Traitements

Menée sur des lignées cellulaires humaines de cancer du col de l'utérus, cette étude montre que les cellules initiatrices de cancer expriment des marqueurs caractéristiques des cellules souches et de la transition épithélio-mésenchymateuse, et, par ailleurs, qu'elles sont particulièrement résistantes aux rayonnements ionisants

• Cancer-initiating cells derived from established cervical cell lines exhibit stem-cell markers and increased radioresistance
  • BMC Cancer, Vol. 12 (1), pp. 48, 2012 (article en libre accès)
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  Menée sur des lignées cellulaires humaines de cancer du col de l'utérus, cette étude montre que les cellules initiatrices de cancer expriment des marqueurs caractéristiques des cellules souches et de la transition épithélio-mésenchymateuse, et, par ailleurs, qu'elles sont particulièrement résistantes aux rayonnements ionisants

  “Cancer-initiating cells derived from established cervical cell lines exhibit stem-cell markers and increased radioresistance”

  • Lopez, Jacqueline;Poitevin, Adela;Mendoza-Martinez, Veverly;Perez-Plasencia, Carlos;Garcia-Carranca, Alejandro

  BACKGROUND:Cancer-initiating cells (CICs) are proposed to be responsible for the generation of metastasis and resistance to therapy. Accumulating evidences indicates CICs are found among different human cancers and cell lines derived from them. Few studies address the characteristics of CICs in cervical cancer. We identify biological features of CICs from four of the best-know human cell lines from uterine cervix tumors. (HeLa, SiHa, Ca Ski, C-4 I).METHODS:Cells were cultured as spheres under stem-cell conditions. Flow cytometry was used to detect expression of CD34, CD49f and CD133 antigens and Hoechst 33,342 staining to identify side population (SP). Magnetic and fluorescence-activated cell sorting was applied to enrich and purify populations used to evaluate tumorigenicity in nude mice. cDNA microarray analysis and in vitro radioresistance assay were carried out under standard conditionsRESULTS:CICs, enriched as spheroids, were capable to generate reproducible tumor phenotypes in ...

  
  

Mots clés : Col de l'utérus; Traitements (Traitements localisés : découverte et développement)

Mené sur 149 patients présentant des métastases stables et non comprimantes au niveau de la moelle épinière (durée médiane de suivi :15,9 mois), cet essai de phase 1-2 évalue l'intérêt d'une radiothérapie stéréotaxique corporelle

• Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1-2 trial
  • The Lancet Oncology, sous presse, 2012 (résumé)
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  Mené sur 149 patients présentant des métastases stables et non comprimantes au niveau de la moelle épinière (durée médiane de suivi :15,9 mois), cet essai de phase 1-2 évalue l'intérêt d'une radiothérapie stéréotaxique corporelle

  “Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1-2 trial”

  • Wang, Xin Shelley;Rhines, Laurence D.;Shiu, Almon S.;Yang, James N.;Selek, Ugur;Gning, Ibrahima;Liu, Ping;Allen, Pamela K.;Azeem, Syed S.;Brown, Paul D.;Sharp, Hadley J.;Weksberg, David C.;Cleeland, Charles S.;Chang, Eric L.

  Spinal stereotactic body radiation therapy (SBRT) is increasingly used to manage spinal metastases, yet the technique's effectiveness in controlling the symptom burden of spinal metastases has not been well described. We investigated the clinical benefit of SBRT for managing spinal metastases and reducing cancer-related symptoms. 149 patients with mechanically stable, non-cord-compressing spinal metastases (166 lesions) were given SBRT in a phase 1-2 study. Patients received a total dose of 27?30 Gy, typically in three fractions. Symptoms were measured before SBRT and at several time points up to 6 months after treatment, by the Brief Pain Inventory (BPI) and the M D Anderson Symptom Inventory (MDASI). The primary endpoint was frequency and duration of complete pain relief. The study is completed and is registered withClinicalTrials.gov, numberNCT00508443. Median follow-up was 15·9 months (IQR 9·5?30·3). The number of patients reporting no pain from bone metastases, as measured by ...

  
  
• SBRT and spinal metastasis: finding its niche
  • The Lancet Oncology, sous presse, 2012 (commentaire)
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  Mené sur 149 patients présentant des métastases stables et non comprimantes au niveau de la moelle épinière (durée médiane de suivi :15,9 mois), cet essai de phase 1-2 évalue l'intérêt d'une radiothérapie stéréotaxique corporelle

  “SBRT and spinal metastasis: finding its niche”

  • Schiff, David ; Sheehan, Jason P.

  
  

Mots clés : Tissus mous (autre); Traitements (Traitements localisés : applications cliniques)

A partir d'une revue de la littérature, cet article fait le point sur les indications, les limites et les effets indésirables d'une mastectomie conservant le mamelon, et analyse le rôle de la radiothérapie dans le traitement post-opératoire

• Defining a Place for Nipple Sparing Mastectomy in Modern Breast Care: An Evidence Based Review
  • The Breast Journal, sous presse, 2012 (résumé)
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  A partir d'une revue de la littérature, cet article fait le point sur les indications, les limites et les effets indésirables d'une mastectomie conservant le mamelon, et analyse le rôle de la radiothérapie dans le traitement post-opératoire

  “Defining a Place for Nipple Sparing Mastectomy in Modern Breast Care: An Evidence Based Review”

  • Murthy, Vijayashree;Chamberlain, Ronald S.

  Abstract : Breast cancer is a diverse disease that requires a fully integrated multidisciplinary approach. Breast surgery has undergone a revolutionary change leading us from the conventional radical mastectomy of the Halstedian era to the current motion of nipple sparing mastectomy (NSM). Despite the lack of randomized controlled trials, the technique of NSM continues to gain popularity as a prophylactic procedure in high risk patients. The current indications for NSM, if any, in the treatment of early invasive breast cancer remains uncertain and requires rigorous scientific scrutiny. This article aims to critically review the indications and limitations of NSM, discuss evidence based intra-operative protocols and to discuss ways in which radiation therapy may be incorporated in treatment planning following NSM. A comprehensive search of the scientific literature was carried out using PubMed to access all publications related to nipple sparing mastectomy. The search focused ...

  
  

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

Cet article passe en revue les études récentes concernant les techniques de prostatectomie radicale visant à réduire la morbidité post-opératoire et à améliorer la récupération de la continence urinaire sans compromettre les résultats oncologiques

• Optimizing radical prostatectomy for the early recovery of urinary continence
  • Nature Reviews Urology, sous presse, 2012 (résumé)
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  Cet article passe en revue les études récentes concernant les techniques de prostatectomie radicale visant à réduire la morbidité post-opératoire et à améliorer la récupération de la continence urinaire sans compromettre les résultats oncologiques

  “Optimizing radical prostatectomy for the early recovery of urinary continence”

  • Dev, Harveer S.;Sooriakumaran, Prasanna;Srivastava, Abhishek;Tewari, Ashutosh K.

