Traitements

Menée sur des xénogreffes de neuroblastome et de carcinome épidermoïde de la tête et du cou, cette étude montre qu'une thérapie photodynamique peut augmenter l'efficacité d'un vaccin contre les tumeurs primitives et les métastases

• Photodynamic therapy augments the efficacy of oncolytic vaccinia virus against primary and metastatic tumours in mice
  • British Journal of Cancer, sous presse, 2011 (résumé)
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  Menée sur des xénogreffes de neuroblastome et de carcinome épidermoïde de la tête et du cou, cette étude montre qu'une thérapie photodynamique peut augmenter l'efficacité d'un vaccin contre les tumeurs primitives et les métastases

  “Photodynamic therapy augments the efficacy of oncolytic vaccinia virus against primary and metastatic tumours in mice”

  • Gil, M.;Bieniasz, M.;Seshadri, M.;Fisher, D.;Ciesielski, M. J.;Chen, Y.;Pandey, R. K.;Kozbor, D.

  Background : Therapies targeted towards the tumour vasculature can be exploited for the purpose of improving the systemic delivery of oncolytic viruses to tumours. Photodynamic therapy (PDT) is a clinically approved treatment for cancer that is known to induce potent effects on tumour vasculature. In this study, we examined the activity of PDT in combination with oncolytic vaccinia virus (OVV) against primary and metastatic tumours in mice. Methods : The effect of 2-[1-hexyloxyethyl-]-2-devinyl pyropheophorbide-a (HPPH)-sensitised-PDT on the efficacy of oncolytic virotherapy was investigated against subcutaneously implanted syngeneic murine NXS2 neuroblastoma and human FaDu head and neck squamous cell carcinoma xenografts in nude mice. Treatment efficacy was evaluated by monitoring tumour growth and survival. The effects of combination treatment on vascular function were examined using magnetic resonance imaging (MRI) and immunohistochemistry, whereas viral replication in tumour cells ...

  
  

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

Menée sur 45 patientes atteintes d'un cancer avancé et récidivant de l'ovaire, cette étude évalue les résultats cliniques et la toxicité d'une radiothérapie intra-opératoire par faisceaux d'électrons

• Intraoperative radiotherapy electron boost in advanced and recurrent epithelial ovarian carcinoma: a retrospective study
  • BMC Cancer, Vol. 11 (1), pp. 439, 2011 (article en libre accès)
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  Menée sur 45 patientes atteintes d'un cancer avancé et récidivant de l'ovaire, cette étude évalue les résultats cliniques et la toxicité d'une radiothérapie intra-opératoire par faisceaux d'électrons

  “Intraoperative radiotherapy electron boost in advanced and recurrent epithelial ovarian carcinoma: a retrospective study”

  • Gao, Ying;Liu, Zi;Chen, Xi;Luo, Wei;Zhang, Long;Wang, Juan

  BACKGROUND:Relapses of epithelial ovarian carcinoma (EOC) have a poor prognosis and are almost always fatal. The aim of this study was to evaluate the clinical outcome and toxicity of intraoperative electron beam radiation therapy (IOERT) in advanced and recurrent EOC. Methods: Forty-five women with EOC were treated with IOERT. Twenty-five patients had primary disease (PD) without distant metastasis at IOERT, and 20 patients had an isolated local recurrence (ILR) after surgery. All 45 patients in this series underwent optimal cytoreductive ([less than or equal to]1cm) surgery. The whole pelvic (WP) radiotherapy was intraoperatively delivered using 12 Mev electron beam; 43 patients received 18-20Gy and two patients received 10Gy. Thirty-three patients received postoperateive intraperitoneal (IP) chemotherapy, while seven patients received intravenous (IV) chemotherapy. Five patients refused concurrent chemotherapy. Overall survival (OS) rates were analyzed using the Kaplan-Meier ...

  
  

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

Mené sur 46 patientes atteintes d'un cancer récidivant de l'ovaire, de la trompe de Fallope ou du péritoine primitif, cet essai de phase I/II évalue l'activité antitumorale et la toxicité d'un traitement combinant aflibercept et docétaxel

• Phase 1/2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer
  • The Lancet Oncology, sous presse, 2011 (résumé)
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  Mené sur 46 patientes atteintes d'un cancer récidivant de l'ovaire, de la trompe de Fallope ou du péritoine primitif, cet essai de phase I/II évalue l'activité antitumorale et la toxicité d'un traitement combinant aflibercept et docétaxel

  “Phase 1/2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer”

  • Coleman, Robert L.;Duska, Linda R.;Ramirez, Pedro T.;Heymach, John V.;Kamat, Aparna A.;Modesitt, Susan C.;Schmeler, Kathleen M.;Iyer, Revathy B.;Garcia, Michael E.;Miller, Debbie L.;Jackson, Edward F.;Ng, Chaan S.;Kundra, Vikas;Jaffe, Robert;Sood, Anil K.

  Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population. For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m2). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage ...

