Traitements

Menée à partir d'échantillons tumoraux prélevés sur 506 patients atteints d'un carcinome nasopharyngé non métastatique, cette étude rétrospective évalue l'efficacité d'une radiothérapie conformationnelle par modulation d'intensité en fonction du stade tumoral défini par le système de l' "American Joint Committee on Cancer"

• Promising treatment outcomes of intensity-modulated radiation therapy for nasopharyngeal carcinoma patients with N0 disease according to the seventh edition of the AJCC staging system
  • BMC Cancer, Vol. 12 (1), pp. 68, 2012 (article en libre accès)
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  Menée à partir d'échantillons tumoraux prélevés sur 506 patients atteints d'un carcinome nasopharyngé non métastatique, cette étude rétrospective évalue l'efficacité d'une radiothérapie conformationnelle par modulation d'intensité en fonction du stade tumoral défini par le système de l' "American Joint Committee on Cancer"

  “Promising treatment outcomes of intensity-modulated radiation therapy for nasopharyngeal carcinoma patients with N0 disease according to the seventh edition of the AJCC staging system”

  • Sun, Ying;Tang, Linglong;Chen, Lei;Li, Wenfei;Mao, Yanping;Liu, Lizhi;Lin, Aihua;Li, Li;Ma, Jun

  BACKGROUND:Intensity-modulated radiation therapy (IMRT) provides excellent locoregional control for nasopharyngeal carcinoma (NPC), and has gradually replaced two-dimensional conventional radiotherapy as the first-line radiotherapy technique. Furthermore, in the new seventh edition of the American Joint Committee on Cancer (AJCC) staging system, retropharyngeal lymph nodes were upgraded from N0 to N1 disease as a result of their negative impact on the distant metastasis-free survival (DMFS) rates of NPC. This retrospective study was conducted in order to review the treatment outcomes and patterns of failure in NPC patients with N0 disease after IMRT in order to effectively guide treatment in the future.METHODS:We retrospectively reviewed data from 506 biopsy-proven nonmetastatic NPC patients. There were 191 patients with negative cervical lymph node involvement. According to the seventh edition of the American Joint Committee on Cancer (AJCC) staging system, 110 patients (21.7%) were ...

  
  

Mots clés : Voies aérodigestives supérieures; Traitements (Traitements localisés : applications cliniques)

Menée sur 189 patients atteints d'un cancer de la prostate à faible risque de récidive et bénéficiant d'une surveillance active, cette étude prospective observationnelle analyse les caractéristiques clinico-pathologiques des tumeurs après une prostatectomie radicale différée

• Radical Prostatectomy for Low-Risk Prostate Cancer Following Initial Active Surveillance: Results From a Prospective Observational Study
  • European urology, sous presse, 2012 (résumé)
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  Menée sur 189 patients atteints d'un cancer de la prostate à faible risque de récidive et bénéficiant d'une surveillance active, cette étude prospective observationnelle analyse les caractéristiques clinico-pathologiques des tumeurs après une prostatectomie radicale différée

  “Radical Prostatectomy for Low-Risk Prostate Cancer Following Initial Active Surveillance: Results From a Prospective Observational Study”

  • Meelan, Bul;Xiaoye, Zhu;Antti, Rannikko;Frédéric, Staerman;Riccardo, Valdagni;Tom, Pickles;Chris, H. Bangma;Monique, J. Roobol

  Background : Little is known about the outcome of radical prostatectomy (RP) in men initially followed on active surveillance (AS) for low-risk prostate cancer (PCa). Objective : Evaluate pathology findings after RP in our prospective AS cohort. Design, setting, and participants : All men participated in the Prostate Cancer Research International: Active Surveillance (PRIAS) study. Eligible men were initially diagnosed with low-risk PCa (clinical stage 6 and/or more than two positive cores) or a PSA doubling time <3 yr. Measurements : Descriptive statistics were used to report on pathology findings for staging and grading. Results and limitations : Pathology results were available in 167 out of 189 RP ...

  
  

Mots clés : Prostate; Traitements (Traitements localisés : applications cliniques)

Mené sur 56 patients atteints d'un chordome de stade avancé surexprimant PDGFB ou PDGFRB, cet essai de phase II évalue l'activité antitumorale de l'imatinib

• Phase II Study of Imatinib in Advanced Chordoma
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 56 patients atteints d'un chordome de stade avancé surexprimant PDGFB ou PDGFRB, cet essai de phase II évalue l'activité antitumorale de l'imatinib

  “Phase II Study of Imatinib in Advanced Chordoma”

  • Stacchiotti, Silvia;Longhi, Alessandra;Ferraresi, Virginia;Grignani, Giovanni;Comandone, Alessandro;Stupp, Roger;Bertuzzi, Alexia;Tamborini, Elena;Pilotti, Silvana;Messina, Antonella;Spreafico, Carlo;Gronchi, Alessandro;Amore, Paola;Vinaccia, Vincenza;Casali, Paolo Giovanni

  Purpose To explore the antitumor activity of imatinib in patients with advanced platelet-derived growth factor β (PDGFB)/PDGF receptor β (PDGFRB)–positive chordomas.Patients and Methods In a collaborative Italian-Swiss, prospective, phase II clinical study conducted from November 2004 through April 2006, 56 patients with advanced PDGFB and/or PDGFRB chordoma received 800 mg/d of imatinib until progression. The primary end point was the overall tumor response rate (ORR), defined by RECIST. Secondary, exploratory end points included tissue response (ie, changes in tumor density or signal intensity/contrast enhancement, and/or [18F]-fluorodeoxyglucose positron emission tomography [PET] uptake), overall survival, progression-free survival (PFS), and pain score.Results Among 50 patients evaluable by RECIST, the best response was one partial response (PR) obtained at 6 months (ORR, 2%). There were 35 patients with stable disease (SD, 70%) and a 64% clinical benefit rate (ie, RECIST ...

  
  
• The Challenge of Choosing Appropriate End Points in Single-Arm Phase II Studies of Rare Diseases
  • Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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  Mené sur 56 patients atteints d'un chordome de stade avancé surexprimant PDGFB ou PDGFRB, cet essai de phase II évalue l'activité antitumorale de l'imatinib

  “The Challenge of Choosing Appropriate End Points in Single-Arm Phase II Studies of Rare Diseases”

  • Sleijfer, Stefan ; Wagner, Andrew J.