  Radical prostatectomy remains the gold-standard treatment for clinically localized prostate cancer. Although cancer control is the primary goal, secondary outcomes such as continence recovery are of great importance to patients. Thus, it is a challenge for prostate cancer surgeons to optimize continence outcomes without compromising oncologic results. Many high-volume surgeons have demonstrated excellent long-term continence rates in their patients, but early continence is variable and less than ideal even in expert hands. A plethora of individual technical maneuvers exist to optimize early recovery of continence, but as yet there is no composite technique that incorporates the relevant anatomic principles of minimizing damage to the urinary sphincters and their nerves, maximizing functional urethral length, creating a secure and watertight vesicourethral anastomosis, providing circumferential fascioligamentous support to the anastomosis and external sphincter, and ameliorating ...

  
  

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

Menée in vitro, cette étude suggère l'intérêt d'une immunothérapie ciblée contre la kinase ALK dans les neuroblastomes, indépendamment de la présence d'une mutation du gène ALK

• Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma
  • Oncogene, sous presse, 2012 (résumé)
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  Menée in vitro, cette étude suggère l'intérêt d'une immunothérapie ciblée contre la kinase ALK dans les neuroblastomes, indépendamment de la présence d'une mutation du gène ALK

  “Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma”

  • Carpenter, E. L.;Haglund, E. A.;Mace, E. M.;Deng, D.;Martinez, D.;Wood, A. C.;Chow, A. K.;Weiser, D. A.;Belcastro, L. T.;Winter, C.;Bresler, S. C.;Asgharzadeh, S.;Seeger, R. C.;Zhao, H.;Guo, R.;Christensen, J. G.;Orange, J. S.;Pawel, B. R.;Lemmon, M. A.;Mosse, Y. P.

  Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in neuroblastoma, a devastating pediatric cancer of the sympathetic nervous system. Germline and somatically acquired ALK aberrations induce increased autophosphorylation, constitutive ALK activation and increased downstream signaling. Thus, ALK is a tractable therapeutic target in neuroblastoma, likely to be susceptible to both small-molecule tyrosine kinase inhibitors and therapeutic antibodies—as has been shown for other receptor tyrosine kinases in malignancies such as breast and lung cancer. Small-molecule inhibitors of ALK are currently being studied in the clinic, but common ALK mutations in neuroblastoma appear to show de novo insensitivity, arguing that complementary therapeutic approaches must be developed. We therefore hypothesized that antibody targeting of ALK may be a relevant strategy for the majority of neuroblastoma patients likely to have ALK-positive tumors. We show here that an ...

  
  

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

Menée à l'aide de xénogreffes et in vitro, cette étude montre qu'un traitement anti-angiogénique (sunitinib ou bevacizumab) a pour effet d'accroître la population des cellules souches de cancer du sein

• Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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  Menée à l'aide de xénogreffes et in vitro, cette étude montre qu'un traitement anti-angiogénique (sunitinib ou bevacizumab) a pour effet d'accroître la population des cellules souches de cancer du sein

  “Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia”

  • Conley, Sarah J.;Gheordunescu, Elizabeth;Kakarala, Pramod;Newman, Bryan;Korkaya, Hasan;Heath, Amber N.;Clouthier, Shawn G.;Wicha, Max S.

  Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. ...

  
  

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

Menée à l'aide de xénogreffes, cette étude suggère que l'inhibition de PARP1 pourrait être une stratégie thérapeutique intéressante chez les patients atteints de la forme héréditaire du sarcome d'Ewing

• PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma
  • Cancer Research, sous presse, 2012 (résumé)
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  Menée à l'aide de xénogreffes, cette étude suggère que l'inhibition de PARP1 pourrait être une stratégie thérapeutique intéressante chez les patients atteints de la forme héréditaire du sarcome d'Ewing

  “PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma”

  • Brenner, J. Chad;Feng, Felix Y;Han, Sumin;Patel, Sonam;Goyal, Siddharth V;Bou-Maroun, Laura M;Liu, Meilan;Lonigro, Robert J;Prensner, John R;Tomlins, Scott A;Chinnaiyan, Arul M

  Ewing's sarcoma family tumors (ESFTs) are aggressive malignancies which frequently harbor characteristic EWS-FLI1 or EWS-ERG genomic fusions. Here we report that these fusion products interact with the DNA damage response protein and transcriptional co-regulator PARP-1. ESFT cells, primary tumor xenografts and tumor metastases were all highly sensitive to PARP1 inhibition. Addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolamide resulted in complete responses of all treated tumors in an EWS-FLI1-driven mouse xenograft model of ESFT. Mechanistic investigations revealed that DNA damage induced by expression of EWS-FLI1 or EWS-ERG fusion genes was potentiated by PARP1 inhibition in ESFT cell lines. Notably, EWS-FLI1 fusion genes acted in a positive feedback loop to maintain the expression of PARP1, which was required for EWS-FLI-mediated transcription, thereby enforcing oncogene-dependent sensitivity to PARP-1 inhibition. Together, our findings offer a strong ...

  
  

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

Cet article passe en revue les perspectives offertes par les traitements personnalisés du cancer du poumon non à petites cellules

• Individualized therapy for patients with non-small cell lung cancer: Emerging trends and challenges
  • Critical Reviews in Oncology/Hematology, sous presse, 2012 (résumé)
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  Cet article passe en revue les perspectives offertes par les traitements personnalisés du cancer du poumon non à petites cellules

  “Individualized therapy for patients with non-small cell lung cancer: Emerging trends and challenges”

  • Corey J, Langer

  Non-small cell lung cancer is the leading cause of cancer death in the United States. Efforts to improve outcomes have led to a greater understanding of the predictive and prognostic value of histologic and molecular characteristics of individual tumors. In standard practice, biopsy specimens are examined first on a histologic level, then on a molecular level with the recognition that both histologic subtype and gene expression profile can guide treatment decisions and have a profound effect on clinical outcomes. Epidermal growth factor activation mutations were among the first biomarkers shown to have therapeutic implications, and levels of gene expression for an array of other biomarkers are being evaluated in clinical trials. Ongoing studies underscore the need to implement molecular and histologic screening as part of routine clinical practice. To achieve an integration of clinical, histologic, and molecular parameters when making treatment decisions, collaboration between ...

