Menée in vitro et à l'aide de xénogreffes orthotopiques sur un modèle murin, cette étude identifie un processus transcriptionnel dépendant du NAD+ et impliqué dans l'auto-renouvellement et la radiorésistance des cellules de glioblastome

An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar, Amit D. ; Le, Son ; Mao, Diane D. ; Dadey, David Y. A. ; Turski, Alice ; Sasaki, Yo ; Aum, Diane ; Luo, Jingqin ; Dahiya, Sonika ; Yuan, Liya ; Rich, Keith M. ; Milbrandt, Jeffrey ; Hallahan, Dennis E. ; Yano, Hiroko ; Tran, David D. ; Kim, Albert H.

Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD+). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD+ synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). [...]

A partir d'échantillons tumoraux et sanguins prélevés sur 85 patients atteints d'une tumeur stromale gastro-intestinale, puis menée in vitro et in vivo, cette étude suggère l'intérêt d'une immunothérapie anti PD-1/PD-L1 pour renforcer l'efficacité de l'imatinib

PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors

Seifert, Adrian M. ; Zeng, Shan ; Zhang, Jennifer Q. ; Kim, Teresa S. ; Cohen, Noah A. ; Beckman, Michael J. ; Medina, Benjamin D. ; Maltbaek, Joanna H. ; Loo, Jennifer K. ; Crawley, Megan H. ; Rossi, Ferdinand ; Besmer, Peter ; Antonescu, Cristina R. ; DeMatteo, Ronald P.

Purpose: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs. Experimental Design: We analyzed tumor and matched blood samples from 85 patients [...]

Menée in vitro et in vivo sur des modèles de cancer de l'estomac, cette étude met en évidence des mécanismes par lesquels un composé appelé MIA-602, un antagoniste du récepteur de l'hormone libérant l'hormone de croissance, exerce une activité antitumorale

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

Gan, Jinfeng ; Ke, Xiurong ; Jiang, Jiali ; Dong, Hongmei ; Yao, Zhimeng ; Lin, Yusheng ; Lin, Wan ; Wu, Xiao ; Yan, Shumei ; Zhuang, Yixuan ; Chu, Wai Kit ; Cai, Renzhi ; Zhang, Xianyang ; Cheung, Herman S. ; Block, Norman L. ; Pang, Chi Pui ; Schally, Andrew V. ; Zhang, Hao

Gastric cancer (GC) ranks as the fourth most frequent in incidence and second in mortality among all cancers worldwide. The development of effective treatment approaches is an urgent requirement. Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) have been found to be present in a variety of tumoral tissues and cell lines. Therefore the inhibition of GHRH-R was proposed as a promising approach for the treatment of these cancers. However, little is known about GHRH-R and the [...]

Menée in vitro et in vivo sur des modèles de leucémie myéloïde aiguë, cette étude met en évidence des mécanismes par lesquels la perte d'expression du gène EZH2 favorise la résistance à divers médicaments cytoxiques et aux inhibiteurs de tyrosine kinase

Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia

Gollner, Stefanie ; Oellerich, Thomas ; Agrawal-Singh, Shuchi ; Schenk, Tino ; Klein, Hans-Ulrich ; Rohde, Christian ; Pabst, Caroline ; Sauer, Tim ; Lerdrup, Mads ; Tavor, Sigal ; Stölzel, Friedrich ; Herold, Sylvia ; Ehninger, Gerhard ; Kohler, Gabriele ; Pan, Kuan-Ting ; Urlaub, Henning ; Serve, Hubert ; Dugas, Martin ; Spiekermann, Karsten ; Vick, Binje ; Jeremias, Irmela ; Berdel, Wolfgang E. ; Hansen, Klaus ; Zelent, Arthur ; Wickenhauser, Claudia ; Muller, Lutz P. ; Thiede, Christian ; Müller-Tidow, Carsten

In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML [...]

Menée à l'aide de modèles murins de leucémie, cette étude met en évidence des mécanismes par lesquels un jeûne inhibe le développement d'une leucémie lymphoïde aiguë B ou T mais pas celui d'une leucémie myéloïde aiguë

Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation

Lu, Zhigang ; Xie, Jingjing ; Wu, Guojin ; Shen, Jinhui ; Collins, Robert ; Chen, Weina ; Kang, Xunlei ; Luo, Min ; Zou, Yizhou ; Huang, Lily Jun-Shen ; Amatruda, James F. ; Slone, Tamra ; Winick, Naomi ; Scherer, Philipp E. ; Zhang, Cheng Cheng

New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not [...]

