Accueil Nota Bene Cancer V2 Numéro 128 du 20 March 2012 Traitements

Nota Bene Cancer Numéro 128 du 20 March 2012

Traitements

Traitements localisés : découverte et développement

Menée sur des cellules humaines de cancer du poumon, cette étude montre qu'un inhibiteur spécifique de la cyclo-oxygénase 2, le célécoxib, peut augmenter l'effet radiosensibilisant de l' 7-hydroxystaurosporine

Celecoxib Enhances the Radiosensitizing Effect of 7-Hydroxystaurosporine (UCN-01) in Human Lung Cancer Cell Lines
• International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)

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Menée sur des cellules humaines de cancer du poumon, cette étude montre qu'un inhibiteur spécifique de la cyclo-oxygénase 2, le célécoxib, peut augmenter l'effet radiosensibilisant de l' 7-hydroxystaurosporine

“Celecoxib Enhances the Radiosensitizing Effect of 7-Hydroxystaurosporine (UCN-01) in Human Lung Cancer Cell Lines”

• Kim, Young-Mee;Jeong, In-Hye;Pyo, Hongryull

7-Hydroxystaurosporine (UCN-01), a Chk1-specific inhibitor, showed promising in vitro and in vivo chemo- or radiosensitizing activity. However, there have been concerns about its limited therapeutic efficacy and risk of side effects. A method of enhancing the treatment efficacy of UCN-01 while not increasing its side effects on normal tissue may therefore be required to apply this drug in clinical settings. Celecoxib is a cyclooxygenase-2 (COX-2)-specific inhibitor that downregulates ataxia telangiectasia and rad3-related (ATR) protein, an upstream kinase of Chk1. In this study, we investigated whether the addition of celecoxib can potentiate the radiosensitizing effect of UCN-01. The cooperative radiosensitizing effects and the underlying molecular mechanisms of UCN-01 plus celecoxib were determined by clonogenic assay, tumor growth delay assay, flow cytometry, and Western blotting. Synergism of the three agents combined (UCN-01 plus celecoxib plus radiation) were evaluated using ...

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

Menée sur 12 patients atteints d'un lymphome non cutané à cellules T ou d'une leucémie à grands lymphocytes granuleux, cette étude évalue l'efficacité d'un traitement par photophérèse extracorporelle

Extracorporeal photopheresis as a curative treatment strategy in non epidermotropic T-cell lymphoma and large granular lymphocyte leukemia
• Annals of Oncology, sous presse, 2012 (résumé)

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Menée sur 12 patients atteints d'un lymphome non cutané à cellules T ou d'une leucémie à grands lymphocytes granuleux, cette étude évalue l'efficacité d'un traitement par photophérèse extracorporelle

“Extracorporeal photopheresis as a curative treatment strategy in non epidermotropic T-cell lymphoma and large granular lymphocyte leukemia”

• Garban, F.;Carras, S.;Drillat, P.;Jacob, M. C.;Fabre, B.;Callanan, M.;Courby, S.;Makowski, C.;Cahn, J. Y.;Gressin, R.

Background: To evaluate the efficacy of extracorporeal photopheresis (ECP) in noncutaneous T-cell lymphoma and large granular lymphocytes leukemia (LGL).Patients and methods: We have treated 12 refractory/relapsed patients. Six peripheral T-cell lymphoma (PTCL), one T-lymphoblastic lymphoma and five LGL with blood involvement received six biweekly leukapheresis as induction phase, followed by one course a week for 4 weeks as consolidation and one course of maintenance per month for responders until progression/relapse or disappearance of the peripheral clone.Results: Six patients responded to phototherapy. Two PTCL and two LGL achieved a complete response (CR) and two other PTCL a partial response. The median duration of CR was 117 months (45–150 months) for these four patients. The peripheral clone followed by flow cytometry decreased in all six responders. Two patients with a complete disappearance of the peripheral clone have not relapsed.Conclusions: As for cutaneous T-cell ...