  
  

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

Menée sur des lignées cellulaires de cancer ovarien, cette étude montre que la doxorubicine a pour effet d'accroître la population des cellules souches cancéreuses et que ces cellules sont sensibles à un traitement par hormone anti-müllérienne

• Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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  Menée sur des lignées cellulaires de cancer ovarien, cette étude montre que la doxorubicine a pour effet d'accroître la population des cellules souches cancéreuses et que ces cellules sont sensibles à un traitement par hormone anti-müllérienne

  “Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance”

  • Meirelles, Katia;Benedict, Leo Andrew;Dombkowski, David;Pepin, David;Preffer, Frederic I.;Teixeira, Jose;Tanwar, Pradeep Singh;Young, Robert H.;MacLaughlin, David T.;Donahoe, Patricia K.;Wei, Xiaolong

  Women with late-stage ovarian cancer usually develop chemotherapeutic-resistant recurrence. It has been theorized that a rare cancer stem cell, which is responsible for the growth and maintenance of the tumor, is also resistant to conventional chemotherapeutics. We have isolated from multiple ovarian cancer cell lines an ovarian cancer stem cell-enriched population marked by CD44, CD24, and Epcam (3+) and by negative selection for Ecadherin (Ecad−) that comprises less than 1% of cancer cells and has increased colony formation and shorter tumor-free intervals in vivo after limiting dilution. Surprisingly, these cells are not only resistant to chemotherapeutics such as doxorubicin, but also are stimulated by it, as evidenced by the significantly increased number of colonies in treated 3+Ecad− cells. Similarly, proliferation of the 3+Ecad− cells in monolayer increased with treatment, by either doxorubicin or cisplatin, compared with the unseparated or cancer stem cell-depleted ...

  
  

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

Mené sur 131 patients atteints d'un lymphome T périphérique récidivant ou réfractaire, cet essai de phase II évalue la romidepsine, un inhibiteur d'histone déacétylase, après l'échec d'un premier traitement systémique

• Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 131 patients atteints d'un lymphome T périphérique récidivant ou réfractaire, cet essai de phase II évalue la romidepsine, un inhibiteur d'histone déacétylase, après l'échec d'un premier traitement systémique

  “Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy”

  • Coiffier, Bertrand;Pro, Barbara;Prince, H. Miles;Foss, Francine;Sokol, Lubomir;Greenwood, Matthew;Caballero, Dolores;Borchmann, Peter;Morschhauser, Franck;Wilhelm, Martin;Pinter-Brown, Lauren;Padmanabhan, Swaminathan;Shustov, Andrei;Nichols, Jean;Carroll, Susan;Balser, John;Balser, Barbara;Horwitz, Steven

  Purpose Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).Patients and Methods Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee.Results Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell ...

  
  

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

Cet article passe en revue les travaux récents sur la nature des cellules souches dans la leucémie myéloïde aiguë et évalue les perspectives offertes par des anticorps monoclonaux dirigés contre CD33 pour le traitement des diverses formes de la maladie

• Acute myeloid leukemia stem cells and CD33-targeted immunotherapy
  • Blood, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur la nature des cellules souches dans la leucémie myéloïde aiguë et évalue les perspectives offertes par des anticorps monoclonaux dirigés contre CD33 pour le traitement des diverses formes de la maladie

  “Acute myeloid leukemia stem cells and CD33-targeted immunotherapy”

  • Walter, Roland B.;Appelbaum, Frederick R.;Estey, Elihu H.;Bernstein, Irwin D.

  While the identification of cancer stem cells as therapeutic targets is now actively being pursued in many human malignancies, the leukemic stem cells (LSCs) in acute myeloid leukemia (AML) are a paradigm of such a strategy. Heterogeneity of LSCs was suggested by clonal analyses indicating the existence of both leukemias resulting from transformed multipotent CD33- stem cells as well others arising from, or predominantly involving, committed CD33+ myeloid precursors. The latter leukemias, which may be associated with an intrinsically better prognosis, offer a particularly attractive target for stem cell-directed therapies. Targeting the CD33 differentiation antigen with gemtuzumab ozogamicin (GO) was our first attempt of such an approach. Emerging clinical data now indicate that GO is efficacious not only for acute promyelocytic leukemia but, in combination with conventional chemotherapy, also for other favorable- and intermediate-risk AMLs, providing the first proof-of-principle ...

  
  

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

Menée sur un modèle murin, cette étude suggère que, dans les leucémies myéloïdes chroniques caractérisées par l'oncoprotéine BCR-ABL, un inhibiteur de JAK2 est inutile et qu'il est préférable de cibler uniquement la protéine STAT5

• BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia
  • Nature Chemical Biology, sous presse, 2012 (résumé)
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  Menée sur un modèle murin, cette étude suggère que, dans les leucémies myéloïdes chroniques caractérisées par l'oncoprotéine BCR-ABL, un inhibiteur de JAK2 est inutile et qu'il est préférable de cibler uniquement la protéine STAT5

  “BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia”

  • Hantschel, Oliver;Warsch, Wolfgang;Eckelhart, Eva;Kaupe, Ines;Grebien, Florian;Wagner, Kay-Uwe;Superti-Furga, Giulio;Sexl, Veronika

  Constitutive activation of STAT5 is critical for the maintenance of chronic myeloid leukemia (CML) characterized by the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (TKIs) for the STAT5-activating kinase JAK2 have been discussed as a treatment option for CML patients. Using murine leukemia models combined with inducible ablation of JAK2, we show JAK2 dependence for initial lymphoid transformation, which is lost once leukemia is established. In contrast, initial myeloid transformation and leukemia maintenance were independent of JAK2. Nevertheless, several JAK2 TKIs induced apoptosis in BCR-ABL+ cells irrespective of the presence of JAK2. This is caused by the previously unknown direct 'off-target' inhibition of BCR-ABL. Cellular and enzymatic analyses suggest that BCR-ABL phosphorylates STAT5 directly. Our findings suggest uncoupling of the canonical JAK2-STAT5 module upon BCR-ABL expression, thereby making JAK2 targeting dispensable. Thus, attempts to pharmacologically target ...

  
  

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

Menée in vitro, cette étude suggère l'efficacité de petites molécules inhibitrices de la protéine produite par la fusion des gènes MLL et MEN1 pour le traitement des leucémies avec réarrangements du gène MLL

• Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia
  • Nature Chemical Biology, sous presse, 2012 (résumé)
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  Menée in vitro, cette étude suggère l'efficacité de petites molécules inhibitrices de la protéine produite par la fusion des gènes MLL et MEN1 pour le traitement des leucémies avec réarrangements du gène MLL

  “Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia”

  • Grembecka, Jolanta;He, Shihan;Shi, Aibin;Purohit, Trupta;Muntean, Andrew G.;Sorenson, Roderick J.;Showalter, Hollis D.;Murai, Marcelo J.;Belcher, Amalia M.;Hartley, Thomas;Hess, Jay L.;Cierpicki, Tomasz

  Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-molecule inhibitors of the menin–MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compounds effectively reverse MLL fusion protein–mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compounds provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL ...