  
  

Mots clés : Système nerveux central; Traitements (Traitements systémiques : découverte et développement)

Cet article passe en revue les nouvelles stratégies immunothérapeutiques et antiangiogéniques dans le carcinome métastatique à cellules rénales

• Novel Therapies for Metastatic Renal Cell Carcinoma: Efforts to Expand beyond the VEGF/mTOR Signaling Paradigm
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Cet article passe en revue les nouvelles stratégies immunothérapeutiques et antiangiogéniques dans le carcinome métastatique à cellules rénales

  “Novel Therapies for Metastatic Renal Cell Carcinoma: Efforts to Expand beyond the VEGF/mTOR Signaling Paradigm”

  • Pal, Sumanta Kumar;Williams, Stephen;Josephson, David Y.;Carmichael, Courtney;Vogelzang, Nicholas J.;Quinn, David I.

  With six agents approved for metastatic renal cell carcinoma (mRCC) within the past 5 years, there has undoubtedly been progress in treating this disease. However, the goal of cure remains elusive, and the agents nearest approval (i.e., axitinib and tivozanib) abide by the same paradigm as existing drugs (i.e., inhibition of VEGF or mTOR signaling). The current review will focus on investigational agents that diverge from this paradigm. Specifically, novel immunotherapeutic strategies will be discussed, including vaccine therapy, cytotoxic T-lymphocyte antigen 4 (CTLA4) blockade, and programmed death-1 (PD-1) inhibition, as well as novel approaches to angiogenesis inhibition, such as abrogation of Ang/Tie-2 signaling. Pharmacologic strategies to block other potentially relevant signaling pathways, such as fibroblast growth factor receptor or MET inhibition, are also in various stages of development. Although VEGF and mTOR inhibition have dramatically improved outcomes for patients ...

  
  

Mots clés : Rein; Traitements (Traitements systémiques : découverte et développement)

Menée sur des modèles murins de lymphome et de cancer de la prostate, ces deux études évaluent les effets de l'inhibition de la télomérase sur la croissance tumorale

• Telomerase Reactivation following Telomere Dysfunction Yields Murine Prostate Tumors with Bone Metastases
  • Cell, sous presse, 2012 (résumé)
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  Menée sur des modèles murins de lymphome et de cancer de la prostate, ces deux études évaluent les effets de l'inhibition de la télomérase sur la croissance tumorale

  “Telomerase Reactivation following Telomere Dysfunction Yields Murine Prostate Tumors with Bone Metastases”

  • Ding, Zhihu;Wu, Chang-Jiun;Jaskelioff, Mariela;Ivanova, Elena;Kost-Alimova, Maria;Protopopov, Alexei;Chu, Gerald C;Wang, Guocan;Lu, Xin;Labrot, Emma S;Hu, Jian;Wang, Wei;Xiao, Yonghong;Zhang, Hailei;Zhang, Jianhua;Zhang, Jingfang;Gan, Boyi;Perry, Samuel R;Jiang, Shan;Li, Liren;Horner, James W.;Wang, Y.  Alan;Chin, Lynda;DePinho, Ronald A

  To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-²/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, ...

  
  
• Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer
  • Cell, Vol. 148 (4), pp. 651-663, 2012 (résumé)
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  Menée sur des modèles murins de lymphome et de cancer de la prostate, ces deux études évaluent les effets de l'inhibition de la télomérase sur la croissance tumorale

  “Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer”

  • Hu, Jian ; Hwang, Soyoon Sarah ; Liesa, Marc ; Gan, Boyi ; Sahin, Ergun ; Jaskelioff, Mariela ; Ding, Zhihu ; Ying, Haoqiang ; Boutin, Adam T ; Zhang, Hailei ; Johnson, Shawn ; Ivanova, Elena ; Kost-Alimova, Maria ; Protopopov, Alexei ; Wang, Yaoqi Alan ; Shirihai, Orian S ; Chin, Lynda ; DePinho, Ronald A

  To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm / mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1², a master regulator of mitochondrial biogenesis and function, and they showed ...

  
  
• Telomeres and Cancer: From Crisis to Stability to Crisis to Stability
  • Cell, Vol. 148 (4), pp. 633-635, 2012 (commentaire)
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  Menée sur des modèles murins de lymphome et de cancer de la prostate, ces deux études évaluent les effets de l'inhibition de la télomérase sur la croissance tumorale

  “Telomeres and Cancer: From Crisis to Stability to Crisis to Stability”

  • Campbell, Peter J

  Telomere attrition unleashes genomic instability, promoting cancer development. Once established, however, the malignant clone often re-establishes genomic stability through overexpression of telomerase. In two papers, one in this issue of Cell and one in the subsequent issue, DePinho and colleagues explore the consequences of telomerase re-expression and its validity as a therapeutic target in mouse models of cancer.

  
  

Mots clés : Prostate; Traitements (Traitements systémiques : découverte et développement)

Menée sur un modèle murin, cette étude suggère qu'un anticorps bloquant l'angiopoïétine 2 inhibe la dissémination de métastases dans le poumon

• Effects of Angiopoietin-2-Blocking Antibody on Endothelial Cell–Cell Junctions and Lung Metastasis
  • Journal of the National Cancer Institute, sous presse, 2012 (résumé)
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  Menée sur un modèle murin, cette étude suggère qu'un anticorps bloquant l'angiopoïétine 2 inhibe la dissémination de métastases dans le poumon

  “Effects of Angiopoietin-2-Blocking Antibody on Endothelial Cell–Cell Junctions and Lung Metastasis”

  • Holopainen, Tanja;Saharinen, Pipsa;D’Amico, Gabriela;Lampinen, Anita;Eklund, Lauri;Sormunen, Raija;Anisimov, Andrey;Zarkada, Georgia;Lohela, Marja;Heloterä, Hanna;Tammela, Tuomas;Benjamin, Laura E.;Ylä-Herttuala, Seppo;Leow, Ching Ching;Koh, Gou Young;Alitalo, Kari

  Background Angiopoietin-2 (Ang2), a ligand for endothelial TEK (Tie2) tyrosine kinase receptor, is induced in hypoxic endothelial cells of tumors, where it promotes tumor angiogenesis and growth. However, the effects of Ang2 on tumor lymphangiogenesis and metastasis are poorly characterized.Methods We addressed the effect of Ang2 on tumor progression and metastasis using systemic Ang2 overexpression in mice carrying tumor xenografts, endothelium-specific overexpression of Ang2 in VEC-tTA/Tet-OS-Ang2 transgenic mice implanted with isogenic tumors, and administration of Ang2-blocking antibodies to tumor-bearing immunodeficient mice. Fisher's exact test was used for analysis of metastasis occurrence, and repeated measures one-way analysis of variance was used for the analysis of primary tumor growth curves. Unpaired t test was used for all other analyses. All statistical tests were two-sided.Results Adenoviral expression of Ang2 increased lymph node and lung metastasis in tumor ...