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

Traitements localisés : applications cliniques

Menée sur 50 patientes atteintes d'un cancer du sein unilatéral de stade 0-II et traitées par chirurgie conservatrice, cette étude identifie les facteurs ne permettant pas une irradiation partielle accélérée du sein par radiothérapie conformationnelle 3D

Identifying Patients Who Are Unsuitable for Accelerated Partial Breast Irradiation Using Three-dimensional External Beam Conformal Techniques
• International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)

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Menée sur 50 patientes atteintes d'un cancer du sein unilatéral de stade 0-II et traitées par chirurgie conservatrice, cette étude identifie les facteurs ne permettant pas une irradiation partielle accélérée du sein par radiothérapie conformationnelle 3D

“Identifying Patients Who Are Unsuitable for Accelerated Partial Breast Irradiation Using Three-dimensional External Beam Conformal Techniques”

• Shikama, Naoto;Nakamura, Naoki;Kunishima, Naoaki;Hatanaka, Shogo;Sekiguchi, Kenji

Several recent studies reported that severe late toxicities including soft-tissue fibrosis and fat necrosis are present in patients treated with accelerated partial breast irradiation (APBI) and that these toxicities are associated with the large volume of tissue targeted by high-dose irradiation. The present study was performed to clarify which patients are unsuitable for APBI to avoid late severe toxicities. Study subjects comprised 50 consecutive patients with Stage 0−II unilateral breast cancer who underwent breast-conserving surgery, and in whom five or six surgical clips were placed during surgery. All patients were subsequently replanned using three-dimensional conformal radiotherapy (3D-CRT) APBI techniques according to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39 and Radiation Therapy Oncology Group (RTOG) 0413 protocol. The beam arrangements included mainly noncoplanar four- or five-field beams using 6-MV photons alone. Dose–volume histogram (DVH) ...

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

Menée sur 145 patientes atteintes d'un carcinome canalaire in situ du sein traité par chirurgie conservatrice et radiothérapie entre 1980 et 1993 (durée médiane de suivi :19,3 ans), cette étude rétrospective évalue les résultats cliniques à long terme du point de vue de la récidive ipsilatérale et de la survie

Long-Term Outcome in Patients with Ductal Carcinoma in situ Treated with Breast-Conserving Therapy: Implications for Optimal Follow-up Strategies
• International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)

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Menée sur 145 patientes atteintes d'un carcinome canalaire in situ du sein traité par chirurgie conservatrice et radiothérapie entre 1980 et 1993 (durée médiane de suivi :19,3 ans), cette étude rétrospective évalue les résultats cliniques à long terme du point de vue de la récidive ipsilatérale et de la survie

“Long-Term Outcome in Patients with Ductal Carcinoma in situ Treated with Breast-Conserving Therapy: Implications for Optimal Follow-up Strategies”

• Shaitelman, Simona F.;Wilkinson, J. Ben;Kestin, Larry L.;Ye, Hong;Goldstein, Neal S.;Martinez, Alvaro A.;Vicini, Frank A.

To determine 20-year rates of local control and outcome-associated factors for ductal carcinoma in situ (DCIS) after breast-conserving therapy (BCT). All DCIS cases receiving BCT between 1980 and 1993 were reviewed. Patient demographics and pathologic factors were analyzed for effect on outcomes, including ipsilateral breast tumor recurrence (IBTR) and survival. One hundred forty-five cases were evaluated; the median follow-up time was 19.3 years. IBTR developed in 25 patients, for 5-, 10-, 15-, and 20-year actuarial rates of 9.9%, 12.2%, 13.7%, and 17.5%, respectively. One third of IBTRs were elsewhere failures, and 68% of IBTRs occurred <10 years after diagnosis. Young age and cancerization of lobules predicted for IBTR at <10 years, and increased slide involvement and atypical ductal hyperplasia were associated with IBTR at later time points. Patients with DCIS treated with BCT have excellent long-term rates of local control. Predictors of IBTR vary over time, and the risk of ...