  
  

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

Menée in vitro et à l'aide d'un modèle murin, cette étude identifie un mécanisme par lequel le bortezomib agit sur l'apoptose, ce qui ouvre la voie à un développement thérapeutique dans certaines formes de leucémie

• Bortezomib interferes with C-KIT processing and transforms the t(8;21)-generated fusion proteins into tumor-suppressing fragments in leukemia cells
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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  Menée in vitro et à l'aide d'un modèle murin, cette étude identifie un mécanisme par lequel le bortezomib agit sur l'apoptose, ce qui ouvre la voie à un développement thérapeutique dans certaines formes de leucémie

  “Bortezomib interferes with C-KIT processing and transforms the t(8;21)-generated fusion proteins into tumor-suppressing fragments in leukemia cells”

  • Fang, Hai-Tong;Zhang, Bo;Pan, Xiao-Fen;Gao, Li;Zhen, Tao;Zhao, Hong-Xia;Ma, Liang;Xie, Jun;Liu, Zi;Yu, Xian-Jun;Cheng, Xin;Feng, Ting-Ting;Zhang, Feng-Xiang;Yang, Yong;Hu, Zhong-Guo;Sheng, Guo-Qing;Chen, Yong-Long;Chen, Sai-Juan;Chen, Zhu;Zhou, Guang-Biao

  The boronic acid dipeptide bortezomib inhibits the chymotrypsin-like activity of the 26S proteasome and shows significant therapeutic efficacy in multiple myeloma. However, recent studies suggest that bortezomib may have more complex mechanisms of action in treating cancer. We report here that the endocytosis and lysosomal degradation of the receptor tyrosine kinase C-KIT are required for bortezomib- but not tyrosine kinase inhibitor imatinib-caused apoptosis of t(8;21) leukemia and gastrointestinal stromal tumor cells, suggesting that C-KIT may recruit an apoptosis initiator. We show that C-KIT binds and phosphorylates heat shock protein 90β (Hsp90β), which sequestrates apoptotic protease activating factor 1 (Apaf-1). Bortezomib dephosphorylates pHsp90β and releases Apaf-1. Although the activated caspase-3 is not sufficient to cause marked apoptosis, it cleaves the t(8;21) generated acute myeloid leukemia 1-eight twenty one (AML1-ETO) and AML1-ETO9a fusion proteins, with ...

  
  

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

Menée in vitro et in vivo, cette étude met en évidence que, dans les cellules de cancer du côlon présentant la mutation BRAF(V600E), le vemurafenib seul est inefficace parce qu'il active EGFR

• Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR
  • Nature, sous presse, 2012 (résumé)
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  Menée in vitro et in vivo, cette étude met en évidence que, dans les cellules de cancer du côlon présentant la mutation BRAF(V600E), le vemurafenib seul est inefficace parce qu'il active EGFR

  “Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR”

  • Prahallad, Anirudh;Sun, Chong;Huang, Sidong;Di Nicolantonio, Federica;Salazar, Ramon;Zecchin, Davide;Beijersbergen, Roderick L.;Bardelli, Alberto;Bernards, Rene

  Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harbouring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation ...

  
  

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

Cet article passe en revue les travaux récents sur le rôle des radicaux libres dans le développement et la progression d'un cancer, puis identifie de nouvelles stratégies thérapeutiques basées sur la prévention ou l'induction d'un stress oxydant

• Long-term effects of systemic cancer treatment on DNA oxidative damage: the potential for targeted therapies
  • Cancer Letters, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur le rôle des radicaux libres dans le développement et la progression d'un cancer, puis identifie de nouvelles stratégies thérapeutiques basées sur la prévention ou l'induction d'un stress oxydant

  “Long-term effects of systemic cancer treatment on DNA oxidative damage: the potential for targeted therapies”

  • Vera-Ramirez, Laura;Ramirez-Tortosa, MCarmen;Perez-Lopez, Patricia;Granados-Principal, Sergio;Battino, Maurizio;Quiles, José L.

  The main pathological consequence of free radical exposure is DNA damage, which is known to induce cell transformation and to facilitate important mutations in cancer progression. It is a matter of intense discussion whether the drug-induced production of free radicals limits the therapeutic efficacy of chemotherapeutics and enhances their toxicity or whether they may be enhanced to provoke cancer cell apoptosis. This paper reviews essential molecular processes to better understand the controversial role of free radicals in cancer development and progression, and discusses some novel therapeutic strategies based on oxidative stress induction and prevention.

  
  

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

Menée à l'aide de xénogreffes d'adénocarcinome du poumon et de carcinome colorectal, cette étude évalue l'activité antitumorale d'un traitement combinant le selumetinib, un inhibiteur de MEK1/2, et un composé appelé AZD8055, un inhibiteur de mTORC1 et mTORC2

• Enhanced apoptosis and tumor growth suppression elicited by combination of MEK and mTOR kinase inhibitors
  • Cancer Research, sous presse, 2012 (résumé)
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  Menée à l'aide de xénogreffes d'adénocarcinome du poumon et de carcinome colorectal, cette étude évalue l'activité antitumorale d'un traitement combinant le selumetinib, un inhibiteur de MEK1/2, et un composé appelé AZD8055, un inhibiteur de mTORC1 et mTORC2

  “Enhanced apoptosis and tumor growth suppression elicited by combination of MEK and mTOR kinase inhibitors”

  • Holt, Sarah V;Logie, Armelle;Davies, Barry R;Alferez, Denis;Runswick, Sarah;Fenton, Sarah;Chresta, Christine M;Gu, Yi;Zhang, Jingchuan;Wu, Yi-Long;Wilkinson, Robert W.;Guichard, Sylvie;Smith, Paul D

  The MAPK and PI3K/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MEK1/2 inhibitor, selumetinib (AZD6244), with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (NSCLC) and colorectal carcinoma (CRC) was well tolerated and produced increased anti-tumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic ...