Menée à l'aide de modèles murins d'adénocarcinome canalaire du pancréas, cette étude met en évidence des mécanismes par lesquels, en bloquant la progression tumorale et en normalisant le réseau vasculaire, un antagoniste de la nucléoline (N6L) renforce l'efficacité de la gemcitabine

Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature

Gilles, Maud-Emmanuelle ; Maione, Federica ; Cossutta, Mélissande ; Carpentier, Gilles ; Caruana, Laure ; Di Maria, Silvia ; Houppe, Claire ; Destouches, Damien ; Shchors, Ksenya ; Prochasson, Christopher ; Mongelard, Fabien ; Lamba, Simona ; Bardelli, Alberto ; Bouvet, Philippe ; Couvelard, Anne ; Courty, José ; Giraudo, Enrico ; Cascone, Ilaria

Pancreatic cancer is a highly aggressive tumor, mostly resistant to the standard treatments. Nucleolin is overexpressed in cancers and its inhibition impairs tumor growth. Herein, we showed that nucleolin was overexpressed in human specimens of pancreatic ductal adenocarcinoma (PDAC) and that the overall survival significantly increased in patients with low levels of nucleolin. The nucleolin antagonist N6L strongly impaired the growth of primary tumors and liver metastasis in an orthotopic [...]

Menée sur des lignées cellulaires de cancer du poumon, cette étude identifie des mutations du gène EGFR (T790M, L792F et C797S) impliquées dans la résistance à l'afatinib

Characterization of EGFR T790M, L792F, and C797S mutations as mechanisms of acquired resistance to afatinib in lung cancer

Kobayashi, Yoshihisa ; Azuma, Koichi ; Nagai, Hiroki ; Kim, Young Hak ; Togashi, Yosuke ; Sesumi, Yuichi ; Chiba, Masato ; Shimoji, Masaki ; Sato, Katsuaki ; Tomizawa, Kenji ; Takemoto, Toshiki ; Nishio, Kazuto ; Mitsudomi, Tetsuya

Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs). We previously reported that tumors with exon 18 mutations are particularly sensitive to irreversible second-generation (2G) afatinib compared with 1G-TKIs. However, data on the mechanisms of acquired resistance to afatinib are limited. We established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 (G719A and Del18) mutations and subjecting them to chronic exposure to [...]

Menée in vitro et in vivo sur des modèles de cancer du poumon, cette étude met en évidence des mécanismes suggérant l'intérêt d'une stratégie basée sur l'inhibition du micro-ARN miR-155 pour surmonter la résistance à une chimiothérapie

Combining anti-miR-155 with chemotherapy for the treatment of lung cancers

Van Roosbroeck, Katrien ; Fanini, Francesca ; Setoyama, Tetsuro ; Ivan, Cristina ; Rodriguez-Aguayo, Cristian ; Fuentes-Mattei, Enrique ; Xiao, Lianchun ; Vannini, Ivan ; Redis, Roxana ; Abundo, Lucilla ; Zhang, Xinna ; Nicoloso, Milena S. ; Rossi, Simona ; Gonzalez-Villasana, Vianey ; Rupaimoole, Rajesha ; Ferracin, Manuela ; Morabito, Fortunato ; Neri, Antonino ; Ruvolo, Peter ; Ruvolo, Vivian R. ; Pecot, Chad V. ; Amadori, Dino ; Aruzzo, Lynne ; Calin, Steliana ; Wang, Xuemei ; You, M. James ; Ferrajoli, Alessandra ; Orlowski, Robert Z. ; Plunkett, William ; Lichtenberg, Tara ; Davuluri, Ramana V. ; Berindan-Neagoe, Ioana ; Negrini, Massimo ; Wistuba, Ignacio I. ; Hagop, Kantarjian ; Sood, Anil K. ; Lopez-Berestein, Gabriel ; Keating, Michael J. ; Fabbri, Muller ; Calin, George A.

Purpose The oncogenic miR-155 is upregulated in many human cancers and its expression is increased in more aggressive and therapy resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design We performed in vitro studies on cell lines to investigate the [...]