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

A partir des données du registre américain du cancer portant sur 6 933 patients (âge médian : 70 ans) atteints d'un carcinome broncho-alvéolaire de stade I / III diagnostiqué entre 2001 et 2007 et non réséqué, cette étude montre que la radiothérapie améliore la survie globale à 2 ans des patients

Radiotherapy Improves Survival in Unresected Stage I–III Bronchoalveolar Carcinoma
• International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)

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A partir des données du registre américain du cancer portant sur 6 933 patients (âge médian : 70 ans) atteints d'un carcinome broncho-alvéolaire de stade I / III diagnostiqué entre 2001 et 2007 et non réséqué, cette étude montre que la radiothérapie améliore la survie globale à 2 ans des patients

“Radiotherapy Improves Survival in Unresected Stage I–III Bronchoalveolar Carcinoma”

• Urban, Damien;Mishra, Mark;Onn, Amir;Dicker, Adam P.;Symon, Zvi;Pfeffer, M. Raphael;Lawrence, Yaacov Richard

To test the hypothesis that radiotherapy (RT) improves the outcome of patients with unresected, nonmetastatic bronchoalveolar carcinoma (BAC) by performing a population-based analysis within the Surveillance, Epidemiology, and End Results (SEER) registry. Inclusion criteria were as follows: patients diagnosed with BAC, Stage I–III, between 2001 and 2007. Exclusion criteria included unknown stage, unknown primary treatment modality, Stage IV disease, and those diagnosed at autopsy. Demographic data, treatment details, and overall survival were retrieved from the SEER database. Survival was analyzed using the Kaplan-Meier method and log–rank test. A total of 6933 patients with Stage I–III BAC were included in the analysis. The median age at diagnosis was 70 years (range, 10–101 years). The majority of patients were diagnosed with Stage I (74.4%); 968 patients (14%) did not undergo surgical resection. Unresected patients were more likely to be older (p < 0.0001), male (p = ...

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

Traitements systémiques : découverte et développement

Cette étude évalue l'efficacité de nanovecteurs incluant des anticorps spécifiques pour acheminer des molécules thérapeutiques dans les tumeurs de glioblastome

Antibody-Targeted Nanovectors for the Treatment of Brain Cancers
• ACS Nano, sous presse, 2012 (résumé)

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Cette étude évalue l'efficacité de nanovecteurs incluant des anticorps spécifiques pour acheminer des molécules thérapeutiques dans les tumeurs de glioblastome

“Antibody-Targeted Nanovectors for the Treatment of Brain Cancers”

• Sharpe, Martyn A.;Marcano, Daniela C.;Berlin, Jacob M.;Widmayer, Marsha A.;Baskin, David S.;Tour, James M.

Introduced here is the hydrophilic carbon clusters (HCCs) antibody drug enhancement system (HADES), a methodology for cell-specific drug delivery. Antigen-targeted, drug-delivering nanovectors are manufactured by combining specific antibodies with drug-loaded poly(ethylene glycol)?HCCs (PEG?HCCs). We show that HADES is highly modular, as both the drug and antibody component can be varied for selective killing of a range of cultured human primary glioblastoma multiforme. Using three different chemotherapeutics and three different antibodies, without the need for covalent bonding to the nanovector, we demonstrate extreme lethality toward glioma, but minimal toxicity toward human astrocytes and neurons.