  
  

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

Cet article passe en revue les perspectives offertes par l'inhibition de la signalisation MET pour le traitement des tumeurs solides

• Targeting MET in cancer: rationale and progress
  • Nature Reviews Cancer, Vol. 12 (2), pp. 89-103, 2012 (résumé)
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  Cet article passe en revue les perspectives offertes par l'inhibition de la signalisation MET pour le traitement des tumeurs solides

  “Targeting MET in cancer: rationale and progress”

  • Gherardi, Ermanno;Birchmeier, Walter;Birchmeier, Carmen;Woude, George Vande

  Uncontrolled cell survival, growth, angiogenesis and metastasis are essential hallmarks of cancer. Genetic and biochemical data have demonstrated that the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the tyrosine kinase MET, have a causal role in all of these processes, thus providing a strong rationale for targeting these molecules in cancer. Parallel progress in understanding the structure and function of HGF/SF, MET and associated signalling components has led to the successful development of blocking antibodies and a large number of small-molecule MET kinase inhibitors. In this Review, we discuss these advances, as well as results from recent clinical studies that demonstrate that inhibiting MET signalling in several types of solid human tumours has major therapeutic value.

  
  

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

Mené sur 337 patients atteints d'un cancer à cellules germinales de pronostic intermédiaire, cet essai de phase III évalue, du point de vue de la survie sans progression à 3 ans, l'ajout de paclitaxel à un traitement BEP (bléomycine, étoposide et cisplatine)

• Randomized Phase III Study Comparing Paclitaxel–Bleomycin, Etoposide, and Cisplatin (BEP) to Standard BEP in Intermediate-Prognosis Germ-Cell Cancer: Intergroup Study EORTC 30983
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 337 patients atteints d'un cancer à cellules germinales de pronostic intermédiaire, cet essai de phase III évalue, du point de vue de la survie sans progression à 3 ans, l'ajout de paclitaxel à un traitement BEP (bléomycine, étoposide et cisplatine)

  “Randomized Phase III Study Comparing Paclitaxel–Bleomycin, Etoposide, and Cisplatin (BEP) to Standard BEP in Intermediate-Prognosis Germ-Cell Cancer: Intergroup Study EORTC 30983”

  • de Wit, Ronald;Skoneczna, Iwona;Daugaard, Gedske;De Santis, Maria;Garin, August;Aass, Nina;Witjes, Alfred J.;Albers, Peter;White, Jeffery D.;Germa-Lluch, José R.;Marreaud, Sandrine;Collette, Laurence

  Purpose To compare the efficacy of four cycles of paclitaxel–bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC).Patients and Methods Patients were randomly assigned to receive either T-BEP or standard BEP. Patients assigned to the T-BEP group received paclitaxel 175 mg/m2 in a 3-hour infusion. Patients who were administered T-BEP received primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. The study was designed as a randomized open-label phase II/III study. To show a 10% improvement in 3-year progression-free survival (PFS), the study aimed to recruit 498 patients but closed with 337 patients as a result of slow accrual.Results Accrual was from November 1998 to April 2009. A total of 169patients were administered BEP, and 168 patients were administered T-BEP. Thirteen patients in both arms were ineligible, mainly as a result of a ...

  
  
• Classical Clinical Trial Design in Testicular Cancer: Time to Move On
  • Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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  Mené sur 337 patients atteints d'un cancer à cellules germinales de pronostic intermédiaire, cet essai de phase III évalue, du point de vue de la survie sans progression à 3 ans, l'ajout de paclitaxel à un traitement BEP (bléomycine, étoposide et cisplatine)

  “Classical Clinical Trial Design in Testicular Cancer: Time to Move On”

  • Nichols, Craig R. ; Roth, Bruce ; Kollmannsberger, Christian

  
  

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

Menées respectivement sur 1 206 et 1 948 patientes atteintes d'un cancer métastatique du sein, ces deux études évaluent l'ajout de bevacizumab à une chimiothérapie néoadjuvante

• Neoadjuvant Chemotherapy and Bevacizumab for HER2-Negative Breast Cancer
  • New England Journal of Medicine, Vol. 366 (4), pp. 299-309, 2012 (résumé)
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  Menées respectivement sur 1 206 et 1 948 patientes atteintes d'un cancer métastatique du sein, ces deux études évaluent l'ajout de bevacizumab à une chimiothérapie néoadjuvante

  “Neoadjuvant Chemotherapy and Bevacizumab for HER2-Negative Breast Cancer”

  • von Minckwitz, Gunter;Eidtmann, Holger;Rezai, Mahdi;Fasching, Peter A.;Tesch, Hans;Eggemann, Holm;Schrader, Iris;Kittel, Kornelia;Hanusch, Claus;Kreienberg, Rolf;Solbach, Christine;Gerber, Bernd;Jackisch, Christian;Kunz, Georg;Blohmer, Jens-Uwe;Huober, Jens;Hauschild, Maik;Fehm, Tanja;Müller, Berit Maria;Denkert, Carsten;Loibl, Sibylle;Nekljudova, Valentina;Untch, Michael

  Background: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer. We evaluated the efficacy, measured according to the rate of pathological complete response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes), and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer. Methods: We randomly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors, hormone-receptor–negative disease, or hormone-receptor–positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or ...

  
  
• Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer
  • New England Journal of Medicine, Vol. 366 (4), pp. 310-320, 2012 (résumé)
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  Menées respectivement sur 1 206 et 1 948 patientes atteintes d'un cancer métastatique du sein, ces deux études évaluent l'ajout de bevacizumab à une chimiothérapie néoadjuvante

  “Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer”

  • Bear, Harry D. ; Tang, Gong ; Rastogi, Priya ; Geyer, Charles E. ; Robidoux, André ; Atkins, James N. ; Baez-Diaz, Luis ; Brufsky, Adam M. ; Mehta, Rita S. ; Fehrenbacher, Louis ; Young, James A. ; Senecal, Francis M. ; Gaur, Rakesh ; Margolese, Richard G. ; Adams, Paul T. ; Gross, Howard M. ; Costantino, Joseph P. ; Swain, Sandra M. ; Mamounas, Eleftherios P. ; Wolmark, Norman

  Background: Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)–negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response. Methods: We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine ...

  
  
• Fighting Fire with Fire: Rekindling the Bevacizumab Debate
  • New England Journal of Medicine, Vol. 366 (4), pp. 374-375, 2012 (éditorial)
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  Menées respectivement sur 1 206 et 1 948 patientes atteintes d'un cancer métastatique du sein, ces deux études évaluent l'ajout de bevacizumab à une chimiothérapie néoadjuvante

  “Fighting Fire with Fire: Rekindling the Bevacizumab Debate”

  • Montero, Alberto J. ; Vogel, Charles

  The results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial1 and the GeparQuinto (GBG44) trial,2 both of which are reported in this issue of the Journal, are particularly timely given the definitive announcement by the Food and Drug Administration (FDA) on November 18, 2011, revoking approval of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer (see www.fda.gov/downloads/NewsEvents/Newsroom/UCM280546.pdf). Bevacizumab, a monoclonal antibody against circulating vascular endothelial growth factor A, was granted accelerated FDA approval in 2008 for the first-line treatment of human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer. Initial approval . . .