Menée à l'aide de modèles murins de cancer du poumon non à petites cellules avec métastases cérébrales, cette étude met en évidence la capacité d'un composé appelé AZD3759, un inhibiteur d'EGFR, à franchir la barrière hémato-encéphalique et à prévenir le développement des métastases

AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases

Yang, Zhenfan ; Guo, Qiuli ; Wang, Yingchun ; Chen, Kan ; Zhang, Lin ; Cheng, Ziqiang ; Xu, YanPing ; Yin, Xiaolu ; Bai, Yu ; Rabbie, Sarit ; Kim, Dong-Wan ; Ahn, Myung-Ju ; Yang, James Chih-Hsin ; Zhang, Xiaolin

Non–small-cell lung cancer remains difficult to treat despite recent advances in targeted therapy. One reason for this is metastasis to the central nervous system. Drugs that inhibit the epidermal growth factor receptor (EGFR), a common target in this cancer, do not effectively penetrate the blood-brain barrier, which means that metastatic tumors can grow unchecked once they spread to the brain or spinal cord. Yang et al. have now developed a drug that not only can inhibit EGFR as effectively [...]

Cet article passe en revue les perspectives thérapeutiques offertes par les travaux récents ayant mis en évidence une forte hétérogénéité, d'une tumeur à l'autre et à l'intérieur d'une même tumeur, dans les cancers colorectaux

From tumour heterogeneity to advances in precision treatment of colorectal cancer

Punt, Cornelis J. A. ; Koopman, Miriam ; Vermeulen, Louis

In recent years, the high heterogeneity of colorectal cancer (CRC) has become evident. Hence, biomarkers need to be developed that enable the stratification of patients with CRC into different prognostic subgroups and in relation to response to therapies, according to the distinctive tumour biology. Currently, only RAS-mutation status is used routinely as a negative predictive marker to avoid treatment with anti-EGFR agents in patients with metastatic CRC, and mismatch-repair status can guide [...]

Menée in vitro et in vivo sur des modèles de cancer du sein présentant des mutations PIK3CA, cette étude met en évidence des mécanismes suggérant l'intérêt d'un traitement combinant un inhibiteur de mTOR et un inhibiteur de BCL-XL

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation

Anderson, Grace R. ; Wardell, Suzanne E. ; Cakir, Merve ; Crawford, Lorin ; Leeds, Jim C. ; Nussbaum, Daniel P. ; Shankar, Pallavi S. ; Soderquist, Ryan S. ; Stein, Elizabeth M. ; Tingley, Jennifer P. ; Winter, Peter S. ; Zieser-Misenheimer, Elizabeth K. ; Alley, Holly M. ; Yllanes, Alexander ; Haney, Victoria ; Blackwell, Kimberly L. ; McCall, Shannon J. ; McDonnell, Donald P. ; Wood, Kris C.

The usual goal of cancer treatment is to kill malignant cells, not just slow down their growth. A class of drugs called BH3 mimetics serves this purpose by inhibiting antiapoptotic proteins and thus helping drive the cells toward apoptosis (programmed cell death). MCL-1 is an antiapoptotic protein that is not targeted by currently bioavailable BH3 mimetics, and it is often responsible for resistance to these drugs. Anderson et al. have discovered that breast cancers with the commonly observed [...]

Cet article passe en revue les perspectives thérapeutiques offertes par les travaux récents sur les mécanismes moléculaires impliqués dans le développement des cancers du sein triplement négatifs et dans la réponse aux traitements

Molecular alterations in triple-negative breast cancer - the road to new treatment strategies

Denkert, Carsten ; Liedtke, Cornelia ; Tutt, Andrew ; von Minckwitz, Gunter

Triple-negative breast cancer is a heterogeneous disease and specific therapies have not been available for a long time. Therefore, conventional chemotherapy is still considered the clinical state of the art. Different subgroups of triple-negative breast cancer have been identified on the basis of protein expression, mRNA signatures, and genomic alterations. Important elements of triple-negative breast cancer biology include high proliferative activity, an increased immunological infiltrate, a [...]

Cet article passe en revue les progrès récents dans le traitement des patientes atteintes d'un cancer du sein ER+ de stade avancé

Advances in the treatment of advanced oestrogen-receptor-positive breast cancer

Turner, Nicholas C. ; Neven, Patrick ; Loibl, Sibylle ; Andre, Fabrice

Oestrogen-receptor-positive breast cancer is the most common subtype of breast cancer. Endocrine therapies that target the dependence of this subtype on the oestrogen receptor have substantial activity, yet the development of resistance to therapy is inevitable in advanced cancer. Major progress has been made in identifying the drivers of oestrogen-receptor-positive breast cancer and the mechanisms of resistance to endocrine therapy. This progress has translated into major advances in the [...]