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

Menée in vitro sur des lignées cellulaires de neuroblastome, cette étude met en évidence un mécanisme par lequel les facteurs de transcription FOXO, en interagissant avec le promoteur du gène PDGFRA, régulent la différenciation cellulaire induite par un traitement au TPA (12-O-tétra-décanoyl-phorbol 13 acétate)

Regulation of neuroblastoma differentiation by forkhead transcription factors FOXO1/3/4 through the receptor tyrosine kinase PDGFRA
• Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)

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Menée in vitro sur des lignées cellulaires de neuroblastome, cette étude met en évidence un mécanisme par lequel les facteurs de transcription FOXO, en interagissant avec le promoteur du gène PDGFRA, régulent la différenciation cellulaire induite par un traitement au TPA (12-O-tétra-décanoyl-phorbol 13 acétate)

“Regulation of neuroblastoma differentiation by forkhead transcription factors FOXO1/3/4 through the receptor tyrosine kinase PDGFRA”

• Mei, Yang;Wang, Zhanxiang;Zhang, Lei;Zhang, Yiru;Li, Xiaoyu;Liu, Huihui;Ye, Jing;You, Han

Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial early event in neuroblastoma pathogenesis is arrested differentiation of neuroblasts at various stages. Treatment of neuroblastoma with TPA and PDGF-BB leads to terminal differentiation of neuroblastoma cells. However, the signaling pathways that are involved in this process remain largely unknown. Here, we report that inhibition of endogenous FOXO proteins attenuated TPA/PDGF-BB mediated differentiation of neuroblastoma cells. Activated FOXO transcription factors acted on PDGFRA promoter to direct its basal mRNA expression as well as its induction upon serum deprivation. Depletion of endogenous PDGFRA in neuroblastoma cells significantly diminished neurite formation and extension under TPA/PDGF-BB treatment. Furthermore, ectopic expression of PDGFRA abolished the blockage of neuroblastoma differentiation by FOXOs inhibition. These findings define the ...

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

Cet article passe en revue les perspectives offertes par le ciblage de la voie de signalisation du facteur de croissance analogue à l'insuline pour le traitement des cancers du sein

Targeting insulin-like growth factor in breast cancer therapeutics
• Critical Reviews in Oncology/Hematology, sous presse, 2012 (résumé)

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Cet article passe en revue les perspectives offertes par le ciblage de la voie de signalisation du facteur de croissance analogue à l'insuline pour le traitement des cancers du sein

“Targeting insulin-like growth factor in breast cancer therapeutics”

• Karamouzis, Michalis V.;Papavassiliou, Athanasios G.

The insulin-like growth factor (IGF) pathway holds crucial role in cell growth, differentiation and proliferation. Aberrant regulation of the IGF system has been attributed to the pathogenesis of breast cancer and has been shown to contribute to various stages of breast carcinogenesis. Therefore, targeting the IGF-related axis represents a promising strategy, mainly aiming to bypass the resistance of currently employed treatment options in breast cancer patients. Nevertheless, major limitations have aroused despite the early stage of clinical development of various IGF-system modulators. The present review highlights the current status and considers the future perspectives of IGF-system targeting in breast cancer therapeutics.

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

Menée in vitro, cette étude évalue la faisabilité d'une méthode à base de bibliothèques d'ADN complémentaire pour identifier des antigènes associés aux tumeurs susceptibles d'induire une réponse antitumorale dans le traitement du mélanome

Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma
• Nature Biotechnology, sous presse, 2012 (résumé)

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Menée in vitro, cette étude évalue la faisabilité d'une méthode à base de bibliothèques d'ADN complémentaire pour identifier des antigènes associés aux tumeurs susceptibles d'induire une réponse antitumorale dans le traitement du mélanome

“Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma”

• Pulido, Jose;Kottke, Timothy;Thompson, Jill;Galivo, Feorillo;Wongthida, Phonphimon;Diaz, Rosa Maria;Rommelfanger, Diana;Ilett, Elizabeth;Pease, Larry;Pandha, Hardev;Harrington, Kevin;Selby, Peter;Melcher, Alan;Vile, Richard