  
  

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

Mené sur 3 714 patientes autrichiennes atteintes d'un cancer du sein ER+ après la ménopause, cet essai de phase III compare l'efficacité, du point de vue de la survie sans récidive, d'un traitement au tamoxifène seul pendant 5 ans et d'un traitement au tamoxifène pendant 2 ans suivi par de l'anastrazole pendant 3 ans (durée médiane de suivi : 5 ans)

• Tamoxifen and Anastrozole As a Sequencing Strategy: A Randomized Controlled Trial in Postmenopausal Patients With Endocrine-Responsive Early Breast Cancer From the Austrian Breast and Colorectal Cancer Study Group
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 3 714 patientes autrichiennes atteintes d'un cancer du sein ER+ après la ménopause, cet essai de phase III compare l'efficacité, du point de vue de la survie sans récidive, d'un traitement au tamoxifène seul pendant 5 ans et d'un traitement au tamoxifène pendant 2 ans suivi par de l'anastrazole pendant 3 ans (durée médiane de suivi : 5 ans)

  “Tamoxifen and Anastrozole As a Sequencing Strategy: A Randomized Controlled Trial in Postmenopausal Patients With Endocrine-Responsive Early Breast Cancer From the Austrian Breast and Colorectal Cancer Study Group”

  • Dubsky, Peter C.;Jakesz, Raimund;Mlineritsch, Brigitte;Pöstlberger, Sabine;Samonigg, Hellmut;Kwasny, Werner;Tausch, Christoph;Stöger, Herbert;Haider, Karin;Fitzal, Florian;Singer, Christian F.;Stierer, Michael;Sevelda, Paul;Luschin-Ebengreuth, Gero;Taucher, Susanne;Rudas, Margaretha;Bartsch, Rupert;Steger, Günther G.;Greil, Richard;Filipcic, Lidija;Gnant, Michael

  Purpose Anastrozole (ANA) alone delivers significant disease-free survival benefits over tamoxifen (TAM) monotherapy in postmenopausal women with early estrogen receptor–positive breast cancer. The ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) study is a large phase III clinical trial addressing the sequence strategy containing ANA in comparison with 5 years of TAM in a low- to intermediate-risk group of postmenopausal patients.Patients and Methods Endocrine receptor–positive patients with G1 or G2 tumors were eligible. After surgery, patients were randomly assigned to 5 years of TAM or 2 years of TAM followed by 3 years of ANA. Adjuvant chemotherapy and G3 and T4 tumors were exclusion criteria. Intention-to-treat and censored analyses of on-treatment recurrence-free survival (RFS) were performed, and exploratory survival end points and toxicity were investigated.Results Information from 3,714 patients, including 17,563 woman-years, with a median of 60 months of ...

  
  
• Deep Time: The Long and the Short of Adjuvant Endocrine Therapy for Breast Cancer
  • Journal of Clinical Oncology, sous presse, 2012 (éditorial en libre accès)
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  Mené sur 3 714 patientes autrichiennes atteintes d'un cancer du sein ER+ après la ménopause, cet essai de phase III compare l'efficacité, du point de vue de la survie sans récidive, d'un traitement au tamoxifène seul pendant 5 ans et d'un traitement au tamoxifène pendant 2 ans suivi par de l'anastrazole pendant 3 ans (durée médiane de suivi : 5 ans)

  “Deep Time: The Long and the Short of Adjuvant Endocrine Therapy for Breast Cancer”

  • Burstein, Harold J. ; Griggs, Jennifer J.

  
  

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

Cet article passe en revue les travaux récents sur les traitements des métastases osseuses chez les patients atteints d'un cancer de la prostate résistant à la castration

• Recent developments in treatments targeting castration-resistant prostate cancer bone metastases
  • Annals of Oncology, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur les traitements des métastases osseuses chez les patients atteints d'un cancer de la prostate résistant à la castration

  “Recent developments in treatments targeting castration-resistant prostate cancer bone metastases”

  • Loriot, Y.;Massard, C.;Fizazi, K.

  Background: Prostate cancer is the most common male cancer and one of the top causes of male cancer-related death. Most patients with prostate cancer respond to initial androgen deprivation therapy before progressing to castration-resistant prostate cancer (CRPC) and eventually developing bone metastases. Growth of prostate cancer metastases in the bone microenvironment produces numerous factors that disrupt the dynamic equilibrium of osteogenesis and osteolysis existing in healthy bone, leading to progressive morbidity, poor quality of life, and increased treatment costs.Materials and methods: Relevant studies of CRPC and targeted therapies were identified from literature and clinical trial databases, websites, and conference abstracts.Results: Available data on agents potentially targeting bone metastatic CRPC or the bone microenvironment in patients with CRPC are discussed, including inhibitors of tumor growth/survival and bone turnover (SRC family kinase inhibitors, endothelin-1 ...

  
  

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

Mené sur 174 patients européens atteints d'un cancer du poumon non à petites cellules présentant des mutations EGFR, cet essai de phase III évalue la toxicité et l'efficacité, du point de vue de la survie sans progression, de l'erlotinib en traitement de première ligne

• Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial
  • The Lancet Oncology, sous presse, 2012 (résumé)
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  Mené sur 174 patients européens atteints d'un cancer du poumon non à petites cellules présentant des mutations EGFR, cet essai de phase III évalue la toxicité et l'efficacité, du point de vue de la survie sans progression, de l'erlotinib en traitement de première ligne

  “Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial”

  • Rosell, Rafael;Carcereny, Enric;Gervais, Radj;Vergnenegre, Alain;Massuti, Bartomeu;Felip, Enriqueta;Palmero, Ramon;Garcia-Gomez, Ramon;Pallares, Cinta;Sanchez, Jose Miguel;Porta, Rut;Cobo, Manuel;Garrido, Pilar;Longo, Flavia;Moran, Teresa;Insa, Amelia;De Marinis, Filippo;Corre, Romain;Bover, Isabel;Illiano, Alfonso;Dansin, Eric;de Castro, Javier;Milella, Michele;Reguart, Noemi;Altavilla, Giuseppe;Jimenez, Ulpiano;Provencio, Mariano;Moreno, Miguel Angel;Terrasa, Josefa;Muñoz-Langa, Jose;Valdivia, Javier;Isla, Dolores;Domine, Manuel;Molinier, Olivier;Mazieres, Julien;Baize, Nathalie;Garcia-Campelo, Rosario;Robinet, Gilles;Rodriguez-Abreu, Delvys;Lopez-Vivanco, Guillermo;Gebbia, Vittorio;Ferrera-Delgado, Lioba;Bombaron, Pierre;Bernabe, Reyes;Bearz, Alessandra;Artal, Angel;Cortesi, Enrico;Rolfo, Christian;Sanchez-Ronco, Maria;Drozdowskyj, Ana;Queralt, Cristina;de Aguirre, Itziar;Ramirez, Jose Luis;Sanchez, Jose Javier;Molina, Miguel Angel;Taron, Miquel;Paz-Ares, Luis

  Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ?6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m2on day 1 plus ...