  
  
• Angiopoietin2 and Tie2: Tied to Lymphangiogenesis and Lung Metastasis. New Perspectives in Antimetastatic Antiangiogenic Therapy
  • Journal of the National Cancer Institute, sous presse, 2012 (éditorial en libre accès)
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  Menée sur un modèle murin, cette étude suggère qu'un anticorps bloquant l'angiopoïétine 2 inhibe la dissémination de métastases dans le poumon

  “Angiopoietin2 and Tie2: Tied to Lymphangiogenesis and Lung Metastasis. New Perspectives in Antimetastatic Antiangiogenic Therapy”

  • Albini, Adriana ; Noonan, Douglas M.

  
  

Mots clés : Poumon; Traitements (Traitements systémiques : découverte et développement)

Menée sur un modèle murin immunodéprimé, cette étude met en évidence le rôle joué par la protéine LMP1 dans la surveillance immunitaire et la transformation de cellules B infectées par le virus d'Epstein-Barr

• Immune Surveillance and Therapy of Lymphomas Driven by Epstein-Barr Virus Protein LMP1 in a Mouse Model
  • Cell, Vol. 148 (4), pp. 739-751, 2012 (résumé)
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  Menée sur un modèle murin immunodéprimé, cette étude met en évidence le rôle joué par la protéine LMP1 dans la surveillance immunitaire et la transformation de cellules B infectées par le virus d'Epstein-Barr

  “Immune Surveillance and Therapy of Lymphomas Driven by Epstein-Barr Virus Protein LMP1 in a Mouse Model”

  • Zhang, Baochun;Kracker, Sven;Yasuda, Tomoharu;Casola, Stefano;Vanneman, Matthew;Hömig-Hölzel, Cornelia;Wang, Zhe;Derudder, Emmanuel;Li, Shuang;Chakraborty, Tirtha;Cotter, Shane E;Koyama, Shohei;Currie, Treeve;Freeman, Gordon J;Kutok, Jeffery L;Rodig, Scott J;Dranoff, Glenn;Rajewsky, Klaus

  B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1+ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and ...

  
  

Mots clés : Lymphome; Traitements (Traitements systémiques : découverte et développement)

Menée in vitro et in vivo, cette étude montre que, dans les leucémies myélogènes chroniques, l'inhibition de SIRT1 active l'expression de p53 et augmente les effets d'un traitement par imatinib sur les cellules souches cancéreuses

• Activation of p53 by SIRT1 Inhibition Enhances Elimination of CML Leukemia Stem Cells in Combination with Imatinib
  • Cancer cell, Vol. 21 (2), pp. 266-281, 2012 (résumé)
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  Menée in vitro et in vivo, cette étude montre que, dans les leucémies myélogènes chroniques, l'inhibition de SIRT1 active l'expression de p53 et augmente les effets d'un traitement par imatinib sur les cellules souches cancéreuses

  “Activation of p53 by SIRT1 Inhibition Enhances Elimination of CML Leukemia Stem Cells in Combination with Imatinib”

  • Li, Ling;Wang, Lisheng;Li, Liang;Wang, Zhiqiang;Ho, Yinwei;McDonald, Tinisha;Holyoake, Tessa L;Chen, WenYong;Bhatia, Ravi

  BCR-ABL tyrosine kinase inhibitors (TKI) fail to eliminate quiescent leukemia stem cells (LSC) in chronic myelogenous leukemia (CML). Thus, strategies targeting LSC are required to achieve cure. We show that the NAD+-dependent deacetylase SIRT1 is overexpressed in human CML LSC. Pharmacological inhibition of SIRT1 or SIRT1 knockdown increased apoptosis in LSC of chronic phase and blast crisis CML and reduced their growth in vitro and in vivo. SIRT1 effects were enhanced in combination with the BCR-ABL TKI imatinib. SIRT1 inhibition increased p53 acetylation and transcriptional activity in CML progenitors, and the inhibitory effects of SIRT1 targeting on CML cells depended on p53 expression and acetylation. Activation of p53 via SIRT1 inhibition represents a potential approach to target CML LSC. º SIRT1 expression and activity is enhanced in CML compared to normal stem cells º SIRT1 inhibition cooperates with Imatinib to increase elimination of CML stem cells º SIRT1 inhibition ...

  
  
• aSIRTing Control over Cancer Stem Cells
  • Cancer cell, Vol. 21 (2), pp. 140-142, 2012 (commentaire)
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  Menée in vitro et in vivo, cette étude montre que, dans les leucémies myélogènes chroniques, l'inhibition de SIRT1 active l'expression de p53 et augmente les effets d'un traitement par imatinib sur les cellules souches cancéreuses

  “aSIRTing Control over Cancer Stem Cells”

  • Ito, Takahiro ; Zimdahl, Bryan ; Reya, Tannishtha

  Cancer stem cells lie at the root of chronic myelogenous leukemia (CML) and mediate its continued growth. Their resistance to current therapies results in an inability to eradicate the disease. In this issue of Cancer Cell, Li et al. identify SIRT1 as a new target for eliminating CML cancer stem cells.

  
  

Mots clés : Leucémie; Traitements (Traitements systémiques : découverte et développement)

Mené sur 49 patients atteints d'une leucémie lymphocytaire aiguë récidivante et réfractaire, cet essai de phase II évalue, du point de vue de la réponse globale, l'inotuzumab ozogamicine, un anticorps monoclonal anti-CD22 conjugué à une toxine, la calicheamicine

• Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study
  • The Lancet Oncology, sous presse, 2012 (résumé)
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  Mené sur 49 patients atteints d'une leucémie lymphocytaire aiguë récidivante et réfractaire, cet essai de phase II évalue, du point de vue de la réponse globale, l'inotuzumab ozogamicine, un anticorps monoclonal anti-CD22 conjugué à une toxine, la calicheamicine

  “Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study”

  • Kantarjian, Hagop;Thomas, Deborah;Jorgensen, Jeffrey;Jabbour, Elias;Kebriaei, Partow;Rytting, Michael;York, Sergernne;Ravandi, Farhad;Kwari, Monica;Faderl, Stefan;Rios, Mary Beth;Cortes, Jorge;Fayad, Luis;Tarnai, Robert;Wang, Sa A.;Champlin, Richard;Advani, Anjali;O'Brien, Susan

  The outlook for patients with refractory and relapsed acute lymphocytic leukaemia (ALL) is poor. CD22 is highly expressed in patients with ALL. Inotuzumab ozogamicin is a CD22 monoclonal antibody conjugated to the toxin calecheamicin. We did a phase 2 study to assess the efficacy of this antibody. We recruited patients at the MD Anderson Cancer Center, Houston, TX, USA, between June, 2010, and March, 2011. Adults and children with refractory and relapsed ALL were eligible. Ten adults were treated before enrolment of children started. Patients were given 1·8 mg/m2inotuzumab ozogamicin intravenously over 1 h every 3?4 weeks (the first three adults and three children received 1·3 mg/m2in the first course). The primary endpoint was overall response (complete response or marrow complete response with no recovery of platelet count or incomplete recovery of neutrophil and platelet counts). Analysis was done by intention to treat. This study is registered, numberNCT01134575. 49 patients ...