Multiple intravenous injections of a cDNA library, derived from human melanoma cell lines and expressed using the highly immunogenic vector vesicular stomatitis virus (VSV), cured mice with established melanoma tumors. Successful tumor eradication was associated with the ability of mouse lymphoid cells to mount a tumor-specific CD4+ interleukin (IL)-17 recall response in vitro. We used this characteristic IL-17 response to screen the VSV-cDNA library and identified three different VSV-cDNA virus clones that, when used in combination but not alone, achieved the same efficacy against tumors as the complete parental virus library. VSV-expressed cDNA libraries can therefore be used to identify tumor rejection antigens that can cooperate to induce anti-tumor responses. This technology should be applicable to antigen discovery for other cancers, as well as for other diseases in which immune reactivity against more than one target antigen contributes to disease pathology.

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

Mené sur 38 patients atteints d'une leucémie réfractaire ou récidivante (âge médian : 69 ans), cet essai de phase II évalue la toxicité et l'efficacité du ruxolitinib, un inhibiteur sélectif de JAK

Phase II study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including post myeloproliferative neoplasms (MPN) acute myeloid leukemia (AML)
• Blood, sous presse, 2012 (résumé)

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Mené sur 38 patients atteints d'une leucémie réfractaire ou récidivante (âge médian : 69 ans), cet essai de phase II évalue la toxicité et l'efficacité du ruxolitinib, un inhibiteur sélectif de JAK

“Phase II study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including post myeloproliferative neoplasms (MPN) acute myeloid leukemia (AML)”

• Eghtedar, Alireza;Verstovsek, Srdan;Estrov, Zeev;Burger, Jan;Cortes, Jorge;Bivins, Carol;Faderl, Stefan;Ferrajoli, Alessandra;Borthakur, Gautam;George, Solly;Scherle, Peggy A;Newton, Robert C;Kantarjian, Hagop M;Ravandi, Farhad

We conducted a phase II study of ruxolitinib in patients with relapsed/refractory leukemias. Patients with acceptable performance status (0-2), adequate organ function and no active infection, received ruxolitinib 25 mg orally twice a day for four weeks (1 cycle). Response was assessed after every 2 cycles of treatment and patients who completed 2 cycles were allowed to continue treatment until disease progression. Dose escalation to 50 mg twice daily was permitted in patients demonstrating a benefit. Thirty-eight patients, with a median age of 69 (range, 45-88), were treated. The median number of prior therapies was 2 (range, 1-6). Twelve patients had JAK2V617F mutation. Patients received a median of 2 cycles of therapy (range, 1-22). Three of 18 patients with post-MPN AML showed a significant response; two achieved complete remission (CR) and one achieved a CR with insufficient recovery of blood counts (CRi). The responding patients with palpable spleens also had significant ...

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

Cet article passe en revue les travaux récents en matière d'immunothérapie à base d'anticorps pour le traitement des cancers

Antibody-Based Immunotherapy of Cancer
• Cell, Vol. 148 (6), pp. 1081-1084, 2012 (article en libre accès)

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Cet article passe en revue les travaux récents en matière d'immunothérapie à base d'anticorps pour le traitement des cancers

“Antibody-Based Immunotherapy of Cancer”

• Weiner, Louis M;Murray, Joseph C;Shuptrine, Casey W

By targeting surface antigens expressed on tumor cells, monoclonal antibodies have demonstrated efficacy as cancer therapeutics. Recent successful antibody-based strategies have focused on enhancing antitumor immune responses by targeting immune cells, irrespective of tumor antigens. We discuss these innovative strategies and propose how they will impact the future of antibody-based cancer therapy.

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

Cet article passe en revue les perspectives offertes par les thérapies cellulaires adoptives pour le traitement des mélanomes et d'autres types de cancer

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer
• Journal of Translational Medicine, Vol. 10 (1), pp. 48, 2012 (article en libre accès)

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Cet article passe en revue les perspectives offertes par les thérapies cellulaires adoptives pour le traitement des mélanomes et d'autres types de cancer

“New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer”

• Stroncek, David;Berger, Carolina;Cheever, Martin;Childs, Richard;Dudley, Mark;Flynn, Peter;Gattinoni, Luca;Heath, James;Kalos, Micheal;Marincola, Francesco;Miller, Jeffery;Mostoslavsky, Gustavo;Powell, Daniel;Rao, Mahendra;Restifo, Nicholas;Rosenberg, Steven;O'Shea, John;Melief, Cornelis

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naive and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies.