Menée in vitro et in vivo sur des modèles de gliome, cette étude suggère l'intérêt de développer des thérapies ciblant un long ARN non codant (TUG1) pour éliminer les cellules souches cancéreuses

Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment

Katsushima, Keisuke ; Natsume, Atsushi ; Ohka, Fumiharu ; Shinjo, Keiko ; Hatanaka, Akira ; Ichimura, Norihisa ; Sato, Shinya ; Takahashi, Satoru ; Kimura, Hiroshi ; Totoki, Yasushi ; Shibata, Tatsuhiro ; Naito, Mitsuru ; Kim, Hyun Jin ; Miyata, Kanjiro ; Kataoka, Kazunori ; Kondo, Yutaka

Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1. TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress [...]

Menée à l'aide de modèles murins de cancer de la cavité buccale, cette étude met en évidence des mécanismes par lesquels un inhibiteur du récepteur des acides gras CD36 réprime le processus métastatique

Targeting metastasis-initiating cells through the fatty acid receptor CD36

Pascual, Gloria ; Avgustinova, Alexandra ; Mejetta, Stefania ; Martín, Mercè ; Castellanos, Andrés ; Attolini, Camille Stephan-Otto ; Berenguer, Antoni ; Prats, Neus ; Toll, Agustí ; Hueto, Juan Antonio ; Bescós, Coro ; Di Croce, Luciano ; Benitah, Salvador Aznar

The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44bright cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic [...]

Menée sur 17 patients atteints d'une leucémie myéloïde aiguë et en phase de rémission, cet essai évalue l'efficacité d'un vaccin thérapeutique personnalisé, basé sur la fusion de cellules dendritiques et de cellules tumorales autologues modifiées puis réinjectées au patient, pour prolonger la phase de rémission et prévenir la récidive

Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions

Rosenblatt, Jacalyn ; Stone, Richard M. ; Uhl, Lynne ; Neuberg, Donna ; Joyce, Robin ; Levine, James D. ; Arnason, Jon ; McMasters, Malgorzata ; Luptakova, Katarina ; Jain, Salvia ; Zwicker, Jeffrey I. ; Hamdan, Ayad ; Boussiotis, Vassiliki ; Steensma, David P. ; DeAngelo, Daniel J. ; Galinsky, Ilene ; Dutt, Poorvi Somaiya ; Logan, Emma ; Bryant, Mary Paty ; Stroopinsky, Dina ; Werner, Lillian ; Palmer, Kristen ; Coll, Max ; Washington, Abigail ; Cole, Leandra ; Kufe, Donald ; Avigan, David

We developed a personalized cancer vaccine in which patient-derived acute myeloid leukemia (AML) cells are fused with autologous dendritic cells, generating a hybridoma that potently stimulates broad antitumor responses. We report results obtained from the first 17 AML patients, who achieved remission after chemotherapy and were then serially vaccinated to target minimal residual disease and prevent relapse. Vaccination was well tolerated and induced inflammatory responses at the site of [...]

Mené sur 12 patients atteints d'un mésothéliome pleural malin de stade avancé (âge médian : 67 ans), cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression à 3 mois, et la toxicité du dovitinib, après l'échec d'une chimiothérapie combinant sels de platine et antifolates

A phase II trial of Dovitinib in previously-treated advanced pleural mesothelioma: the Ontario Clinical Oncology Group

Laurie, Scott A. ; Hao, Desiree ; Leighl, Natasha B. ; Goffin, John ; Khomani, Abderrahim ; Gupta, Ashish ; Addison, Christina L. ; Bane, Anita ; Seely, Jean ; Filion, Marc L. ; Pond, Gregory R. ; Levine, Mark N.

Objectives : Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFRs, and could be active in MPM. Methods : This open-label multicentre phase II trial [NCT01769547] [...]

A partir d'une revue des essais cliniques, cette étude analyse le rapport bénéfices/risques des agents anti-angiogéniques développés dans des essais de phase III pour traiter les patients atteints d'un cancer du poumon non à petites cellules (notamment le ramucirumab, le nintédanib, l'aflibercept, le sunitinib, le sorafénib, le cédiranib et le vandétanib)

Exploring the Benefit/Risk Associated With Antiangiogenic Agents for the Treatment of Non-Small Cell Lung Cancer Patients

Kurzrock, Razelle ; Stewart, David J.