  
  
• Anti-CD22 therapy in acute lymphoblastic leukaemia
  • The Lancet Oncology, sous presse, 2012 (commentaire en libre accès)
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  Mené sur 49 patients atteints d'une leucémie lymphocytaire aiguë récidivante et réfractaire, cet essai de phase II évalue, du point de vue de la réponse globale, l'inotuzumab ozogamicine, un anticorps monoclonal anti-CD22 conjugué à une toxine, la calicheamicine

  “Anti-CD22 therapy in acute lymphoblastic leukaemia”

  • Hoelzer, Dieter

  
  

Mots clés : Leucémie; Traitements (Traitements systémiques : découverte et développement)

Menée in vitro et in vivo à l'aide de xénogreffes de carcinome hépatocellulaire, cette étude évalue l'activité antitumorale d'un anticorps monoclonal ciblant le facteur fibroblastique de croissance 2

• A Novel Monoclonal Antibody to Fibroblast Growth Factor 2 Effectively Inhibits Growth of Hepatocellular Carcinoma Xenografts
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Menée in vitro et in vivo à l'aide de xénogreffes de carcinome hépatocellulaire, cette étude évalue l'activité antitumorale d'un anticorps monoclonal ciblant le facteur fibroblastique de croissance 2

  “A Novel Monoclonal Antibody to Fibroblast Growth Factor 2 Effectively Inhibits Growth of Hepatocellular Carcinoma Xenografts”

  • Wang, Lihong;Park, Hangil;Chhim, Sophea;Ding, Yi;Jiang, Wei;Queen, Cary;Kim, K. Jin

  Expression of Fibroblast Growth Factor 2 (FGF2) is believed to be a contributing factor to the growth of a number of tumor types, including hepatocellular carcinoma (HCC). However, the potential of monoclonal antibodies that neutralize FGF2 for treatment of cancer patients has not yet been explored in clinical trials. We therefore generated a novel monoclonal antibody (mAb), GAL-F2, specific for FGF2 and characterized its properties in vitro and in vivo. GAL-F2 binds to a different epitope than several previous anti-FGF2 mAbs tested: this novel epitope was defined using chimeric FGF1/FGF2 proteins and alanine scanning mutagenesis and shown to comprise amino acids in both the amino and carboxy regions of FGF2. GAL-F2 blocked binding of FGF2 to each of its four cellular receptors, strongly inhibited FGF2-induced proliferation and downstream signaling in HUVEC, and inhibited proliferation and downstream signaling in two HCC cell lines. Moreover, GAL-F2, administered at 5 mg/kg i.p. twice ...

  
  

Mots clés : Foie; Traitements (Traitements systémiques : découverte et développement)

Menée in vitro, cette étude suggère que l'inhibition de l'activité de la protéine kinase TAK1 pourrait être une stratégie thérapeutique pertinente pour les cancers du côlon réfractaires aux traitements actuels et présentant une signalisation KRAS et Wnt aberrante

• TAK1 Inhibition Promotes Apoptosis in KRAS-Dependent Colon Cancers
  • Cell, Vol. 148 (4), pp. 639-650, 2012 (résumé)
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  Menée in vitro, cette étude suggère que l'inhibition de l'activité de la protéine kinase TAK1 pourrait être une stratégie thérapeutique pertinente pour les cancers du côlon réfractaires aux traitements actuels et présentant une signalisation KRAS et Wnt aberrante

  “TAK1 Inhibition Promotes Apoptosis in KRAS-Dependent Colon Cancers”

  • Singh, Anurag;Sweeney, Michael F;Yu, Min;Burger, Alexa;Greninger, Patricia;Benes, Cyril;Haber, Daniel A;Settleman, Jeff

  Colon cancers frequently harbor KRAS mutations, yet only a subset of KRAS mutant colon cancer cell lines are dependent upon KRAS signaling for survival. In a screen for kinases that promote survival of KRAS-dependent colon cancer cells, we found that the TAK1 kinase (MAP3K7) is required for tumor cell viability. The induction of apoptosis by RNAi-mediated depletion or pharmacologic inhibition of TAK1 is linked to its suppression of hyperactivated Wnt signaling, evident in both endogenous and genetically reconstituted cells. In APC mutant/KRAS-dependent cells, KRAS stimulates BMP-7 secretion and BMP signaling, leading to TAK1 activation and enhancement of Wnt-dependent transcription. An in vitro-derived TAK1 dependency signature is enriched in primary human colon cancers with mutations in both APC and KRAS, suggesting potential clinical utility in stratifying patient populations. Together, these findings identify TAK1 inhibition as a potential therapeutic strategy for a ...

  
  

Mots clés : Colon-rectum; Traitements (Traitements systémiques : découverte et développement)

Menée sur un modèle murin de cancer colorectal, cette étude évalue l'activité antitumorale d'un nouveau composé par voie orale appelé CEP-33779, un inhibiteur de l'activité de JAK2

• Therapeutic Efficacy of CEP-33779, a Novel Selective JAK2 Inhibitor, in a Mouse Model of Colitis-induced Colorectal Cancer
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
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  Menée sur un modèle murin de cancer colorectal, cette étude évalue l'activité antitumorale d'un nouveau composé par voie orale appelé CEP-33779, un inhibiteur de l'activité de JAK2

  “Therapeutic Efficacy of CEP-33779, a Novel Selective JAK2 Inhibitor, in a Mouse Model of Colitis-induced Colorectal Cancer”

  • Seavey, Matthew M;Lu, Lily D;Stump, Kristine L;Wallace, Nate H;Hockeimer, William;O'Kane, Teresa M;Ruggeri, Bruce;Dobrzanski, Pawel

  Constitutively activated STAT3 and STAT5 are expressed in a wide variety of human malignancies including solid and hematopoietic cancers and often correlate with a poor prognosis and resistance to multiple therapies. Given the well established role of STAT3 in tumorigenesis, inhibition of JAK2 activity might represent an attractive therapeutic approach. Using a mouse model of colitis-induced colorectal cancer we show that a novel, orally active, selective JAK2 inhibitor, CEP-33779, induced regression of established colorectal tumors, reduced angiogenesis and proliferation of tumor cells. Histopathological analysis confirmed reduced incidence of histological-grade neoplasia by CEP-33779. Tumor regression correlated with inhibition of STAT3 and NF-kB (RelA/p65) activation in a CEP-33779-dose dependent manner. In addition, the expression of pro-inflammatory, tumor-promoting cytokines IL-6 and IL-1b was strongly reduced upon JAK2 inhibition. The ability of CEP-33779 to suppress growth of ...