  
  
• VEGF inhibitors and advanced ovarian cancer
  • The Lancet Oncology, sous presse, 2011 (commentaire)
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  Mené sur 46 patientes atteintes d'un cancer récidivant de l'ovaire, de la trompe de Fallope ou du péritoine primitif, cet essai de phase I/II évalue l'activité antitumorale et la toxicité d'un traitement combinant aflibercept et docétaxel

  “VEGF inhibitors and advanced ovarian cancer”

  • Jayson, Gordon

  
  

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

Cet article passe en revue les travaux récents sur la résistance des cellules souches cancéreuses de glioblastome au témozolomide

• Chemoresistance of glioblastoma cancer stem cells - much more complex than expected
  • Molecular Cancer, Vol. 10 (1), pp. 128, 2011 (article en libre accès)
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  Cet article passe en revue les travaux récents sur la résistance des cellules souches cancéreuses de glioblastome au témozolomide

  “Chemoresistance of glioblastoma cancer stem cells - much more complex than expected”

  • Beier, Dagmar;Schulz, Joerg;Beier, Christoph

  Glioblastomas (GBM) are a paradigm for the investigation of cancer stem cells (CSC) in solid malignancies. The susceptibility of GBM CSC to standard chemotherapeutic drugs is controversial as the existing literature presents conflicting experimental data. Here, we summarize the experimental evidence on the resistance of GBM CSC to alkylating chemotherapeutic agents, with a special focus on temozolomide (TMZ). The data suggests that CSC are neither resistant nor susceptible to chemotherapy per se. Detoxifying proteins such as O6-methylguanine-DNA-methyltransferase (MGMT) confer a strong intrinsic resistance to CSC in all studies. Extrinsic factors may also contribute to the resistance of CSC to TMZ. These may include TMZ concentrations in the brain parenchyma, TMZ dosing schemes, hypoxic microenvironments, niche factors and the re-acquisition of stem cell properties by non-stem cells. Thus, the interaction of CSC and chemotherapy is more complex than may be expected and it is necessary ...

  
  

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

Menée in vitro et sur un modèle murin, cette étude suggère que la perturbation de l'interaction moléculaire entre les domaines SH2 et kinase de Bcr-Abl est une stratégie prometteuse pour le traitement des leucémies myélogènes chroniques, notamment dans le cas d'une résistance aux inhibiteurs de tyrosine kinase existants

• Targeting the SH2-Kinase Interface in Bcr-Abl Inhibits Leukemogenesis
  • Cell, Vol. 147 (2), pp. 306-319, 2011 (article en libre accès)
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  Menée in vitro et sur un modèle murin, cette étude suggère que la perturbation de l'interaction moléculaire entre les domaines SH2 et kinase de Bcr-Abl est une stratégie prometteuse pour le traitement des leucémies myélogènes chroniques, notamment dans le cas d'une résistance aux inhibiteurs de tyrosine kinase existants

  “Targeting the SH2-Kinase Interface in Bcr-Abl Inhibits Leukemogenesis”

  • Grebien, Florian;Hantschel, Oliver;Wojcik, John;Kaupe, Ines;Kovacic, Boris;Wyrzucki, Arkadiusz M;Gish, Gerald D;Cerny-Reiterer, Sabine;Koide, Akiko;Beug, Hartmut;Pawson, Tony;Valent, Peter;Koide, Shohei;Superti-Furga, Giulio

  Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with the tyrosine kinase inhibitor (TKI) imatinib. However, emerging TKI resistance prevents complete cure. Therefore, alternative strategies targeting regulatory modules of Bcr-Abl in addition to the kinase active site are strongly desirable. Here, we show that an intramolecular interaction between the SH2 and kinase domains in Bcr-Abl is both necessary and sufficient for high catalytic activity of the enzyme. Disruption of this interface led to inhibition of downstream events critical for CML signaling and, importantly, completely abolished leukemia formation in mice. Furthermore, disruption of the SH2-kinase interface increased sensitivity of imatinib-resistant Bcr-Abl mutants to TKI inhibition. An engineered Abl SH2-binding fibronectin type III monobody inhibited Bcr-Abl kinase activity both in vitro and in primary CML cells, where it induced apoptosis. This work ...

  
  

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

Mené sur 84 patients atteints d'une leucémie myélogène aiguë (âge médian : 76 ans), cet essai de phase II évalue l'activité et la toxicité du tipifarnib en combinaison avec l'étoposide

• Multi-institutional Phase II clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia
  • Blood, sous presse, 2011 (résumé)
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  Mené sur 84 patients atteints d'une leucémie myélogène aiguë (âge médian : 76 ans), cet essai de phase II évalue l'activité et la toxicité du tipifarnib en combinaison avec l'étoposide

  “Multi-institutional Phase II clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia”

  • Karp, Judith E.;Vener, Tatiana I.;Raponi, Mitch;Ritchie, Ellen K.;Smith, B. Douglas;Gore, Steven D.;Morris, Lawrence E.;Feldman, Eric J.;Greer, Jacqueline M.;Malek, Sami;Carraway, Hetty E.;Ironside, Valerie;Galkin, Steven;Levis, Mark J.;McDevitt, Michael A.;Roboz, Gail R.;Gocke, Christopher D.;Derecho, Carlo;Palma, John;Wang, Yixin;Kaufmann, Scott H.;Wright, John J.;Garrett-Mayer, Elizabeth

  Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a Phase I trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized Phase II trial in 84 adults (age 70-90, median 76) who were not candidates for conventional chemotherapy. Arms A (T 600 mg BID x 14 days, E 100 mg days 1-3 and 8-10) and B (T 400 mg BID x 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A two-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T+E on this study showed that AMLs with a RASGRP1:APTX ratio of > 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based ...