  
  
• Optimising therapy for EGFR-addicted NSCLC: just the start
  • The Lancet Oncology, sous presse, 2012 (commentaire en libre accès)
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  Mené sur 174 patients européens atteints d'un cancer du poumon non à petites cellules présentant des mutations EGFR, cet essai de phase III évalue la toxicité et l'efficacité, du point de vue de la survie sans progression, de l'erlotinib en traitement de première ligne

  “Optimising therapy for EGFR-addicted NSCLC: just the start”

  • Govindan, Ramaswamy ; Subramanian, Janakiraman

  
  

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

Cette étude présente les données relatives au suivi à long terme de 177 patients inclus, entre 2002 et 2005, dans trois essais cliniques évaluant l'ipilumumab pour le traitement d'un mélanome métastatique

• CTLA-4 Blockade with Ipilimumab: Long-Term Follow-up of 177 Patients with Metastatic Melanoma
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Cette étude présente les données relatives au suivi à long terme de 177 patients inclus, entre 2002 et 2005, dans trois essais cliniques évaluant l'ipilumumab pour le traitement d'un mélanome métastatique

  “CTLA-4 Blockade with Ipilimumab: Long-Term Follow-up of 177 Patients with Metastatic Melanoma”

  • Prieto, Peter A;Yang, James C.;Sherry, Richard M.;Hughes, Marybeth S.;Kammula, Udai S.;White, Donald E;Levy, Catherine L;Rosenberg, Steven A.;Phan, Giao Q

  Purpose: Treatment with ipilimumab can cause objective tumor responses in patients with metastatic melanoma. We have treated 177 evaluable patients in three clinical trials and have long-term follow-up to evaluate the durability of responses. Patients and Methods: Patients with metastatic melanoma were treated in three trials from 2002 to 2005: In Protocol 1, fifty-six patients received ipilimumab with gp100 peptides. In Protocol 2, thirty-six patients received ipilimumab with interleukin-2. In Protocol 3, eighty-five patients received ipilimumab with intra-patient dose escalation and were randomized to receive gp100 peptides. We have analyzed their long-term follow-up and survival data. Results: With median follow-up for Protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16, and 13 months with five-year survival being 13%, 25%, and 23%, respectively. Patients in Protocol 2 had a 17% complete response (CR) rate, compared to 7% in Protocol 1 and 6% in Protocol ...

  
  

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

Mené sur 18 patients âgés de 42 à 66 ans et atteints d'un carcinome épidermoïde de la tête et du cou de stade III ou IV sans métastase, cet essai de phase I évalue la toxicité et la tolérabilité de l'erlotinib en combinaison avec une chimioradiothérapie concomittante

• A Phase I Trial of Erlotinib and Concurrent Chemoradiotherapy (CCR) for Stage III and IV (M0) Squamous Cell Carcinoma of the Head and Neck
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Mené sur 18 patients âgés de 42 à 66 ans et atteints d'un carcinome épidermoïde de la tête et du cou de stade III ou IV sans métastase, cet essai de phase I évalue la toxicité et la tolérabilité de l'erlotinib en combinaison avec une chimioradiothérapie concomittante

  “A Phase I Trial of Erlotinib and Concurrent Chemoradiotherapy (CCR) for Stage III and IV (M0) Squamous Cell Carcinoma of the Head and Neck”

  • Gilbert, Jill;Rudek, Michelle A.;Higgins, Michaela J;Zhao, Ming;Bienvenu, Sara;Tsottles, Nancy;Wahl, Richard L;Forastiere, Arlene A;Gillison, Maura L.

  Background: Erlotinib, an orally active EGFR tyrosine kinase inhibitor, exhibits anti-tumor activity in head and neck cancer (HNSCC). This Phase I dose-escalation study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of erlotinib in combination with chemoradiotherapy in locally advanced HNSCC. Methods:The principal objective was Maximally Tolerated Dose of the combination of erlotinib, low dose daily cisplatin and standard fractionation radiation therapy. Erlotinib was given daily as a 14 day run in and continued until RT was completed. 18F-FDG PET was performed at baseline and at day 14. Standard fractionation radiotherapy started on day 15 and was given concurrently with low dose daily cisplatin at 6 mg/m2 and erlotinib. Results:The MTD of erlotinib in combination with chemoradiotherapy was defined as 150 mg/day. Grade 3 or 4 toxicities attributed to erlotinib included lymphopenia, diarrhea, rash and pneumonitis. 18F-FDG PET demonstrated significant ...

  
  

Mots clés : Voies aérodigestives supérieures; Traitements (Combinaison de traitements localisés et systémiques)

Mené sur 546 patients atteints d'un cancer du poumon non à petites cellules de stade III et non résécable, cet essai de phase III évalue l'intérêt d'un ajout de thalidomide à une radiothérapie thoracique combinée au paclitaxel et au carboplatine

• Randomized Phase III Study of Thoracic Radiation in Combination With Paclitaxel and Carboplatin With or Without Thalidomide in Patients With Stage III Non–Small-Cell Lung Cancer: The ECOG 3598 Study
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Mené sur 546 patients atteints d'un cancer du poumon non à petites cellules de stade III et non résécable, cet essai de phase III évalue l'intérêt d'un ajout de thalidomide à une radiothérapie thoracique combinée au paclitaxel et au carboplatine

  “Randomized Phase III Study of Thoracic Radiation in Combination With Paclitaxel and Carboplatin With or Without Thalidomide in Patients With Stage III Non–Small-Cell Lung Cancer: The ECOG 3598 Study”

  • Hoang, Tien;Dahlberg, Suzanne E.;Schiller, Joan H.;Mehta, Minesh P.;Fitzgerald, Thomas J.;Belinsky, Steven A.;Johnson, David H.

