer B ; Chen, Lijing ; Chernov-Rogan, Tania ; Goyal, Bindu ; Janes, Julie R. ; Laidig, Guy J. ; Lewis, Evan R. ; Li, Jim ; MacKinnon, Andrew L. ; Parlati, Francesco ; Rodriguez, Mirna L.M. ; Shwonek, Peter J. ; Sjogren, Eric B. ; Stanton, Timothy F. ; Wang, Taotao ; Yang, Jinfu ; Zhao, Frances Y. ; Bennett, Mark K.

Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had anti-proliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, [...]

Mené sur 204 patients atteints d'un cancer de la prostate résistant à la castration, cet essai de phase II évalue l'efficacité, du point de vue de la réponse du PSA, et la toxicité de l'ajout de figitumumab à un traitement combinant docétaxel et prednisone

Phase II Randomized Study of Figitumumab plus Docetaxel and Docetaxel Alone with Crossover for Metastatic Castration-Resistant Prostate Cancer

de Bono, Johann S. ; Piulats, Josep Maria ; Pandha, Hardev S. ; Petrylak, Daniel P ; Saad, Fred ; Antón-Aparicio, Luis M ; Sandhu, Shahneen K. ; Fong, Peter ; Gillessen, Silke ; Hudes, Gary R ; Wang, Tao ; Scranton, Judith ; Pollak, Michael N.

Background: Figitumumab is a human IgG2 monoclonal antibody targeting insulin-like growth factor 1 receptor (IGF-1R), with antitumor activity in prostate cancer. This phase II trial randomized chemotherapy-naïve men with progressing castration-resistant prostate cancer to receive figitumumab every 3 weeks with docetaxel/prednisone (Arm A) or docetaxel/prednisone alone (Arm B1). At progression on Arm B1, patients could cross over to the combination (Arm B2). Methods: Prostate-specific antigen [...]

Cet article passe en revue les travaux récents sur l'intérêt des thérapies ciblées (bevacizumab, sunitinib, sorafenib, lapatinib, iniparib et cetuximab) pour le traitement des patientes atteintes d'un cancer du sein triplement négatif de stade métastatique

Efficacy of biological agents in metastatic triple-negative breast cancer

Bramati, Annalisa ; Girelli, Serena ; Torri, Valter ; Farina, Gabriella ; Galfrascoli, Elena ; Piva, Sheila ; Moretti, Anna ; Dazzani, Maria Chiara ; Sburlati, Paola ; La Verde, Nicla Maria

Metastatic triple-negative breast cancer (mTNBC) represents 15% of invasive breast cancers. Prognosis is poor, and there is no specific target therapy but biological agents combined with chemotherapy may be effective. To assess the role of biological agents in metastatic triple-negative breast cancer we performed a systematic review of phase III randomized controlled trials published from January 2006 to February 2013 and presentations at ESMO, ASCO, and SABCS congresses in 2010–2012. We [...]

Menée sur un modèle murin de cancer du côlon, cette étude montre que l'efficacité d'un traitement anti-tumoral par cavitation ultrasonique peut être améliorée par l'administration concomitante d'un anti-angiogénique

Anti-tumor efficacy of ultrasonic cavitation is potentiated by concurrent delivery of anti-angiogenic drug in colon cancer

Zhang, Chao ; Huang, Pintong ; Zhang, Ying ; Chen, Jian ; Shentu, Weihui ; Sun, Yu ; Yang, Zhijian ; Chen, Shuyuan

This study investigated the efficacy of concurrent delivery of an anti-angiogenic drug and ultrasonic cavitation therapy in a mouse model of human colon cancer. A biotinylated form of the anti-angiogenic drug Endostar was conjugated to a streptavidin-coated microbubble (MB). Mice bearing subcutaneous tumors (HT29) were divided into 4 groups. Group 1 served as an untreated control. Group 2 served as a cavitation control and received naked microbubbles and sham ultrasonic cavitation (MB+sham [...]

Menée sur des lignées cellulaires de cancer du col utérin et à l'aide de xénogreffes, cette étude montre que le rigosertib est plus efficace que le cisplatine pour sensibiliser les cellules tumorales aux rayonnements ionisants dans le cadre d'une chimioradiothérapie concomitante

Rigosertib Is a More Effective Radiosensitizer Than Cisplatin in Concurrent Chemoradiation Treatment of Cervical Carcinoma, In Vitro and In Vivo

Agoni, Lorenzo ; Basu, Indranil ; Gupta, Seema ; Alfieri, Alan ; Gambino, Angela ; Goldberg, Gary L. ; Reddy, E. Premkumar ; Guha, Chandan

To compare rigosertib versus cisplatin as an effective radiosensitizing agent for cervical malignancies. Rigosertib and cisplatin were tested in cervical cancer cell lines, HeLa and C33A. A 24-hour incubation with rigosertib and cisplatin, before irradiation (2-8 Gy), was used for clonogenic survival assays. Cell cycle analysis (propidium iodide staining) and DNA damage (γ-H2AX expression) were evaluated by fluorescence-activated cell sorter cytometry. Rigosertib was also tested in vivo in [...]

A partir d'une revue de la littérature publiée après 2000, cette étude française identifie les facteurs associés à l'utilisation de la chimiothérapie en combinaison avec une radiothérapie pour traiter un cancer des glandes salivaires

A rationale for chemoradiation (vs radiotherapy) in salivary gland cancers? on behalf of the REFCOR (French rare head and neck cancer network)

Cerda, Thomas ; Sun, Xu Shan ; Stéphane, Vignot ; Marcy, Pierre-Yves ; Baujat, Bertrand ; Baglin, Anne-Catherine ; Ali, Ali Mohamed ; Testelin, Sylvie ; Reyt, Emile ; Janot, Francois ; Thariat, Juliette

Background : Salivary gland carcinomas constitute a heterogeneous group of tumors, with over 20 histological subtypes of various prognoses. The mainstay of treatment is surgery, with radiotherapy advocated for unresectable disease or postoperatively in case of poor prognostic factors such as high grade, locally advanced and/or incompletely resected tumors. Concurrent chemotherapy is sometimes advocated in routine practice based on criteria extrapolated from squamous cell carcinomas of the head [...]

Cet article présente le résumé d'une table-ronde organisée par l'Institute of Medicine aux Etats-Unis sur le co-développement de thérapies ciblées et de tests compagnons

Codevelopment of genome-based therapeutics and companion diagnostics: Insights from an institute of medicine roundtable

McCormack, R. T. ; Armstrong, J. ; Leonard, D.

More than 100 therapeutics, mostly for oncology, have biomarker tests recommended in their US Food and Drug Administration (FDA) labels. Moreover, a strategy to codevelop and cosubmit to the FDA a diagnostic test (companion diagnostic [CoDx]) that specifically targets a drug to patients predicted to respond has had success recently with vemurafenib, targeting the BRAF V600 mutation in metastatic melanoma, and with crizotinib, targeting the EML4-ALK mutation in non–small cell lung cancer. [...]