Following the approval of bevacizumab, an antibody targeting vascular endothelial growth factor-A (VEGF-A), for advanced non-squamous non-small cell lung cancer (NSCLC) in 2006, intensive efforts were put into the clinical development of antiangiogenic agents for NSCLC. Currently, the other antiangiogenic agents approved for NSCLC are ramucirumab, a VEGF receptor-2 (VEGFR-2)-targeting antibody indicated for both squamous and non-squamous NSCLC in the United States, and nintedanib, an [...]

Mené sur 419 patients atteints d'un cancer avancé du poumon non à petites cellules présentant la mutation Thr790M du gène EGFR, cet essai de phase III compare l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'osimertinib, un inhibiteur d'EGFR, et d'un traitement à base de sels de platine et de pémétrexed, après l'échec d'un traitement de première ligne par un autre inhibiteur d'EGFR

Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer

Mok, Tony S. ; Wu, Yi-Long ; Ahn, Myung-Ju ; Garassino, Marina C. ; Kim, Hye R. ; Ramalingam, Suresh S. ; Shepherd, Frances A. ; He, Yong ; Akamatsu, Hiroaki ; Theelen, Willemijn S.M.E. ; Lee, Chee K. ; Sebastian, Martin ; Templeton, Alison ; Mann, Helen ; Marotti, Marcelo ; Ghiorghiu, Serban ; Papadimitrakopoulou, Vassiliki A.

Background : Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non–small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. (....) Methods : In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non–small-cell lung cancer, [...]

A partir des données de 4 essais de phase III sur le pémétrexed incluant 2 671 patients atteints d'un cancer du poumon non à petites cellules non épidermoïde, cette méta-analyse évalue la survie globale en fonction de l'âge (<65 ans, ≥65 ans, ≥70 ans) et de la phase thérapeutique (première ligne, deuxième ligne, entretien)

Meta-analysis examining impact of age on overall survival with pemetrexed for the treatment of advanced non-squamous non-small cell lung cancer

Paz-Ares, Luis G. ; Zimmermann, Annamaria ; Ciuleanu, Tudor ; Bunn, Paul A. ; Antonio, Belen San ; Denne, Jonathan ; Iturria, Nancy ; John, William ; Scagliotti, Giorgio V.

Objective : In clinical practice, elderly patients are often undertreated relative to younger patients. This meta-analysis was designed to determine whether older patients with non-squamous non-small cell lung cancer (NSCLC) could derive an overall survival (OS) benefit from pemetrexed treatment comparable to that experienced by younger patients in the first-line, second-line, or maintenance settings. Methods : Data from 2671 patients with non-squamous NSCLC participating in four pemetrexed [...]

Mené sur 499 patients atteints d'un cancer du poumon MET+ non à petites cellules de stade IIIB ou IV, cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'ajout de l'onartuzumab à un traitement par erlotinib, après l'échec d'une chimiothérapie à base de sels de platine

Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non–Small-Cell Lung Cancer: METLung

David R. Spigel ; Martin J. Edelman ; Kenneth O’Byrne ; Luis Paz-Ares ; Simonetta Mocci ; See Phan ; David S. Shames ; Dustin Smith ; Wei Yu ; Virginia E. Paton ; Tony Mok

Purpose : The phase III OAM4971g study (METLung) examined the efficacy and safety of onartuzumab plus erlotinib in patients with locally advanced or metastatic non–small-cell lung cancer selected by MET immunohistochemistry whose disease had progressed after treatment with a platinum-based chemotherapy regimen. Patients and Methods : Patients were randomly assigned at a one-to-one ratio to receive onartuzumab (15 mg/kg intravenously on day 1 of each 21-day cycle) plus daily oral erlotinib 150 [...]

