A partir de données des registres américains du cancer et de la base Medicare portant sur une cohorte de 55 947 patients atteints d'un cancer de la prostate diagnostiqué entre 2004 et 2009, cette étude évalue, par rapport aux traitements conventionnels (radiothérapie externe, prostatectomie radicale par voie ouverte), l'utilisation des traitements employant une technologie avancée (radiothérapie avec modulation d'intensité, prostatectomie assistée par robot) chez les patients présentant un faible risque de décès par cancer de la prostate

Use of advanced treatment technologies among men at low risk of dying from prostate cancer

Jacobs Bl, Zhang Y. Schroeck F. R. ; et al.,

Importance : The use of advanced treatment technologies (ie, intensity-modulated radiotherapy [IMRT] and robotic prostatectomy) for prostate cancer is increasing. The extent to which these advanced treatment technologies have disseminated among patients at low risk of dying from prostate cancer is uncertain. Objective : To assess the use of advanced treatment technologies, compared with prior standards (ie, traditional external beam radiation treatment [EBRT] and open radical prostatectomy) and [...]

Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé S49076, un inhibiteur des signalisations MET, AXL/MER et FGFR1/2/3, seul ou en combinaison avec le bevacizumab

S49076 is a Novel Kinase Inhibitor of MET, AXL and FGFR with Strong Preclinical Activity Alone and in Association with Bevacizumab

Burbridge, Mike F ; Bossard, Celine J. ; Saunier, Carine ; Fejes, Imre ; Bruno, Alain ; Leonce, Stephane ; Ferry, Gilles ; Da Violante, Georges ; Bouzom, Francois ; Cattan, Valerie ; Jacquet-Bescond, Anne ; Comoglio, Paolo M. ; Lockhart, Brian P ; Boutin, Jean A. ; Cordi, Alex ; Ortuno, Jean-Claude ; Pierre, Alain ; Hickman, John A ; Cruzalegui, Francisco H. ; Depil, Stephane

Aberrant activity of the receptor tyrosine kinases MET, AXL and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anti-cancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, FGFRs and inhibited downstream signaling in vitro and [...]

A partir de données initiales portant sur 20 patients atteints d'un mélanome traité à l'aide de vemurafenib, puis validée sur un ensemble complémentaire de patients atteints d'un mélanome, d'un cancer du pancréas ou du côlon-rectum, cette étude évalue l'intérêt d'un modèle mathématique permettant de prédire la réponse à une combinaison de deux ou trois thérapies ciblées

Evolutionary dynamics of cancer in response to targeted combination therapy

Ivana Bozic ; Johannes G Reiter ; Benjamin Allen ; Tibor Antal ; Krishnendu Chatterjee ; Preya Shah ; Yo Sup Moon ; Amin Yaqubie ; Nicole Kelly ; Dung T Le ; Evan J Lipson ; Paul B Chapman ; Luis A Diaz, Jr ; Bert Vogelstein ; Martin A Nowak

In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé SU1124, ciblant la signalisation cMET, pour le traitement d'un myélome multiple

Novel targeting of phospho-cMET overcomes drug resistance and induces anti-tumor activity in multiple myeloma

Moschetta, Michele ; Basile, Antonio ; Ferrucci, Arianna ; Frassanito, Maria Antonia ; Rao, Luigia ; Ria, Roberto ; Solimando, Antonio Giovanni ; Giuliani, Nicola ; Boccarelli, Angelina ; Fumarola, Fabio ; Coluccia, Mauro ; Rossini, Bernardo ; Ruggieri, Simona ; Nico, Beatrice ; Maiorano, Eugenio ; Ribatti, Domenico ; Roccaro, Aldo M. ; Vacca, Angelo

Purpose: aim of the study was to verify the hypothesis that the cMET oncogene is implicated in chemio- and novel drug- resistance in MM. Experimental Design: we have evaluated the expression levels of cMET/p-cMET and the activity of the novel selective p-cMET inhibitor (SU11274) in MM cells, either sensitive (RPMI8226 and MM.1S) or resistant (R5 and MM.1R) to anti-MM drugs, in primary PCs and in MM xenograft models. Results:we found that resistant R5 and MM1R cells presented with higher cMET [...]