  Purpose The primary objective of this study was to compare the survival of patients with unresectable stage III non–small-cell lung cancer (NSCLC) treated with combined chemoradiotherapy with or without thalidomide.Patients and Methods Patients were randomly assigned to the control arm (PC) involving two cycles of induction paclitaxel 225 mg/m2 and carboplatin area under the curve (AUC) 6 followed by 60 Gy thoracic radiation administered concurrently with weekly paclitaxel 45 mg/m2 and carboplatin AUC 2, or to the experimental arm (TPC), receiving the same treatment in combination with thalidomide at a starting dose of 200 mg daily. The protocol allowed an increase in thalidomide dose up to 1,000 mg daily based on patient tolerability.Results A total of 546 patients were eligible, including 275 in the PC arm and 271 in the TPC arm. Median overall survival, progression-free survival, and overall response rate were 15.3 months, 7.4 months, and 35.0%, respectively, for patients in the ...

  
  

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

Menée sur 121 patients atteints d'un lymphome primitif médiastinal à grandes cellules B, cette étude évalue l'efficacité d'une chimiothérapie R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine et prednisone) combinée ou non à une radiothérapie

• Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone with or Without Radiotherapy in Primary Mediastinal Large B-Cell Lymphoma: The Emerging Standard of Care
  • The Oncologist, sous presse, 2012 (résumé)
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  Menée sur 121 patients atteints d'un lymphome primitif médiastinal à grandes cellules B, cette étude évalue l'efficacité d'une chimiothérapie R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine et prednisone) combinée ou non à une radiothérapie

  “Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone with or Without Radiotherapy in Primary Mediastinal Large B-Cell Lymphoma: The Emerging Standard of Care”

  • Vassilakopoulos, Theodoros P.;Pangalis, Gerassimos A.;Katsigiannis, Andreas;Papageorgiou, Sotirios G.;Constantinou, Nikos;Terpos, Evangelos;Zorbala, Alexandra;Vrakidou, Effimia;Repoussis, Panagiotis;Poziopoulos, Christos;Galani, Zacharoula;Dimopoulou, Maria N.;Kokoris, Stella I.;Sachanas, Sotirios;Kalpadakis, Christina;Dimitriadou, Evagelia M.;Siakantaris, Marina P.;Kyrtsonis, Marie-Christine;Dervenoulas, John;Dimopoulos, Meletios A.;Meletis, John;Roussou, Paraskevi;Panayiotidis, Panayiotis;Beris, Photis;Angelopoulou, Maria K.

  Abstract More aggressive treatment approaches (methotrexate, cytarabine, cyclophosphamide, vincristine, prednisone, and bleomycin [the MACOP-B regimen] or consolidation with high-dose therapy and autologous stem cell transplantation) have been considered to be superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with primary mediastinal large B-cell lymphoma (PMLBCL). Rituximab-CHOP (R-CHOP) is the standard of care for diffuse large B-cell lymphoma, whereas efficacy in PMLBCL has not been adequately confirmed.Patient and Methods. Seventy-six consecutive PMLBCL patients who received R-CHOP with or without radiotherapy (RT) were compared with 45 consecutive historical controls treated with CHOP with or without RT. Baseline characteristics of the two groups were balanced.Results. The rate of early treatment failure was much lower with R-CHOP with or without RT (9% versus 30%; p = .004). The 5-year freedom from progression rate after R-CHOP with or ...

  
  

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

Menée in vitro et à l'aide d'un modèle murin, cette étude évalue l'efficacité de l'électroporation du calcium pour induire la nécrose des cellules tumorales

• Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis
  • Cancer Research, sous presse, 2012 (résumé)
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  Menée in vitro et à l'aide d'un modèle murin, cette étude évalue l'efficacité de l'électroporation du calcium pour induire la nécrose des cellules tumorales

  “Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis”

  • Frandsen, Stine Krog;Gissel, Hanne;Hojman, Pernille;Tramm, Trine;Eriksen, Jens;Gehl, Julie

  Electroporation of cells with short, high-voltage pulses causes a transient permeabilisation of cell membranes that permits passage of otherwise non-permeating ions and molecules. In this study, we illustrate how electroporation with isotonic calcium can achieve highly effective cancer cell kill in vivo. Calcium electroporation elicited dramatic antitumor responses in which 89% of treated tumors were eliminated. Histological analyses indicated complete tumor necrosis. Mechanistically, calcium electroporation caused acute ATP depletion likely due to a combination of increased cellular use of ATP, decreased production of ATP due to effects on the mitochondria, as well as loss of ATP through the permeabilised cell membrane. Taken together, our findings offer a preclinical proof of concept for the use of electroporation to load cancer cells with calcium as an efficient anti-cancer treatment. Electroporation equipment is already used clinically to enhance the delivery of chemotherapy to ...

  
  

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

Cet article présente des recommandations pour la conception d'essais cliniques de phase II/III

• Design Issues in Randomized Phase II/III Trials
  • Journal of Clinical Oncology, sous presse, 2012 (résumé)
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  Cet article présente des recommandations pour la conception d'essais cliniques de phase II/III

  “Design Issues in Randomized Phase II/III Trials”

  • Korn, Edward L.;Freidlin, Boris;Abrams, Jeffrey S.;Halabi, Susan

  Phase II trials are used to show sufficient preliminary activity of a new treatment (in single-arm designs or randomized screening designs) or to select among treatments with demonstrated activity (in randomized selection designs). The treatments prioritized in a phase II trial are then tested definitively against a control treatment in a randomized phase III trial. Randomized phase II/III trials use an adaptive trial design that combines these two types of trials in one, with potential gains in time and reduced numbers of patients required to be treated. Two key considerations in designing a phase II/III trial are whether to suspend accrual while the phase II data mature and the choice of phase II target treatment effect. We discuss these phase II/III design parameters, give examples of phase II/III trials, and provide recommendations concerning efficient phase II/III trial designs.

  
  

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

Cet article présente un consortium américain qui, dédié à la recherche translationnelle, jouerait le rôle d'un laboratoire virtuel à l'échelle nationale

• A Virtual National Laboratory for Reengineering Clinical Translational Science
  • Science Translational Medicine, Vol. 4 (118), pp. 118cm2, 2012 (commentaire)
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  Cet article présente un consortium américain qui, dédié à la recherche translationnelle, jouerait le rôle d'un laboratoire virtuel à l'échelle nationale

  “A Virtual National Laboratory for Reengineering Clinical Translational Science”

  • Dilts, David M.;Rosenblum, Daniel;Trochim, William M.

  Clinical research is burdened by inefficiencies and complexities, with a poor record of trial completion, none of which is desirable. The Clinical and Translational Science Award (CTSA) Consortium, including more than 60 clinical research institutions, supports a unified national effort to become, in effect, a virtual national laboratory designed to identify, implement, evaluate, and extend process improvements across all parts of clinical research, from conception to completion. If adequately supported by academic health centers, industry, and funding agencies, the Consortium could become a test bed for improvements that can dramatically reduce wasteful complexity, thus increasing the likelihood of clinical trial completion.

  
  

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