Menée à partir de données de deux cohortes prospectives incluant un total de 190 patientes atteintes d'un cancer du sein triple négatif de stade I à III, cette étude analyse l'efficacité, du point de vue du taux de réponse complète, d'une chimiothérapie néoadjuvante combinant carboplatine et docétaxel

Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts

Sharma, Priyanka ; López-Tarruella, Sara ; Garcia-Saenz, José Ángel ; Ward, Claire ; Connor, Carol S. ; Gomez, Henry L. ; Prat, Aleix ; Moreno, Fernando ; Jerez-Gilarranz, Yolanda ; Barnadas, Augusti ; Picornell, Antoni C. ; del Monte-Millán, Maria ; Gonzalez-Rivera, Milagros ; Massarrah, Tatiana ; Pelaez-Lorenzo, Beatriz ; Palomero, María Isabel ; González del Val, Ricardo ; Cortés, Javier ; Fuentes Rivera, Hugo ; Bretel Morales, Denisse ; Márquez-Rodas, Iván ; Perou, Charles M. ; Wagner, Jamie L. ; Mammen, Joshua M.V. ; McGinness, Marilee K. ; Klemp, Jennifer R. ; Amin, Amanda L. ; Fabian, Carol J. ; Heldstab, Jaimie ; Godwin, Andrew K. ; Jensen, Roy A. ; Kimler, Bruce F. ; Khan, Qamar J. ; Martin, Miguel

Purpose: Recent studies demonstrate that addition of neoadjuvant (NA) carboplatin to anthracycline/taxane chemotherapy improves pathologic complete response (pCR) in triple-negative breast cancer (TNBC). Effectiveness of anthracycline-free platinum combinations in TNBC is not well known. Here, we report efficacy of NA carboplatin + docetaxel (CbD) in TNBC. Experimental Design: The study population includes 190 patients with stage I–III TNBC treated uniformly on two independent prospective [...]

Mené sur 129 patients atteints d'un glioblastome récidivant, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout de l'onartuzumab, un inhibiteur monovalent de MET, au bévacizumab

Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Onartuzumab Plus Bevacizumab Versus Placebo Plus Bevacizumab in Patients With Recurrent Glioblastoma: Efficacy, Safety, and Hepatocyte Growth Factor and O6-Methylguanine–DNA Methyltransferase Biomarker Analyses

Timothy Cloughesy ; Gaetano Finocchiaro ; Cristóbal Belda-Iniesta ; Lawrence Recht ; Alba A. Brandes ; Estela Pineda ; Tom Mikkelsen ; Olivier L. Chinot ; Carmen Balana ; David R. Macdonald ; Manfred Westphal ; Kirsten Hopkins ; Michael Weller ; Carlos Bais ; Thomas Sandmann ; Jean-Marie Bruey ; Hartmut Koeppen ; Bo Liu ; Wendy Verret ; See-Chun Phan ; David S. Shames

Purpose : Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods : At first recurrence after chemoradiation, [...]

Mené sur 45 patients atteints d'un carcinome épidermoïde du canal anal de stade I à III et infectés par le VIH, cet essai de phase II évalue, du point de vue de la réduction du taux d'échec locorégional à 3 ans, l'intérêt d'ajouter le cétuximab à une chimioradiothérapie

Cetuximab Plus Chemoradiotherapy for HIV-Associated Anal Carcinoma : A Phase II AIDS Malignancy Consortium Trial

Sparano, Joseph A. ; Lee, Jeannette Y. ; Palefsky, Joel ; Henry, David H. ; Wachsman, William ; Rajdev, Lakshmi ; Aboulafia, David ; Ratner, Lee ; FitzGerald, Thomas J. ; Kachnic, Lisa ; Mitsuyasu, Ronald

Purpose : Squamous cell carcinoma of the anal canal (SCCAC) is characterized by high locoregional failure (LRF) rates after definitive chemoradiation (CRT), associated with anogenital human papilloma virus, and often appears in HIV infection. Because cetuximab enhances the effect of radiation therapy in human papilloma virus–associated oropharyngeal SCC, we hypothesized that adding cetuximab to CRT would reduce LRF in SCCAC. Methods : Forty-five patients with stage I to III SCCAC and HIV [...]

A partir d'une revue systématique de la littérature publiée jusqu'en mars 2016 (19 études incluant 12 380 patients au total), cette méta-analyse compare l'efficacité, du point de vue de la survie sans progression, de la survie spécifique et de la survie globale, et les complications d'une cystectomie radicale et d'un traitement combinant une radiothérapie, une chimiothérapie concomitante et une résection transurétrale maximale de la tumeur chez les patients atteints d'un cancer de la vessie

Radical Cystectomy Compared to Combined Modality Treatment for Muscle-Invasive Bladder Cancer : A Systematic Review and Meta-Analysis of over 12,000 patients

Vashistha, Vishal ; Wang, Hanzhang ; Mazzone, Andrew ; Liss, Michael A. ; Svatek, Robert S. ; Schleicher, Mary ; Kaushik, Dharam

Purpose : Radical cystectomy (RC) has been the mainstay treatment for muscle-invasive bladder cancer (MIBC) while combined modality treatment (CMT-radiation therapy, concurrent chemotherapy and maximal transurethral resection of bladder tumor) is preserved for patients with substantial comorbidities. We performed a comprehensive assessment of overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), and treatment-related complications between RC and CMT. Methods : [...]