  
  

Mots clés : Colon-rectum; Traitements (Traitements systémiques : découverte et développement)

Menée in vitro, cette étude évalue les revendications de spécificité des principaux inhibiteurs de PARP actuellement en essai clinique

• Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors
  • Nature Biotechnology, sous presse, 2012 (résumé)
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  Menée in vitro, cette étude évalue les revendications de spécificité des principaux inhibiteurs de PARP actuellement en essai clinique

  “Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors”

  • Wahlberg, Elisabet;Karlberg, Tobias;Kouznetsova, Ekaterina;Markova, Natalia;Macchiarulo, Antonio;Thorsell, Ann-Gerd;Pol, Ewa;Frostell, Asa;Ekblad, Torun;Oncu, Delal;Kull, Bjorn;Robertson, Graeme Michael;Pellicciari, Roberto;Schuler, Herwig;Weigelt, Johan

  Inhibitors of poly-ADP-ribose polymerase (PARP) family proteins are currently in clinical trials as cancer therapeutics, yet the specificity of many of these compounds is unknown. Here we evaluated a series of 185 small-molecule inhibitors, including research reagents and compounds being tested clinically, for the ability to bind to the catalytic domains of 13 of the 17 human PARP family members including the tankyrases, TNKS1 and TNKS2. Many of the best-known inhibitors, including TIQ-A, 6(5H)-phenanthridinone, olaparib, ABT-888 and rucaparib, bound to several PARP family members, suggesting that these molecules lack specificity and have promiscuous inhibitory activity. We also determined X-ray crystal structures for five TNKS2 ligand complexes and four PARP14 ligand complexes. In addition to showing that the majority of PARP inhibitors bind multiple targets, these results provide insight into the design of new inhibitors.

  
  

Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Cet article analyse les raisons de l'échec des essais de phase III d'anticorps anti-IGF1R dans le traitement des cancers et identifie des stratégies thérapeutiques alternatives

• The insulin and insulin-like growth factor receptor family in neoplasia: an update
  • Nature Reviews Cancer, sous presse, 2012 (résumé)
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  Cet article analyse les raisons de l'échec des essais de phase III d'anticorps anti-IGF1R dans le traitement des cancers et identifie des stratégies thérapeutiques alternatives

  “The insulin and insulin-like growth factor receptor family in neoplasia: an update”

  • Pollak, Michael

  Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K–AKT pathway inhibitors.

  
  

Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par le facteur de transcription Nanog dans l'évolution des cellules tumorales en réponse à une immunothérapie

• Cancer vaccination drives Nanog-dependent evolution of tumor cells towards an immune-resistant and stem-like phenotype
  • Cancer Research, sous presse, 2012 (résumé)
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  Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par le facteur de transcription Nanog dans l'évolution des cellules tumorales en réponse à une immunothérapie

  “Cancer vaccination drives Nanog-dependent evolution of tumor cells towards an immune-resistant and stem-like phenotype”

  • Noh, Kyung Hee;Lee, Young-Ho;Jeon, Ju-Hong;Kang, Tae Heung;Mao, Chih-Ping;Wu, T.-C.;Kim, Tae Woo

  Due to the exquisite specificity and potency of the immune system, vaccination is in theory the most precise and powerful approach for controlling cancer. However, current data from clinical trials indicate that vaccination rarely yields significant benefits for cancer patients in terms of tumor progression and long-term survival. The poor clinical outcomes of vaccination are primarily caused by mechanisms of immune tolerance, especially within the tumor microenvironment. Here we report that vaccination drives the evolution of tumor cells towards an immune-resistant and stem-like phenotype that promotes tumor growth and nullifies the cytotoxic T lymphocyte (CTL) response. The emergence of this phenotype required the transcription factor Nanog, which is induced as a consequence of immune selection. Nanog expression enhanced the stem-like features of tumor cells and protected them from killing by tumor-reactive CTLs. Delivery of siNanog into tumor-bearing mice rendered the tumor ...

  
  

Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Mené sur 40 patients atteints d'une tumeur solide, cet essai de phase I évalue l'activité antitumorale du rigosertib en combinaison avec la gemcitabine

• Phase 1 study of rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Mené sur 40 patients atteints d'une tumeur solide, cet essai de phase I évalue l'activité antitumorale du rigosertib en combinaison avec la gemcitabine

  “Phase 1 study of rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer”

  • Ma, Wen Wee;Messersmith, Wells A.;Dy, Grace K;Weekes, Colin D.;Whitworth, Amy;Ren, Chen;Maniar, Manoj;Wilhem, Francois;Eckhardt, S. Gail;Adjeii, Alex A;Jimeno, Antonio

  Purpose: Rigosertib (R), a dual non-ATP inhibitor of polo-like kinase and phosphatidylinositol 3-kinase pathways, and gemcitabine (G) have synergistic anti-tumor activity when combined in preclinical studies. This phase 1 study aimed to determine the recommended phase 2 dose (RPTD) of the combination of rigosertib and gemcitabine in cancer patients. Methods: Patients with solid tumors who failed standard therapy or were candidates for gemcitabine-based therapy were eligible. Gemcitabine was administered on days 1, 8 and 15 on a 28-day cycle; rigosertib on days 1, 4, 8, 11, 15 and 18. Pharmacokinetic studies were performed during an expansion cohort of advanced pancreatic ductal adenocarcinoma (PDA) patients. Results: Forty patients were treated, 19 in the dose escalation phase and 21 in the expansion cohort. Dose levels evaluated were (G/R mg/m2): 750/600 (n=4), 750/1200 (3), 1000/600 (3), 1000/1200 (3) and 1000/1800 (6+21). One dose limiting toxicity (death) occurred at the highest ...