  
  

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

Cette étude analyse les réponses de lignées cellulaires de divers types de cancer du sein à 77 composés thérapeutiques

• Subtype and pathway specific responses to anticancer compounds in breast cancer
  • Proceedings of the National Academy of Sciences, sous presse, 2011 (résumé)
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  Cette étude analyse les réponses de lignées cellulaires de divers types de cancer du sein à 77 composés thérapeutiques

  “Subtype and pathway specific responses to anticancer compounds in breast cancer”

  • Heiser, Laura M.;Sadanandam, Anguraj;Kuo, Wen-Lin;Benz, Stephen C.;Goldstein, Theodore C.;Ng, Sam;Gibb, William J.;Wang, Nicholas J.;Ziyad, Safiyyah;Tong, Frances;Bayani, Nora;Hu, Zhi;Billig, Jessica I.;Dueregger, Andrea;Lewis, Sophia;Jakkula, Lakshmi;Korkola, James E.;Durinck, Steffen;Pepin, François;Guan, Yinghui;Purdom, Elizabeth;Neuvial, Pierre;Bengtsson, Henrik;Wood, Kenneth W.;Smith, Peter G.;Vassilev, Lyubomir T.;Hennessy, Bryan T.;Greshock, Joel;Bachman, Kurtis E.;Hardwicke, Mary Ann;Park, John W.;Marton, Laurence J.;Wolf, Denise M.;Collisson, Eric A.;Neve, Richard M.;Mills, Gordon B.;Speed, Terence P.;Feiler, Heidi S.;Wooster, Richard F.;Haussler, David;Stuart, Joshua M.;Gray, Joe W.;Spellman, Paul T.

  Breast cancers are comprised of molecularly distinct subtypes that may respond differently to pathway-targeted therapies now under development. Collections of breast cancer cell lines mirror many of the molecular subtypes and pathways found in tumors, suggesting that treatment of cell lines with candidate therapeutic compounds can guide identification of associations between molecular subtypes, pathways, and drug response. In a test of 77 therapeutic compounds, nearly all drugs showed differential responses across these cell lines, and approximately one third showed subtype-, pathway-, and/or genomic aberration-specific responses. These observations suggest mechanisms of response and resistance and may inform efforts to develop molecular assays that predict clinical response.

  
  

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

Cette étude suggère que, chez les patients traités pour un lymphome, l'observation de faibles niveaux de STAT4, un facteur de transcription activant notamment la production d'interféron gamma, est un effet de la chimiothérapie

• Acquired STAT4 deficiency as a consequence of cancer chemotherapy
  • Blood, sous presse, 2011 (résumé)
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  Cette étude suggère que, chez les patients traités pour un lymphome, l'observation de faibles niveaux de STAT4, un facteur de transcription activant notamment la production d'interféron gamma, est un effet de la chimiothérapie

  “Acquired STAT4 deficiency as a consequence of cancer chemotherapy”

  • Lupov, Ivan P.;Voiles, Larry;Han, Ling;Schwartz, Allysia;DeLa Rosa, Manuel;Oza, Kinnari;Pelloso, David;Sahu, Ravi P.;Travers, Jeffrey B.;Robertson, Michael J.;Chang, Hua-Chen

  Signal Transducer and Activator of Transcription 4 (STAT4) is a transcription factor that is activated by IL-12 signaling and promotes Th1 cell differentiation and interferon (IFN)-γ production. Defective IFN-γ production due to STAT4 mRNA and protein deficiency occurs after autologous stem cell transplantation for lymphoma. The mechanisms of STAT4 deficiency in lymphoma patients were investigated. The tumor-bearing state is not responsible, as STAT4 levels were not significantly different in peripheral blood mononuclear cells (PBMCs) obtained from healthy control subjects versus lymphoma patients before treatment. STAT4 protein levels were significantly decreased in PBMCs and T cells obtained from lymphoma patients after standard dose chemotherapy. Furthermore, treatment of normal PBMC cultures or a natural killer (NK) cell line with chemotherapy drugs in vitro also resulted in reduced STAT4 protein and diminished IL-12-induced IFN-γ production. Translation of STAT4 protein was ...