Menée à partir des données de 20 essais incluant au total 5 144 patients atteints d'un carcinome rhinopharyngé de stade localement avancé, cette méta-analyse évalue, du point de vue du contrôle de la maladie, de la survie sans progression et de la survie globale, l'intérêt d'ajouter une chimiothérapie concomitante, une chimiothérapie adjuvante et/ou une chimiothérapie d'induction à une radiothérapie

What is the Best Treatment of Locally Advanced Nasopharyngeal Carcinoma ? An Individual Patient Data Network Meta-Analysis

Ribassin-Majed, Laureen ; Marguet, Sophie ; Lee, Anne W. M. ; Ng, Wai Tong ; Ma, Jun ; Chan, Anthony T. C. ; Huang, Pei-yu ; Zhu, Guopei ; Chua, Daniel T. T. ; Chen, Yong ; Mai, Hai-Qiang ; Kwong, Dora L. W. ; Cheah, Shie-Lee ; Moon, James ; Tung, Yuk ; Chi, Kwan-Hwa ; Fountzilas, George ; Bourhis, Jean ; Pignon, Jean Pierre ; Blanchard, Pierre

Purpose : The role of adjuvant chemotherapy (AC) or induction chemotherapy (IC) in the treatment of locally advanced nasopharyngeal carcinoma is controversial. The individual patient data from the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma database were used to compare all available treatments. Methods : All randomized trials of radiotherapy (RT) with or without chemotherapy in nonmetastatic nasopharyngeal carcinoma were considered. Overall, 20 trials and 5,144 patients were [...]

Cet article présente les recommandations, issues d'une conférence internationale de consensus, sur la prise en charge d'un cancer du sein de stade avancé

3rd ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3)

Cardoso, F. ; Costa, A. ; Senkus, E. ; Aapro, M. ; André, F. ; Barrios, C. H. ; Bergh, J. ; Bhattacharyya, G. ; Biganzoli, L. ; Cardoso, M. J. ; Carey, L. ; Corneliussen-James, D. ; Curigliano, G. ; Dieras, V. ; El Saghir, N. ; Eniu, A. ; Fallowfield, L. ; Fenech, D. ; Francis, P. ; Gelmon, K. ; Gennari, A. ; Harbeck, N. ; Hudis, C. ; Kaufman, B. ; Krop, I. ; Mayer, M. ; Meijer, H. ; Mertz, S. ; Ohno, S. ; Pagani, O. ; Papadopoulos, E. ; Peccatori, F. ; Pernault-Llorca, F. ; Piccart, M. J. ; Pierga, J. Y. ; Rugo, H. ; Shockney, L. ; Sledge, G. ; Swain, S. ; Thomssen, C. ; Tutt, A. ; Vorobiof, D. ; Xu, B. ; Norton, L. ; Winer, E.

Advanced Breast Cancer (ABC) comprises both locally advanced (LABC) and metastatic breast cancer (MBC). Although treatable, MBC remains an incurable disease with a median overall survival of ∼2–3 years and a 5-year survival of only ∼25% [2–4]. Some more recent series seem to indicate an improvement in median overall survival. A recent comprehensive report of the advances in this field in the last decade shows that progress has been slow in terms of improved outcomes, quality of life, awareness [...]

Cet article analyse les enjeux associés à l'inclusion d'adolescents (12-17 ans) dans les essais cliniques menés sur des patients adultes en oncologie

Enrolling Adolescents in Disease/Target-Appropriate Adult Oncology Clinical Trials of Investigational Agents

Chuk, Meredith K. ; Mulugeta, Yeruk ; Roth-Cline, Michelle ; Mehrotra, Nitin ; Reaman, Gregory H.

The enrollment of adolescents with cancer in clinical trials is much lower than that of younger pediatric patients. For adolescents with “adult-type” cancers, lack of access to relevant trials is cited as one of the reasons for this discrepancy. Adolescents are generally not eligible for enrollment in adult oncology trials, and initial pediatric trials for many drugs are conducted years later, often after the drug is approved. As a result, accrual of adolescents to these trials may be slow due [...]