Menée à l'aide d'un modèle murin transgénique développant spontanément un carcinome pancréatique luminescent, cette étude évalue l'activité antitumorale de nanoparticules micellaires enrichies en oxaliplatine

Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis

Cabral, Horacio ; Murakami, Mami ; Hojo, Hironori ; Terada, Yasuko ; Kano, Mitsunobu R. ; Chung, Ung-il ; Nishiyama, Nobuhiro ; Kataoka, Kazunori

Nanoscaled drug-loaded carriers are of particular interest for efficient tumor therapy as numerous studies have shown improved targeting and efficacy. Nevertheless, most of these studies have been performed against allograft and xenograft tumor models, which have altered microenvironment features affecting the accumulation and penetration of nanocarriers. Conversely, the evaluation of nanocarriers on genetically engineered mice, which can gradually develop clinically relevant tumors, permits [...]

Menée in vitro et in vivo, cette étude compare l'activité antitumorale du nab-paclitaxel, de la gemcitabine et du docetaxel pour le traitement de première ligne d'un adénocarcinome canalaire du pancréas

Comparative Benefits of Nab-paclitaxel over Gemcitabine or Polysorbate-based Docetaxel in Experimental Pancreatic Cancer

Awasthi, Niranjan ; Zhang, Changhua ; Schwarz, Anna M. ; Hinz, Stefan ; Wang, Changguang ; Williams, Noelle S. ; Schwarz, Margaret A. ; Schwarz, Roderich E.

Gemcitabine (Gem) has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). The solvent-based traditional taxanes docetaxel (DT) and paclitaxel have not shown clinical results superior to gemcitabine. Nab-paclitaxel (NPT), a water-soluble albumin-bound paclitaxel, may carry superior distribution properties into the tumor microenvironment and has shown efficacy in multiple tumor types. We evaluated nab-paclitaxel effects compared with gemcitabine or docetaxel. For PDAC cells [...]

Cet article passe en revue les travaux récents sur les mécanismes de résistance au gefitinib, à l'erlotinib et au crizotinib dans le traitement d'un cancer du poumon non à petites cellules

Mechanisms of resistance to EGFR tyrosine kinase inhibitors gefitinib/erlotinib and to ALK inhibitor crizotinib

Tartarone, Alfredo ; Lazzari, Chiara ; Lerose, Rosa ; Conteduca, Vincenza ; Improta, Giuseppina ; Zupa, Angela ; Bulotta, Alessandra ; Aieta, Michele ; Gregorc, Vanesa

The discovery of several molecular alterations that underlie non-small cell lung cancer (NSCLC) pathogenesis has led to the development of targeted therapies. In particular, gefitinib and erlotinib have become the standard of care in patients harboring epidermal growth factor receptor mutations, while crizotinib showed an impressive efficacy in patients with ALK-positive NSCLC. Nevertheless, the occurrence of clinical resistance limits the long term results of these novel agents. The [...]

Menée sur des lignées cellulaires, cette étude met en évidence le rôle joué par le récepteur RON dans la résistance au lapatinib pour le traitement d'un cancer du sein HER2+

RON confers lapatinib resistance in HER2-positive breast cancer cells

Wang, Quanren ; Quan, Haitian ; Zhao, Jie ; Xie, Chengying ; Wang, Lei ; Lou, Liguang

Lapatinib-resistance is a major problem for HER2-positive breast cancer treatment. SK-BR-3-LR, a lapatinib-resistant cell clone, was established from HER2-positive SK-BR-3 breast cancer cells following chronic exposure to lapatinib. The PI3K/AKT signaling pathway was demonstrated to be resistant to HER2 inhibition in SK-BR-3-LR cells. However, both small-molecular Recepteur d’Origine Nantais (RON) inhibitors and RON-targeted small interfering RNA (siRNA) effectively restored lapatinib [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude suggère l'intérêt d'ajouter un inhibiteur de PI3K à l'everolimus, un inhibiteur de mTOR, pour le traitement d'un cancer du sein ER+