  
  

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

Menée à l'aide de xénogreffes, cette étude montre qu'une protéine recombinante appelée JO-1 augmente l'efficacité d'un traitement comprenant du trastuzumab ou du cétuximab

• Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer
  • Cancer Research, sous presse, 2011 (résumé)
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  Menée à l'aide de xénogreffes, cette étude montre qu'une protéine recombinante appelée JO-1 augmente l'efficacité d'un traitement comprenant du trastuzumab ou du cétuximab

  “Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer”

  • Beyer, Ines;van Rensburg, Ruan;Strauss, Robert;Li, ZongYi;Wang, Hongjie;Persson, Jonas;Yumul, Roma;Feng, Qinghua;Song, Hui;Bartek, Jiri;Fender, Pascal;Lieber, Andre

  The efficacy of monoclonal antibodies (mAbs) used to treat solid tumors is limited by intercellular junctions which tightly link epithelial tumor cells to each another. In this study, we define a small, recombinant adenovirus serotype 3-derived protein, termed junction opener 1 (JO-1), which binds to the epithelial junction protein desmoglein 2 (DSG2). In mouse xenograft models employing Her2/neu- and EGFR-positive human cancer cell lines, JO-1 mediated cleavage of DSG2 dimers and activated intracellular signaling pathways which reduced E-cadherin expression in tight junctions. Notably, JO-1-triggered changes allowed for increased intratumoral penetration of the anti-Her2/neu mAb trastuzumab (Herceptin) as well as improved access to its target receptor, Her2/neu, which is partly trapped in tight junctions. This effect translated directly into increased therapeutic efficacy of trastuzumab in mouse xenograft models using breast, gastric, and ovarian cancer cells that were ...

  
  

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

Menée in vitro et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un traitement comprenant deux molécules ciblant la voie de signalisation bioénergétique de la tumeur, un inhibiteur de la glycolyse (2DG) et la metformine

• Dual inhibition of Tumor Energy Pathway by 2-deoxy glucose and metformin Is Effective Against a Broad Spectrum of Preclinical Cancer Models
  • Molecular Cancer Therapeutics, sous presse, 2011 (résumé)
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  Menée in vitro et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un traitement comprenant deux molécules ciblant la voie de signalisation bioénergétique de la tumeur, un inhibiteur de la glycolyse (2DG) et la metformine

  “Dual inhibition of Tumor Energy Pathway by 2-deoxy glucose and metformin Is Effective Against a Broad Spectrum of Preclinical Cancer Models”

  • Cheong, Jae-Ho;Park, Eun-Sung;Liang, Jiyong;Dennison, Jennifer B;Tsavachidou, Dimitra;Nguyen-Charles, Catherine;Cheng, Kwai Wa;Hall, Hassan;Zhang, Dong;Lu, Yiling;Ravoori, Murali;Kundra, Vikas;Ajani, Jaffer A;Lee, Ju-Seog;Hong, Waun Ki;Mills, Gordon B.

  Tumor cell proliferation requires both growth signals and sufficient cellular bioenergetics.The AMP-activated kinase (AMPK) pathway appears dominant over the oncogenic signaling pathway suppressing cell proliferation. This study investigated the preclinical efficacy of targeting the tumor bioenergetic pathway using a glycolysis inhibitor 2-deoxy glucose (2DG) and AMPK agonists, AICAR and metformin. We evaluated the in vitro anti-tumor activity of 2DG, metformin or AICAR alone, and 2DG in combination either with metformin or AICAR. We examined in vivo efficacy using xenograft mouse models. 2DG alone was not sufficient to promote tumor cell death, reflecting the limited efficacy demonstrated in clinical trials. A combined use of 2DG and AICAR also failed to induce cell death. However, 2DG and metformin led to significant cell death associated with decrease in cellular ATP, prolonged activation of AMPK, and sustained autophagy. Gene expression analysis and functional assays revealed that ...

  
  

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

Mené sur 26 patients atteints de divers types de cancer métastatique, cet essai de phase I évalue la toxicité et l'activité d'une protéine de fusion, ALT-801

• Phase 1 trial of ALT-801, an interleukin-2/T cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies
  • Clinical Cancer Research, sous presse, 2011 (résumé)
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  Mené sur 26 patients atteints de divers types de cancer métastatique, cet essai de phase I évalue la toxicité et l'activité d'une protéine de fusion, ALT-801

  “Phase 1 trial of ALT-801, an interleukin-2/T cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies”

  • Fishman, Mayer N.;Thompson, John A.;Pennock, Gregory K.;Gonzalez, Rene;Diez, Luz M.;Daud, Adil I.;Weber, Jeffrey S.;Huang, Bee Y.;Tang, Shamay;Rhode, Peter R.;Wong, Hing C.