  
  

Mots clés : Cancer (général); Traitements (Traitements systémiques : découverte et développement)

Mené sur 593 patientes atteints d'un cancer du sein HER- de stade avancé, cet essai de phase III évalue, du point de vue de la survie sans progression, l'ajout de sunitinib au docétaxel

• First-Line Treatment of Advanced Breast Cancer With Sunitinib in Combination With Docetaxel Versus Docetaxel Alone: Results of a Prospective, Randomized Phase III Study
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 593 patientes atteints d'un cancer du sein HER- de stade avancé, cet essai de phase III évalue, du point de vue de la survie sans progression, l'ajout de sunitinib au docétaxel

  “First-Line Treatment of Advanced Breast Cancer With Sunitinib in Combination With Docetaxel Versus Docetaxel Alone: Results of a Prospective, Randomized Phase III Study”

  • Bergh, Jonas;Bondarenko, Igor M.;Lichinitser, Mikhail R.;Liljegren, Annelie;Greil, Richard;Voytko, Nataliya L.;Makhson, Anatoly N.;Cortes, Javier;Lortholary, Alain;Bischoff, Joachim;Chan, Arlene;Delaloge, Suzette;Huang, Xin;Kern, Kenneth A.;Giorgetti, Carla

  Purpose To investigate whether sunitinib plus docetaxel improves clinical outcomes for patients with human epidermal growth factor receptor 2 (HER2)/neu–negative advanced breast cancer (ABC) versus docetaxel alone.Patients and Methods In this phase III study, patients were randomly assigned to open-label combination therapy (sunitinib 37.5 mg/d, days 2 to 15 every 3 weeks; and docetaxel 75 mg/m2, day 1 every 3 weeks) or monotherapy (docetaxel 100 mg/m2 every 3 weeks). Progression-free survival (PFS) was the primary end point.Results Two hundred ninety-six patients were randomly assigned to combination therapy, and 297 patients were assigned to monotherapy. Median PFS times were 8.6 and 8.3 months with combination therapy and monotherapy, respectively (hazard ratio, 0.92; one-sided P = .265). The objective response rate (ORR) was significantly higher with the combination (55%) than with monotherapy (42%; one-sided P = .001). Duration of response was similar in both arms (7.5 months ...

  
  
• Inhibiting Angiogenesis in Breast Cancer: The Beginning of the End or the End of the Beginning?
  • Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
  Détails

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  Mené sur 593 patientes atteints d'un cancer du sein HER- de stade avancé, cet essai de phase III évalue, du point de vue de la survie sans progression, l'ajout de sunitinib au docétaxel

  “Inhibiting Angiogenesis in Breast Cancer: The Beginning of the End or the End of the Beginning?”

  • Rugo, Hope S.

  
  

Mots clés : Sein; Traitements (Traitements systémiques : applications cliniques)

Mené sur 601 patientes atteintes d'un cancer du sein de stade I à IIIC (durée médiane de suivi: 50 mois), cet essai de phase III compare les effets, du point de vue de la survie sans récidive, du paclitaxel et du docétaxel en combinaison avec la capécitabine avant une chmiothérapie FEC (5-FU, épirubicine et cyclophosphamide)

• Phase III Trial Evaluating Weekly Paclitaxel Versus Docetaxel in Combination With Capecitabine in Operable Breast Cancer
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
  Détails

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  Mené sur 601 patientes atteintes d'un cancer du sein de stade I à IIIC (durée médiane de suivi: 50 mois), cet essai de phase III compare les effets, du point de vue de la survie sans récidive, du paclitaxel et du docétaxel en combinaison avec la capécitabine avant une chmiothérapie FEC (5-FU, épirubicine et cyclophosphamide)

  “Phase III Trial Evaluating Weekly Paclitaxel Versus Docetaxel in Combination With Capecitabine in Operable Breast Cancer”

  • Kelly, Catherine M.;Green, Marjorie C.;Broglio, Kristine;Thomas, Eva S.;Brewster, Abenaa M.;Valero, Vicente;Ibrahim, Nuhad K.;Gonzalez-Angulo, Ana M.;Booser, Daniel J.;Walters, Ronald S.;Hunt, Kelly K.;Hortobagyi, Gabriel N.;Buzdar, Aman U.

  Purpose We investigated whether capecitabine and docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) or weekly paclitaxel (WP) followed by FEC would improve relapse-free survival (RFS) in operable breast cancer.Patients and Methods In this single-institution study, patients with clinical stages I to IIIC breast cancer were randomly assigned on a 1:1 basis to WP 80 mg/m2 for 12 weeks followed by fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 (FEC-100) every 3 weeks for four cycles or docetaxel 75 mg/m2 on day 1 and capecitabine (XT) 1,500 mg/m2 on days 1 through 14 every 3 weeks for four cycles followed by FEC for four cycles and stratified by timing of chemotherapy (preoperative v adjuvant). Accrual was stopped short of 930 patients on the basis of a Bayesian predictive calculation that additional accrual would be unlikely to change the qualitative comparison of the two regimens.Results After enrollment of 601 patients and a median ...

  
  
• What Can Be Learned From Trials Running Short of Patients or Events?
  • Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
  Détails

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  Mené sur 601 patientes atteintes d'un cancer du sein de stade I à IIIC (durée médiane de suivi: 50 mois), cet essai de phase III compare les effets, du point de vue de la survie sans récidive, du paclitaxel et du docétaxel en combinaison avec la capécitabine avant une chmiothérapie FEC (5-FU, épirubicine et cyclophosphamide)

  “What Can Be Learned From Trials Running Short of Patients or Events?”

  • von Minckwitz, Gunter ; Nekljudova, Valentina ; Loibl, Sibylle

  
  

Mots clés : Sein; Traitements (Traitements systémiques : applications cliniques)

Cet article passe en revue les travaux récents sur les mécanismes de résistance aux thérapies ciblées, notamment aux inhibiteurs de tyrosine kinase, dans le carcinome métastatique à cellules rénales

• Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma
  • Cancer treatment reviews, sous presse, 2012 (résumé)
  Détails

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  Cet article passe en revue les travaux récents sur les mécanismes de résistance aux thérapies ciblées, notamment aux inhibiteurs de tyrosine kinase, dans le carcinome métastatique à cellules rénales

  “Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma”

  • Ravaud, Alain;Gross-Goupil, Marine

  Targeted agents have substantially improved patient outcomes in metastatic renal cell carcinoma (mRCC) and have now replaced cytokines as standard of care. Despite the clinical benefits observed, resistance to targeted agents has been shown to develop after a median of 5–11months of treatment. Furthermore, a small subset of patients does not experience any clinical benefit from targeted therapy. Two general modes of resistance have been proposed: intrinsic (pre-existing) and evasive (adaptive). Evasive resistance is thought to be the mechanism involved when patients progress after initial clinical benefit. It has been suggested that upregulation of alternative pro-angiogenic factors and/or downregulation of angiostatic factors may be involved. Several strategies have been shown to enable clinical benefit in patients who have experienced disease progression during prior therapy. These strategies include: adjusting the dose of the drug, combination therapy or switching to an ...