Dual inhibition of PI3K and mTOR mitigates feedback-loop pAkt activation to improve tamoxifen response in breast cancer cells

Chen, Xiaosong ; Zhao, Meizhong ; Hao, Mingang ; Sun, Xueqing ; Wang, Jinglong ; Mao, Yan ; Zu, Lidong ; Liu, Junjun ; Shen, Yandong ; Wang, Jianhua ; Shen, Kunwei

Everolimus, a mTOR inhibitor, showed great antitumor efficacy with tamoxifen, letrozole or exemestane in clinical treatment of estrogen receptor (ER) positive breast cancer. However, its anti-tumor activity was compromised by pAkt activation through the feedback-loop pathway. Here, we evaluated whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In MCF-7 and BT474 breast cancer cell lines, we observed that everolimus inhibited the mTOR [...]

Menée à l'aide de xénogreffes sur des rats, cette étude met en évidence la capacité de nanoparticules, enrichies en iodure de dithiazanine, à pénétrer dans le cerveau et à éradiquer les cellules souches de glioblastome

Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma

Zhou, Jiangbing ; Patel, Toral R. ; Sirianni, Rachael W. ; Strohbehn, Garth ; Zheng, Ming-Qiang ; Duong, Nha ; Schafbauer, Thomas ; Huttner, Anita J. ; Huang, Yiyun ; Carson, Richard E. ; Zhang, Ying ; Sullivan, David J. ; Piepmeier, Joseph M. ; Saltzman, W. Mark

Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with [...]

Menée à l'aide d'un modèle murin de glioblastome, cette étude met en évidence des mécanismes de nature inflammatoire associés à la résistance à un traitement anti-angiogénique

Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition

Piao, Yuji ; Liang, Ji ; Holmes, Lindsay S. ; Henry, Verlene ; Sulman, Erik P. ; de Groot, John F.

Purpose: Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy. Experimental Design: Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome wide analyses were [...]

Menée sur des lignées cellulaires de neuroblastome, cette étude met en évidence des mécanismes par lesquels, en régulant l'autophagie, l'histone désacétylase HDAC10 protège les cellules cancéreuses de l'action des agents cytotoxiques

Histone deacetylase 10 promotes autophagy-mediated cell survival

Oehme, Ina ; Linke, Jan-Peter ; Böck, Barbara C. ; Milde, Till ; Lodrini, Marco ; Hartenstein, Bettina ; Wiegand, Inga ; Eckert, Christian ; Roth, Wilfried ; Kool, Marcel ; Kaden, Sylvia ; Gröne, Hermann-Josef ; Schulte, Johannes H. ; Lindner, Sven ; Hamacher-Brady, Anne ; Brady, Nathan R. ; Deubzer, Hedwig E. ; Witt, Olaf

Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, [...]

Cet article passe en revue les travaux récents sur le développement de thérapies ciblées visant à surmonter une résistance aux inhibiteurs d'EGFR dans le traitement d'un cancer de la tête et du cou sans lien avec le papillomavirus humain

Novel targets in HPV-negative head and neck cancer: overcoming resistance to EGFR inhibition

Burtness, Barbara ; Bauman, Julie E. ; Galloway, Thomas

Cancers of the head and neck that arise from habitual exposure to carcinogens have lower cure rates than those that arise from infection with human papillomavirus (HPV), and intensification of cytotoxic chemotherapy and radiation has not improved outcomes. HPV-negative head and neck cancers abundantly express EGFR, and the monoclonal antibody cetuximab, directed against EGFR, is the only targeted therapy that has improved disease survival so far. However, response rates to single-agent [...]