  Purpose: ALT-801 is a bifunctional fusion protein comprising interleukin-2 (IL-2) linked to a soluble, single-chain T cell receptor domain that recognizes a peptide epitope (aa264-272) of the human p53 antigen displayed on cancer cells in the context of HLA-A*0201 (p53+/HLA-A*0201). We evaluated the safety, pharmacokinetics and pharmacodynamics of ALT-801 in p53+/HLA-A*0201 patients with metastatic malignancies. Experimental Design: p53+/HLA-A*0201 patients were treated with ALT-801 on a schedule of 4 daily 15-minute intravenous infusions, then 10 days rest and 4 more daily infusions. Cohorts of patients were treated at 0.015, 0.040, and 0.080 mg/kg/dose. Results: Four, sixteen, and six patients were treated at the 0.015, 0.04 and 0.08 mg/kg cohorts, respectively. Two dose limiting toxicities (a grade 4 transient thrombocytopenia and a myocardial infarction) in the 0.08 mg/kg cohort established the maximum tolerated dose (MTD) at 0.04 mg/kg. Patients treated at the MTD experienced ...

  
  

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

Mené sur 26 patients atteints de diverses tumeurs solides de stade avancé, cet essai de phase I évalue l'activité et la toxicité d'un anticorps monoclonal, le bavituximab, conçu pour perturber le réseau vasculaire et renforcer la réponse immunitaire antitumorale

• Phase I Safety and Pharmacokinetic Study of Bavituximab, a Chimeric Phosphatidylserine-Targeting Monoclonal Antibody, in Patients with Advanced Solid Tumors
  • Clinical Cancer Research, sous presse, 2011 (résumé)
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  Mené sur 26 patients atteints de diverses tumeurs solides de stade avancé, cet essai de phase I évalue l'activité et la toxicité d'un anticorps monoclonal, le bavituximab, conçu pour perturber le réseau vasculaire et renforcer la réponse immunitaire antitumorale

  “Phase I Safety and Pharmacokinetic Study of Bavituximab, a Chimeric Phosphatidylserine-Targeting Monoclonal Antibody, in Patients with Advanced Solid Tumors”

  • Gerber, David E.;Stopeck, Alison T.;Wong, Lucas;Rosen, Lee S.;Thorpe, Philip E.;Shan, Joseph S.;Ibrahim, Nuhad K.

  Purpose: Bavituximab is a chimeric immunoglobulin G1 phosphatidylserine-targeting monoclonal antibody that triggers vascular disruption and enhances antitumor immune response. This phase I study assessed the safety and pharmacokinetics of bavituximab in patients with advanced solid tumors.Experimental Design: Patients with refractory advanced solid tumors were enrolled into four sequential dose-escalation cohorts (0.1, 0.3, 1, or 3 mg/kg bavituximab weekly) with two dosing schedules. Patients in the 0.1 and 0.3 mg/kg cohorts received bavituximab on days 0, 28, 35, and 42. Patients in the 1 and 3 mg/kg cohorts were administered bavituximab on days 0, 7, 14, and 21. Safety, pharmacokinetics, and tumor response were assessed.Results: Twenty-six patients were accrued. No maximum tolerated dose was reached. Six serious adverse events occurred in five patients, including one pulmonary embolism at 3 mg/kg, which was the only dose-limiting toxicity (DLT) in the study. Bavituximab half-life ...

  
  

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

Cet article passe en revue les travaux récents concernant les effets des bisphosphonates, notamment l'acide zolédronique, sur les cellules cancéreuses et leur micro-environnement

• Direct and indirect anticancer activity of bisphosphonates: A brief review of published literature
  • Cancer treatment reviews, sous presse, 2011 (résumé)
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  Cet article passe en revue les travaux récents concernant les effets des bisphosphonates, notamment l'acide zolédronique, sur les cellules cancéreuses et leur micro-environnement

  “Direct and indirect anticancer activity of bisphosphonates: A brief review of published literature”

  • Gnant, Michael;Clézardin, Philippe

  The bone marrow microenvironment provides a site for cancer cells to evade systemic anticancer therapy. Dormant tumor micrometastases are believed to be the source of disease persistence and relapse; however, the exact characteristics of cancer stem cells vs. cancer cells with limited metastatic potential have yet to be elucidated. Bisphosphonates inhibit osteoclast-mediated bone resorption, are approved for treating malignant bone disease from advanced cancers, and have shown efficacy for preventing cancer treatment-induced bone loss. Altering the bone marrow microenvironment to make it less conducive to cancer cell survival is now emerging as an important means to prevent cancer recurrence. This review aims to distill the diverse literature and provide a brief overview of the numerous preclinical and early clinical studies of bisphosphonates demonstrating a variety of direct and indirect anticancer activities that affect both the tumor cell (the “seed”) and surrounding ...

  
  

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

Menée in vitro sur un grand nombre de lignées cellulaires de divers types de cancer et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé GDC-0980, conçu pour inhiber les voies de signalisation PI3K et mTOR

• GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway
  • Molecular Cancer Therapeutics, sous presse, 2011 (résumé)
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  Menée in vitro sur un grand nombre de lignées cellulaires de divers types de cancer et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé GDC-0980, conçu pour inhiber les voies de signalisation PI3K et mTOR

  “GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway”

  • Wallin, Jeffrey J.;Edgar, Kyle A;Guan, Jane;Berry, Megan;Prior, Wei Wei;Lee, Leslie;Lesnick, John D.;Lewis, Cristina;Nonomiya, Jim;Pang, Jodie;Salphati, Laurent;Olivero, Alan G.;Sutherlin, Daniel P.;O'Brien, Carol;Spoerke, Jill M.;Patel, Sonal;Lensun, Letitia;Kassees, Robert;Ross, Leanne;Lackner, Mark R.;Sampath, Deepak;Belvin, Marcia;Friedman, Lori S.

  Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 Kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with ...

  
  

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

A partir de données issues de l'essai ATAC (Arimidex, Tamoxifen Alone or in Combination) mené sur 7 186 femmes ménopausées atteintes d'un cancer du sein de stade précoce, cette analyse rétrospective évalue les effets de l'âge et des comordidités sur le type de traitement administré et le risque de décès

• Influence of Comorbidities and Age on Risk of Death Without Recurrence: A Retrospective Analysis of the Arimidex, Tamoxifen Alone or in Combination Trial
  • Journal of Clinical Oncology, sous presse, 2011 (résumé)
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  A partir de données issues de l'essai ATAC (Arimidex, Tamoxifen Alone or in Combination) mené sur 7 186 femmes ménopausées atteintes d'un cancer du sein de stade précoce, cette analyse rétrospective évalue les effets de l'âge et des comordidités sur le type de traitement administré et le risque de décès

  “Influence of Comorbidities and Age on Risk of Death Without Recurrence: A Retrospective Analysis of the Arimidex, Tamoxifen Alone or in Combination Trial”

  • Ring, Alistair;Sestak, Ivana;Baum, Michael;Howell, Anthony;Buzdar, Aman;Dowsett, Mitch;Forbes, John F.;Cuzick, Jack

  Purpose The Arimidex, Tamoxifen Alone or in Combination (ATAC) study was a double-blind randomized trial in which postmenopausal women with early-stage breast cancer were assigned to receive anastrozole, tamoxifen, or the combination. We have conducted a retrospective analysis to examine the effects of comorbidities and age on treatment received, breast cancer–related mortality, and competing causes of mortality.Patients and Methods The current analyses were based on 10-year median follow-up data in the two monotherapy arms (anastrozole, n = 3,092; tamoxifen, n = 3,094) of the ATAC study. Baseline comorbidities and tumor and treatment characteristics were compared between women age less than 70 years and women age ≥ 70 years. The cumulative incidence of breast cancer–related and non–breast cancer–related mortality was assessed according to age and comorbidities.Results One thousand six hundred sixty-two patients (27%) were age ≥ 70 years at study entry. Older women were ...

  
  
• Embracing the Complexity of Comorbidity
  • Journal of Clinical Oncology, sous presse, 2011 (éditorial en libre accès)
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  A partir de données issues de l'essai ATAC (Arimidex, Tamoxifen Alone or in Combination) mené sur 7 186 femmes ménopausées atteintes d'un cancer du sein de stade précoce, cette analyse rétrospective évalue les effets de l'âge et des comordidités sur le type de traitement administré et le risque de décès

  “Embracing the Complexity of Comorbidity”

  • Hurria, Arti

  
  

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

Mené sur 684 patientes atteints d'un cancer métastatique du sein HER-, cet essai de phase III évalue, en traitement de deuxième ligne, l'efficacité et la toxicité du bevacizumab en complément d'un protocole standard de chimiothérapie

• RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy for Second-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast C
  • Journal of Clinical Oncology, sous presse, 2011 (résumé)
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  Mené sur 684 patientes atteints d'un cancer métastatique du sein HER-, cet essai de phase III évalue, en traitement de deuxième ligne, l'efficacité et la toxicité du bevacizumab en complément d'un protocole standard de chimiothérapie

  “RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy for Second-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast C”

  • Brufsky, Adam M.;Hurvitz, Sara;Perez, Edith;Swamy, Raji;Valero, Vicente;O'Neill, Vincent;Rugo, Hope S.

  Purpose This phase III study compared the efficacy and safety of bevacizumab combined with standard chemotherapy regimens versus chemotherapy alone as second-line treatment of patients with human epidermal growth factor receptor 2 (HER2) –negative metastatic breast cancer.Patients and Methods Patients were randomly assigned 2:1 to chemotherapy + bevacizumab or to chemotherapy + placebo. Before random assignment, investigators chose capecitabine, a taxane (paclitaxel, nab-paclitaxel, or docetaxel), gemcitabine, or vinorelbine. Dosing for bevacizumab or placebo was 15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks, depending on chemotherapy regimen. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, PFS by chemotherapy cohort, objective response rate (ORR), duration of objective response, 1-year survival rate, and safety.Results RIBBON-2 enrolled 684 patients (225, chemotherapy + placebo; 459, chemotherapy + bevacizumab). The ...