  
  

Mots clés : Rein; Traitements (Traitements systémiques : applications cliniques)

Mené sur 1 022 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase III évalue les effets, du point de vue de la survie sans progression, du pemetrexed en traitement d'entretien après un traitement d'induction combinant pemetrexed et cisplatine

• Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, random
  • The Lancet Oncology, sous presse, 2012 (résumé)
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  Mené sur 1 022 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase III évalue les effets, du point de vue de la survie sans progression, du pemetrexed en traitement d'entretien après un traitement d'induction combinant pemetrexed et cisplatine

  “Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, random”

  • Paz-Ares, Luis;de Marinis, Filippo;Dediu, Mircea;Thomas, Michael;Pujol, Jean-Louis;Bidoli, Paolo;Molinier, Olivier;Sahoo, Tarini Prasad;Laack, Eckart;Reck, Martin;Corral, Jesús;Melemed, Symantha;John, William;Chouaki, Nadia;Zimmermann, Annamaria H.;Visseren-Grul, Carla;Gridelli, Cesare

  Patients with advanced non-squamous non-small-cell lung cancer (NSCLC) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing, non-pemetrexed doublet. The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin. In this double-blind, multicentre, phase 3, randomised placebo-controlled trial, patients with advanced non-squamous NSCLC aged 18 years or older, with no previous systemic chemotherapy for lung cancer, with at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 participated. Before randomisation, patients entered an induction phase which consisted of four cycles of induction pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 ...

  
  
• Maintenance chemotherapy in advanced non-small-cell lung cancer
  • The Lancet Oncology, sous presse, 2012 (commentaire en libre accès)
  Détails

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  Mené sur 1 022 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase III évalue les effets, du point de vue de la survie sans progression, du pemetrexed en traitement d'entretien après un traitement d'induction combinant pemetrexed et cisplatine

  “Maintenance chemotherapy in advanced non-small-cell lung cancer”

  • Jassem, Jacek

  
  

Mots clés : Poumon; Traitements (Traitements systémiques : applications cliniques)

Mené en Belgique et en France sur 165 patients atteints d'une leucémie lymphocytaire chronique, cet essai de phase III compare le rituximab et l'alemtuzumab en combinaison avec une chimiothérapie FC (fludarabine et cyclophosphamide)

• Excess mortality following FCCam treatment in previously untreated patients with CLL: safety and efficacy in a randomized, multicenter, phase III trial
  • Blood, sous presse, 2012 (résumé)
  Détails

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  Mené en Belgique et en France sur 165 patients atteints d'une leucémie lymphocytaire chronique, cet essai de phase III compare le rituximab et l'alemtuzumab en combinaison avec une chimiothérapie FC (fludarabine et cyclophosphamide)

  “Excess mortality following FCCam treatment in previously untreated patients with CLL: safety and efficacy in a randomized, multicenter, phase III trial”

  • Lepretre, Stephane;Aurran, Therese;Mahé, Beatrice;Cazin, Bruno;Tournilhac, Olivier;Maisonneuve, Herve;Casasnovas, Olivier;Delmer, Alain;Leblond, Veronique;Royer, Bruno;Corront, Bernadette;Chevret, Sylvie;Delépine, Roselyne;Vaudaux, Sandrine;Van Den Neste, Eric;Béné, Marie Christine;Letestu, Remi;Cymbalista, Florence;Feugier, Pierre

  A French and Belgian multicenter phase III trial was conducted in medically fit patients with untreated chronic lymphocytic leukemia (CLL). Of 178 patients enrolled in the study, 165 were randomly assigned to receive six courses of oral fludarabine and cyclophosphamide (FC) in combination with rituximab (R; 375 mg/m2 in cycle one, 500 mg/m2 in all subsequent cycles) or alemtuzumab (Cam; 30 mg subcutaneously injected on cycle days 1-3); each cycle was 28 days. Recruitment was halted prematurely because of excess toxicity; eight patients died in the FCCam group: three from lymphoma and five from infection. Overall response (OR) rates were 91% with FCR and 90% with FCCam (P=0.79). Complete remission (CR) rates were 33.75% with FCR and 19.2% with FCCam (P=0.04). Three-year progression-free survival (PFS) was 82.6% with FCR and 72.5% with FCCam (P=0.21). Three-year overall survival (OS) was similar between the two arms at 90.1% in the FCR arm and 86.4% in the FCCam arm (P=0.27).These ...

  
  

Mots clés : Leucémie; Traitements (Traitements systémiques : applications cliniques)

Cet article passe en revue les travaux récents sur les traitements du carcinome hépatocellulaire

• Hepatocellular carcinoma
  • The Lancet, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur les traitements du carcinome hépatocellulaire

  “Hepatocellular carcinoma”

  • Forner, Alejandro;Llovet, Josep M.;Bruix, Jordi

  Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. Patients with cirrhosis are at highest risk of developing this malignant disease, and ultrasonography every 6 months is recommended. Surveillance with ultrasonography allows diagnosis at early stages when the tumour might be curable by resection, liver transplantation, or ablation, and 5-year survival higher than 50% can be achieved. Patients with small solitary tumours and very well preserved liver function are the best candidates for surgical resection. Liver transplantation is most beneficial for individuals who are not good candidates for resection, especially those within Milano criteria (solitary tumour ?5 cm and up to three nodules ?3 cm). Donor shortage greatly limits its applicability. Percutaneous ablation is the most frequently used treatment but its effectiveness is limited by tumour size and localisation. In asymptomatic patients with multifocal disease ...

  
  

Mots clés : Foie; Traitements (Traitements systémiques : applications cliniques)

Cet article passe en revue les travaux récents sur le développement de thérapies ciblées pour le traitement d'un cancer avancé de l'estomac

• Targeted Therapy in the Management of Advanced Gastric Cancer: Are We Making Progress in the Era of Personalized Medicine?
  • The Oncologist, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur le développement de thérapies ciblées pour le traitement d'un cancer avancé de l'estomac

  “Targeted Therapy in the Management of Advanced Gastric Cancer: Are We Making Progress in the Era of Personalized Medicine?”

  • Wong, Hilda;Yau, Thomas

  Abstract Background. Gastric cancer is one of the leading causes of cancer death. With greater understanding of the molecular basis of carcinogenesis, targeted agents have led to a modest improvement in the outcome of advanced gastric cancer (AGC) patients.Methods and Results. We conducted an overview of the published evidence regarding the use of targeted therapy in AGC patients. Thus far, the human epidermal growth factor receptor (HER) pathway, angiogenic pathway, and phosphatidylinositol-3-kinase (PI3K)–Akt–mammalian target of rapamycin pathway have emerged as potential avenues for targeted therapy in AGC patients. The promising efficacy results of the Trastuzumab for Gastric Cancer trial led to the approved use of trastuzumab-based therapy as first-line treatment for patients with HER-2+ AGC. On the other hand, the Avastin® in Gastric Cancer trial evaluating bevacizumab in combination with chemotherapy did not meet its primary endpoint of a longer overall survival duration ...