Cet article passe en revue les travaux récents sur le lénalidomide pour le traitement des patients atteints d'un myélome multiple

How lenalidomide is changing the treatment of patients with multiple myeloma

Dimopoulos, Meletios A. ; Terpos, Evangelos ; Niesvizky, Ruben

Lenalidomide is a distinct second-generation immunomodulatory compound with multiple anticancer and immunomodulatory effects against haematological malignancies, in particular multiple myeloma (MM). Dexamethasone synergistically enhances the anticancer effects of lenalidomide, and the combination of lenalidomide and dexamethasone (Len/Dex) is approved for the treatment of patients with relapsed and/or refractory MM. Results from pivotal phase III trials in this setting have demonstrated that [...]

Cet article passe en revue les travaux récents sur les traitements adjuvants d'un adénocarcinome du pancréas

Adjuvant therapy for resectable pancreatic adenocarcinoma: Review of the current treatment approaches and future directions

Antoniou, G. ; Kountourakis, P. ; Papadimitriou, K. ; Vassiliou, V. ; Papamichael, D.

Adenocarcinoma of the pancreas carries a uniformly poor prognosis with high rates of loco-regional as well as systemic recurrence. Outcomes remain poor, even for early stage and resectable disease. It is perceived as inherently resistant to most of the currently available treatment options. Evidence supports the need for adjuvant chemotherapy but controversy remains in relation to the use of combined therapy, novel agents and the most appropriate timing of therapy. Despite no clear consensus, [...]

Mené sur 146 patients atteints d'un carcinome à cellules rénales de stade métastatique, cet essai de phase I évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du bevacizumab en combinaison avec de l'interféron α2a à faible dose (durée médiane de suivi : 29,4 mois)

A multinational phase II trial of bevacizumab with low-dose interferon-α2a as first-line treatment of metastatic renal cell carcinoma: BEVLiN

Melichar, B. ; Bracarda, S. ; Matveev, V. ; Alekseev, B. ; Ivanov, S. ; Zyryanov, A. ; Janciauskiene, R. ; Fernebro, E. ; Mulders, P. ; Osborne, S. ; Jethwa, S. ; Mickisch, G. ; Gore, M. ; van Moorselaar, R. J. A. ; Staehler, M. ; Magne, N. ; Bellmunt, J.

Background Avastin and Roferon in Renal Cell Carcinoma (AVOREN) demonstrated efficacy for bevacizumab plus interferon-α2a (IFN; 9 MIU tiw) in first-line metastatic renal cell carcinoma (mRCC). We evaluated bevacizumab with low-dose IFN in mRCC to determine whether clinical benefit could be maintained with reduced toxicity. Methods BEVLiN was an open-label, single-arm, multinational, phase II trial. Nephrectomized patients with treatment-naive, clear cell mRCC and favourable/intermediate [...]

Mené sur 18 patientes atteintes d'un cancer du sein métastatique, cet essai de phase II évalue, du point de vue de la survie sans progression, un traitement combinant sorafenib et bevacizumab

A phase II study of combined VEGF inhibitor (bevacizumab+sorafenib) in patients with metastatic breast cancer: Hoosier Oncology Group Study BRE06-109

Mina, LidaA ; Yu, Menggang ; Johnson, Cynthia ; Burkhardt, Cyndi ; Miller, KathyD ; Zon, Robin

Purpose: Angiogenesis plays an essential role in tumor development, invasion and metastasis. We evaluated the efficacy and safety of dual angiogenesis blockade with bevacizumab and sorafenib in patients with metastatic breast cancer. Patients and Methods: Patients who had received no more than 2 prior chemotherapy regimens in any setting were treated with sorafenib 200 mg as a single oral dose daily plus bevacizumab intravenously 5 mg/kg every other week. Response was assessed by Response [...]

A partir des données médicales portant sur 224 patientes atteintes d'un cancer du sein de stade T1N0M0 traité par chirurgie conservatrice et radiothérapie (âge : 65 ans et plus ; durée médiane de suivi : 62,6 mois), cette étude évalue les bénéfices du tamoxifène en termes de survie sans récidive, de survie globale et d'incidence du cancer du sein controlatéral

The Relative Benefits of Tamoxifen in Older Women with T1 Early-Stage Breast Cancer Treated with Breast-Conserving Surgery and Radiation Therapy

Khan, Atif J. ; Parikh, Rahul R. ; Neboori, Hanmanth J. ; Goyal, Sharad ; Haffty, Bruce G. ; Moran, Meena S.