  
  

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

Mené sur 335 patients atteints d'une leucémie lymphocytaire chronique récidivante ou réfractaire, cet essai de phase III évalue l'efficacité et la toxicité de l'alemtuzumab en complément de la fludarabine

• Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial
  • The Lancet Oncology, sous presse, 2011 (résumé)
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  Mené sur 335 patients atteints d'une leucémie lymphocytaire chronique récidivante ou réfractaire, cet essai de phase III évalue l'efficacité et la toxicité de l'alemtuzumab en complément de la fludarabine

  “Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial”

  • Elter, Thomas;Gercheva-Kyuchukova, Liana;Pylylpenko, Halyna;Robak, Tadesuz;Jaksic, Branimir;Rekhtman, Grigoriy;Kyrcz-Krzemie, S. awomira;Vatutin, Mykola;Wu, Jingyang;Sirard, Cynthia;Hallek, Michael;Engert, Andreas

  Chronic lymphocytic leukaemia (CLL) is an incurable and chronic disorder, with worsening prognosis for patients as their disease progresses. We compared the efficacy and safety of the combination of fludarabine and alemtuzumab with fludarabine monotherapy in previously treated patients with relapsed or refractory CLL. Patients (aged ?18 years) with CLL Binet stage A, B, or C or Rai stages I?IV were randomly assigned in a 1:1 ratio according to a computer-generated allocation schedule to open-label combination treatment (fludarabine 30 mg/m2per day and alemtuzumab 30 mg per day on days 1?3) or monotherapy (fludarabine 25 mg/m2on days 1?5) by use of an interactive voice response system. Both regimens were given intravenously for a maximum of six 28-day cycles. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered withClinicalTrials.gov, numberNCT00086580. Fludarabine plus alemtuzumab (n=168) resulted in better PFS than did ...

  
  

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

Menée sur 167 patients atteints d'une leucémie myélogène chronique, cette étude analyse différents critères de réponse thérapeutique pour évaluer les effets d'un traitement de première ligne à l'aide d'inhibiteurs de tyrosine kinase de deuxième génération (nilotinib, dasatinib)

• Front-Line Therapy With Second-Generation Tyrosine Kinase Inhibitors in Patients With Early Chronic Phase Chronic Myeloid Leukemia: What Is the Optimal Response?
  • Journal of Clinical Oncology, sous presse, 2011 (résumé)
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  Menée sur 167 patients atteints d'une leucémie myélogène chronique, cette étude analyse différents critères de réponse thérapeutique pour évaluer les effets d'un traitement de première ligne à l'aide d'inhibiteurs de tyrosine kinase de deuxième génération (nilotinib, dasatinib)

  “Front-Line Therapy With Second-Generation Tyrosine Kinase Inhibitors in Patients With Early Chronic Phase Chronic Myeloid Leukemia: What Is the Optimal Response?”

  • Jabbour, Elias;Kantarjian, Hagop M.;O'Brien, Susan;Shan, Jianqin;Quintás-Cardama, Alfonso;Garcia-Manero, Guillermo;Rios, Mary Beth;Cortes, Jorge E.

  Purpose The response definitions proposed by the European LeukemiaNet (ELN) are defined on the basis of imatinib front-line therapy. It is unknown whether these definitions apply to patients treated with second-generation tyrosine kinase inhibitors (TKIs).Patients and Methods One hundred sixty-seven patients with newly diagnosed chronic myelogenous leukemia (CML) in chronic phase were treated with second-generation TKIs in phase II trials (nilotinib, 81; dasatinib, 86). Median follow-up was 33 months. Event-free survival (EFS) was measured from the start of treatment to the date of loss of complete hematologic response, loss of complete or major cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, progression to accelerated or blastic phases, or death at any time.Results Overall, 155 patients (93%) achieved complete cytogenetic response (CCyR), including 146 (87%) with major molecular response (MMR; complete in 46 patients [28%]). According to the ELN ...

  
  

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

Mené sur 561 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase III évalue les effets sur la survie de l'ajout de celecoxib à un traitement combinant doxétaxel et carboplatine

• Randomized, Placebo-Controlled Phase III Study of Docetaxel Plus Carboplatin With Celecoxib and Cyclooxygenase-2 Expression As a Biomarker for Patients With Advanced Non–Small-Cell Lung Cancer: The NVALT-4 Study
  • Journal of Clinical Oncology, sous presse, 2011 (résumé)
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  Mené sur 561 patients atteints d'un cancer avancé du poumon non à petites cellules, cet essai de phase III évalue les effets sur la survie de l'ajout de celecoxib à un traitement combinant doxétaxel et carboplatine

  “Randomized, Placebo-Controlled Phase III Study of Docetaxel Plus Carboplatin With Celecoxib and Cyclooxygenase-2 Expression As a Biomarker for Patients With Advanced Non–Small-Cell Lung Cancer: The NVALT-4 Study”

  • Groen, Harry J.M.;Sietsma, Hannie;Vincent, Andrew;Hochstenbag, Monique M.H.;van Putten, John W.G.;van den Berg, Anke;Dalesio, Otilia;Biesma, Bonne;Smit, Hans J.M.;Termeer, Ariën;Hiltermann, T. Jeroen N.;van den Borne, Ben E.E.M.;Schramel, Franz M.N.H.