  
  

Mots clés : Estomac; Traitements (Traitements systémiques : applications cliniques)

Mené sur 1 608 patients recevant une chimiothérapie pour le traitement d'une tumeur solide métastatique ou avancée, cet essai multicentrique évalue l'intérêt de la sémuloparine en prévention d'événements thrombo-emboliques

• Semuloparin for Thromboprophylaxis in Patients Receiving Chemotherapy for Cancer
  • New England Journal of Medicine, Vol. 366 (7), pp. 601-609, 2012 (résumé)
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  Mené sur 1 608 patients recevant une chimiothérapie pour le traitement d'une tumeur solide métastatique ou avancée, cet essai multicentrique évalue l'intérêt de la sémuloparine en prévention d'événements thrombo-emboliques

  “Semuloparin for Thromboprophylaxis in Patients Receiving Chemotherapy for Cancer”

  • Agnelli, Giancarlo;George, Daniel J.;Kakkar, Ajay K.;Fisher, William;Lassen, Michael R.;Mismetti, Patrick;Mouret, Patrick;Chaudhari, Umesh;Lawson, Francesca;Turpie, Alexander G.G.

  Background: Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism. Limited data support the clinical benefit of antithrombotic prophylaxis. Methods: In this double-blind, multicenter trial, we evaluated the efficacy and safety of the ultra-low-molecular-weight heparin semuloparin for prevention of venous thromboembolism in patients receiving chemotherapy for cancer. Patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy were randomly assigned to receive subcutaneous semuloparin, 20 mg once daily, or placebo until there was a change of chemotherapy regimen. The primary efficacy outcome was the composite of any symptomatic deep-vein thrombosis, any nonfatal pulmonary embolism, and death related to venous thromboembolism. Clinically relevant bleeding (major and nonmajor) was the main safety outcome. Results: The median treatment duration was 3.5 months. Venous thromboembolism occurred in 20 of ...

  
  
• Routine Heparin for Patients with Cancer? One Answer, More Questions
  • New England Journal of Medicine, Vol. 366 (7), pp. 661-662, 2012 (éditorial)
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  Mené sur 1 608 patients recevant une chimiothérapie pour le traitement d'une tumeur solide métastatique ou avancée, cet essai multicentrique évalue l'intérêt de la sémuloparine en prévention d'événements thrombo-emboliques

  “Routine Heparin for Patients with Cancer? One Answer, More Questions”

  • Akl, Elie A. ; Schünemann, Holger J.

  
  

Mots clés : Cancer (général); Traitements (Traitements systémiques : applications cliniques)

Menée sur 437 patients atteints d'un cancer de l'œsophage inopérable, cette étude cas-témoins compare, du point de vue de la survie globale, l'efficacité d'une chimiothérapie combinée ou non à une radiothérapie et d'une insertion de prothèse métallique auto-expansive

• Survival after chemotherapy and/or radiotherapy versus self-expanding metal stent insertion in the setting of inoperable esophageal cancer: a case-control study
  • BMC Cancer, Vol. 12 (1), pp. 70, 2012 (article en libre accès)
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  Menée sur 437 patients atteints d'un cancer de l'œsophage inopérable, cette étude cas-témoins compare, du point de vue de la survie globale, l'efficacité d'une chimiothérapie combinée ou non à une radiothérapie et d'une insertion de prothèse métallique auto-expansive

  “Survival after chemotherapy and/or radiotherapy versus self-expanding metal stent insertion in the setting of inoperable esophageal cancer: a case-control study”

  • Sgourakis, George;Gockel, Ines;Karaliotas, Constantine;Moehler, Markus;Schimanski, Carl;Schmidberger, Heinz;Junginger, Theodor

  BACKGROUND:Our aim was to compare survival of the various treatment modality groups of chemotherapy and/or radiotherapy in relation to SEMS (self-expanding metal stents) in a retrospective case-control study. We have made the hypothesis that the administration of combined chemoradiotherapy improves survival in inoperable esophageal cancer patients.METHODS:All patients were confirmed histologically as having surgically non- resectable esophageal carcinoma. Included were patients with squamous cell carcinoma, undifferentiated carcinoma as well as Siewert type I--but not type II - esophagogastric junctional adenocarcinoma. The decision to proceed with palliative treatments was taken within the context of a multidisciplinary team meeting and full expert review based on patient's wish, co-morbid disease, clinical metastases, distant metastases, M1 nodal metastases, T4-tumor airway, aorta, main stem bronchi, cardiac invasion, and peritoneal disease. Patients not fit enough to tolerate a ...

  
  

Mots clés : Oesophage; Traitements (Combinaison de traitements localisés et systémiques)

Cet article passe en revue les études récentes sur les agents ciblant les protéines inhibitrices de l'apoptose pour sensibiliser les cellules tumorales aux rayonnements ionisants

• Inhibitor of Apoptosis (IAP) proteins as therapeutic targets for radiosensitization of human cancers
  • Cancer treatment reviews, sous presse, 2012 (résumé)
  Détails

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  Cet article passe en revue les études récentes sur les agents ciblant les protéines inhibitrices de l'apoptose pour sensibiliser les cellules tumorales aux rayonnements ionisants

  “Inhibitor of Apoptosis (IAP) proteins as therapeutic targets for radiosensitization of human cancers”

  • Fulda, Simone

  Radiotherapy initiates a variety of signaling events in cancer cells that eventually lead to cell death in case the DNA damage cannot be repaired. However, the signal transduction pathways that mediate cell death in response to radiation-inflicted DNA damage are frequently disturbed in human cancers, contributing to radioresistance. For example, aberrant activation of antiapoptotic programs such as high expression of Inhibitor of Apoptosis (IAP) proteins has been shown to interfere with the efficacy of radiotherapy. Since IAP proteins have been linked to radioresistance in several malignancies, therapeutic targeting of IAP proteins may open new perspectives to overcome radioresistance. Therefore, molecular targeting of IAP proteins may provide novel opportunities to reactivate cell death pathways that mediate radiation-induced cytotoxicity. A number of strategies have been developed in recent years to antagonize IAP proteins for the treatment of cancers. Some of these approaches have ...

  
  

Mots clés : Cancer (général); Traitements (Combinaison de traitements localisés et systémiques)