Small, hormone receptor-positive breast carcinomas in older women are associated with low local recurrence rates. The relative benefits of adjuvant hormonal therapy remain unclear in elderly women with small, node-negative breast cancer after breast-conserving surgery and adjuvant radiation therapy. From our institutional data base, 224 patients ≥65 years of age with T1N0M0 breast cancer treated with BCS+RT were identified. Of these, 102 patients (45.5%) received tamoxifen (TAM) and 122 [...]

Cet article passe en revue les travaux récents concernant l'utilisation de techniques de radiochirurgie stéréotaxique dans le traitement de métastases cérébrales

Stereotactic radiosurgery in the treatment of brain metastases: The current evidence

Lippitz, Bodo ; Lindquist, Christer ; Paddick, Ian ; Peterson, David ; O’Neill, Kevin ; Beaney, Ronald

Chemotherapy has made substantial progress in the therapy of systemic cancer, but the pharmacological efficacy is insufficient in the treatment of brain metastases. Fractionated whole brain radiotherapy (WBRT) has been a standard treatment of brain metastases, but provides limited local tumor control and often unsatisfactory clinical results. Stereotactic radiosurgery using Gamma Knife, Linac or Cyberknife has overcome several of these limitations, which has influenced recent treatment [...]

Menée sur des modèles de cellules cancéreuses du pancréas et à l'aide de xénogreffes, cette étude montre que MK8776, un inhibiteur de la protéine kinase Chk1, peut sensibiliser les cellules tumorales à une chimioradiothérapie à base de gemcitabine

Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor, MK8776

Engelke, Carl ; Parsels, Leslie ; Qian, Yushen ; Zhang, Qiang ; Karnak, David ; Robertson, Jordan ; Tanska, Daria ; Wei, Dongping ; Davis, Mary ; Parsels, Joshua ; Zhao, Lili L. ; Greenson, Joel K. ; Lawrence, Theodore ; Maybaum, Jonathan ; Morgan, Meredith A.

Purpose : The combination of radiation with chemotherapy is the most effective therapy for unresectable pancreatic cancer. To improve upon this regimen, we combined the selective Chk1 inhibitor, MK8776 with gemcitabine-based chemoradiation in preclinical pancreatic cancer models. Experimental Design : We tested the ability of MK8776 to sensitize to gemcitabine-radiation in homologous recombination repair (HRR)- proficient and deficient pancreatic cancer cells and assessed Rad51 focus formation. [...]

Cet article présente la mise à jour des recommandations d'un groupe d'experts européens sur la prise en charge d'une leucémie myéloïde chronique

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

Baccarani, Michele ; Deininger, Michael W. ; Rosti, Gianantonio ; Hochhaus, Andreas ; Soverini, Simona ; Apperley, Jane F. ; Cervantes, Francisco ; Clark, Richard E. ; Cortes, Jorge E. ; Guilhot, François ; Hjorth-Hansen, Henrik ; Hughes, Timothy P. ; Kantarjian, Hagop M. ; Kim, Dong-Wook ; Larson, Richard A. ; Lipton, Jeffrey H. ; Mahon, François-Xavier ; Martinelli, Giovanni ; Mayer, Jiri ; Müller, Martin C. ; Niederwieser, Dietger ; Pane, Fabrizio ; Radich, Jerald P. ; Rousselot, Philippe ; Saglio, Giuseppe ; Saußele, Susanne ; Schiffer, Charles ; Silver, Richard ; Simonsson, Bengt ; Steegmann, Juan-Luis ; Goldman, John M. ; Hehlmann, Rüdiger

Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors (TKIs), mandate regular updating of concepts and management. An ELN expert panel reviewed prior and new studies, to update recommendations made in 2009. We recommend as initial treatment imatinib or nilotinib or dasatinib. Response is assessed with standardized RQ-PCR and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months [...]