  Purpose Cyclooxygenase-2 (COX-2) protein expression in patients with non–small-cell lung cancer (NSCLC) may be not only a prognostic marker but also predictive for COX-2 inhibition. We hypothesized that COX-2 expression is associated with shorter survival and that celecoxib, being a potent COX-2 inhibitor, increases tumor response and survival.Patients and Methods A phase III study was performed in patients with stage IIIb/IV NSCLC who had pathologic confirmation, no prior chemotherapy, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Treatment consisted of docetaxel and carboplatin every 3 weeks for five cycles. Patients were randomly assigned to receive celecoxib 400 mg or placebo twice daily. COX-2 expression on tumor cells was detected by immunohistochemistry. Primary end point was overall survival (OS).Results From July 2003 to December 2007, 561 patients were randomly assigned. Toxicity was mild, and no increase in cardiovascular ...

  
  

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

Menée in vitro sur des lignées cellulaires et in vivo sur une xénogreffe orthotopique, cette étude montre qu'un inhibiteur de la protéine kinase du récepteur TGFbéta augmente la réponse des cellules tumorales à la radiothérapie

• Blockade of TGF-beta signaling by the TGFβR-I kinase Inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma
  • Cancer Research, sous presse, 2011 (résumé)
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  Menée in vitro sur des lignées cellulaires et in vivo sur une xénogreffe orthotopique, cette étude montre qu'un inhibiteur de la protéine kinase du récepteur TGFbéta augmente la réponse des cellules tumorales à la radiothérapie

  “Blockade of TGF-beta signaling by the TGFβR-I kinase Inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma”

  • Mengxian, Zhang;Kleber, Susanne;Roehrich, Manuel;Timke, Carmen;Han, Na;Tuettenberg, Jochen;Martin-Villalba, Ana;Debus, Juergen;Peschke, Peter;Wirkner, Ute;Lahn, Michael M;Huber, Peter E

  Glioblastoma multiform (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because transforming growth factor (TGF)-β is a modifier of radiation responses, we performed a preclinical study of the antitumor effects of the TGF-β receptor (TβR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells (CSLCs), augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival and extended the prolongation of survival induced by radiation treatment. Histological analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed ...

  
  

Mots clés : Système nerveux central; Traitements (Combinaison de traitements localisés et systémiques)

Menée in vitro sur des cellules de glioblastome et des astrocytes humains, cette étude évalue la capacité du MK-1775, un inhibiteur potentiel de la protéine kinase Wee-1, à renforcer la sensibilité des cellules de glioblastome aux rayonnements ionisants

• Targeting radiation-induced G2/M checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines
  • Molecular Cancer Therapeutics, sous presse, 2011 (résumé)
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  Menée in vitro sur des cellules de glioblastome et des astrocytes humains, cette étude évalue la capacité du MK-1775, un inhibiteur potentiel de la protéine kinase Wee-1, à renforcer la sensibilité des cellules de glioblastome aux rayonnements ionisants

  “Targeting radiation-induced G2/M checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines”

  • Sarcar, Bhaswati;Kahali, Soumen;Prabhu, Antony H.;Shumway, Stuart D.;Xu, Yang;Demuth, Tim;Chinnaiyan, Prakash

  Define the capacity of MK-1775, a potent Wee-1 inhibitor, to abrogate the radiation induced G2 checkpoint arrest and modulate radiation sensitivity in glioblastoma cell models and normal human astrocytes. The radiation-induced checkpoint response of established glioblastoma cell lines, glioblastoma neural stem (GNS) cells, and normal human astrocytes were determined in vitro by flow cytometry and in vivo by mitosis-specific staining using immunohistochemistry. Mechanisms underlying MK-1775 radiosensitization were determined by mitotic catastrophe and target modulation was assessed by western blot. Radiation sensitivity was determined in vitro by the clonogenic assay and in vivo by tumor growth delay. MK-1775 abrogated the radiation-induced G2 checkpoint and enhanced radiation sensitivity in established glioblastoma cell lines in vitro and in vivo, without modulating radiation response in normal human astrocytes. MK-1775 appeared to attenuate the "early-phase" of the G2 checkpoint ...

  
  

Mots clés : Système nerveux central; Traitements (Combinaison de traitements localisés et systémiques)

Cet article passe en revue les travaux récents sur l'usage de thérapies géniques et de cellules génétiquement modifiées pour le traitement des cancers

• Targeted Therapeutics
  • Cell, Vol. 147 (2), pp. 253, 2011 (résumé)
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  Cet article passe en revue les travaux récents sur l'usage de thérapies géniques et de cellules génétiquement modifiées pour le traitement des cancers

  “Targeted Therapeutics”

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  Deciphering the molecular underpinnings of a disease is often only the first step toward developing an effective treatment. The path from target identification to a successful therapeutic can be filled with numerous hurdles that call for creative strategies. This Select highlights recent advances in using gene therapy and engineered cells to treat cancers and chronic heart disease. Their success in preliminary trials suggests that these unconventional strategies are close to becoming mainstream options for refractory diseases.

  
  

Mots clés : Cancer (général); Traitements (Ressources et infrastructures (Traitements))