A partir des données de patients atteints de cancer et âgés de 1 à 30 ans, cette étude prospective compare les différents systèmes de classification des ototoxicités induites par un traitement à base de cisplatine et analyse l'efficacité d'un système permettant d'évaluer les résultats audiologiques

Group-Wide, Prospective Study of Ototoxicity Assessment in Children Receiving Cisplatin Chemotherapy (ACCL05C1): A Report From the Children’s Oncology Group

Kristin R. Knight ; Lu Chen ; David Freyer ; Richard Aplenc ; Mary Bancroft ; Bonnie Bliss ; Ha Dang ; Biljana Gillmeister ; Eleanor Hendershot ; Dale F. Kraemer ; Lanie Lindenfeld ; Jane Meza ; Edward A. Neuwelt ; Brad H. Pollock ; Lillian Sung

Purpose : Optimal assessment methods and criteria for reporting hearing outcomes in children who receive treatment with cisplatin are uncertain. The objectives of our study were to compare different ototoxicity classification systems, to evaluate the feasibility of including otoacoustic emissions and extended high frequency audiometry, and to evaluate a central review mechanism for audiologic results for cisplatin-treated children in the cooperative group setting. Patients and Methods : [...]

Cet article présente des recommandations pour améliorer les pratiques des comités de surveillance et de suivi des essais cliniques

Enhancing the scientific integrity and safety of clinical trials: Recommendations for data monitoring committees

Lewis, R. J. ; Calis, K. A. ; DeMets, D. L.

The risks of participating in a clinical trial cannot be predicted with certainty at the time of trial design, especially when evaluating novel therapies. Accordingly, once the trial is initiated, periodic and ongoing review of accumulating study data is necessary to ensure the continued appropriateness of enrolling and treating patients in the trial. This oversight activity is often conducted by a data monitoring committee (DMC), also known as a data and safety monitoring board, generally [...]

Cet article présente un catalogue exhaustif des cibles moléculaires de 1 578 médicaments ayant bénéficié d'une autorisation de mise sur le marché par la FDA

A comprehensive map of molecular drug targets

Santos, Rita ; Ursu, Oleg ; Gaulton, Anna ; Bento, A. Patricia ; Donadi, Ramesh S. ; Bologa, Cristian G. ; Karlsson, Anneli ; Al-Lazikani, Bissan ; Hersey, Anne ; Oprea, Tudor I. ; Overington, John P.

The success of mechanism-based drug discovery depends on the definition of the drug target. This definition becomes even more important as we try to link drug response to genetic variation, understand stratified clinical efficacy and safety, rationalize the differences between drugs in the same therapeutic class and predict drug utility in patient subgroups. However, drug targets are often poorly defined in the literature, both for launched drugs and for potential therapeutic agents in [...]

A partir de données portant sur 5 144 patients atteints d'un carcinome du rhinopharynx et inclus dans 20 essais cliniques, cette étude évalue l'intérêt d'utiliser la survie sans progression et la survie sans métastase à distance comme critères de jugement de substitution à la survie globale

Surrogate End Points for Overall Survival in Loco-Regionally Advanced Nasopharyngeal Carcinoma: An Individual Patient Data Meta-analysis

Rotolo, Federico ; Pignon, Jean-Pierre ; Bourhis, Jean ; Marguet, Sophie ; Leclercq, Julie ; Tong Ng, Wai ; Ma, Jun ; Chan, Anthony T. C. ; Huang, Pei-yu ; Zhu, Guopei ; Chua, Daniel T. T. ; Chen, Yong ; Mai, Hai-Qiang ; Kwong, Dora L. W. ; Soong, Yoke Lim ; Moon, James ; Tung, Yuk ; Chi, Kwan-Hwa ; Fountzilas, George ; Zhang, Li ; Hui, Edwin Pun ; Lee, Anne W. M. ; Blanchard, Pierre ; Michiels, Stefan ; on behalf of the MAC-NPC Collaborative Group

Background: Our objective was to evaluate progression-free survival (PFS) and distant metastasis–free survival (DMFS) as surrogate end points for overall survival (OS) in randomized trials of chemotherapy in loco-regionally advanced nasopharyngeal carcinomas (NPCs). Methods: Individual patient data were obtained from 19 trials of the updated Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) plus one additional trial (total = 5144 patients). Surrogacy was evaluated at the [...]