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

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'une leucémie myéloïde chronique ou d'un cancer du poumon non à petites cellules présentant des mutations du gène EGFR, cette étude identifie un polymorphisme du gène BIM associé à la réponse à un traitement par inhibiteur de tyrosine kinase chez des patients asiatiques

A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer
• Nature Medicine, sous presse, 2012 (résumé)

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Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'une leucémie myéloïde chronique ou d'un cancer du poumon non à petites cellules présentant des mutations du gène EGFR, cette étude identifie un polymorphisme du gène BIM associé à la réponse à un traitement par inhibiteur de tyrosine kinase chez des patients asiatiques

“A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer”

• Ng, King Pan;Hillmer, Axel M.;Chuah, Charles T. H.;Juan, Wen Chun;Ko, Tun Kiat;Teo, Audrey S. M.;Ariyaratne, Pramila N.;Takahashi, Naoto;Sawada, Kenichi;Fei, Yao;Soh, Sheila;Lee, Wah Heng;Huang, John W. J.;Allen, John C.;Woo, Xing Yi;Nagarajan, Niranjan;Kumar, Vikrant;Thalamuthu, Anbupalam;Poh, Wan Ting;Ang, Ai Leen;Mya, Hae Tha;How, Gee Fung;Yang, Li Yi;Koh, Liang Piu;Chowbay, Balram;Chang, Chia-Tien;Nadarajan, Veera S.;Chng, Wee Joo;Than, Hein;Lim, Lay Cheng;Goh, Yeow Tee;Zhang, Shenli;Poh, Dianne;Tan, Patrick;Seet, Ju-Ee;Ang, Mei-Kim;Chau, Noan-Minh;Ng, Quan-Sing;Tan, Daniel S. W.;Soda, Manabu;Isobe, Kazutoshi;Nothen, Markus M.;Wong, Tien Y.;Shahab, Atif;Ruan, Xiaoan;Cacheux-Rataboul, Valere;Sung, Wing-Kin;Tan, Eng Huat;Yatabe, Yasushi;Mano, Hiroyuki;Soo, Ross A.;Chin, Tan Min;Lim, Wan-Teck;Ruan, Yijun;Ong, S. Tiong

Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor–mutated non–small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be ...

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

A partir de données portant sur une immunothérapie dans le cancer de la prostate, cette étude évalue la faisabilité d'une méthode de simulation numérique personnalisée de la réponse à ce type de traitement

Reconsidering the Paradigm of Cancer Immunotherapy by Computationally Aided Real-Time Personalization
• Cancer Research, sous presse, 2012 (résumé)

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A partir de données portant sur une immunothérapie dans le cancer de la prostate, cette étude évalue la faisabilité d'une méthode de simulation numérique personnalisée de la réponse à ce type de traitement

“Reconsidering the Paradigm of Cancer Immunotherapy by Computationally Aided Real-Time Personalization”

• Kogan, Yuri;Halevi-Tobias, Karin;Elishmereni, Moran;Vuk-Pavlović, Stanimir;Agur, Zvia

Although therapeutic vaccination often induces markers of tumor specific immunity, therapeutic responses remain rare. An improved understanding of patient-specific dynamic interactions of immunity and tumor progression, combined with personalized application of immune therapeutics would increase the efficacy of immunotherapy. Here, we developed a method to predict and enhance the individual response to immunotherapy by using personalized mathematical models, constructed in the early phase of treatment. Our approach includes an iterative real-time in-treatment evaluation of patient-specific parameters from the accruing clinical data, construction of personalized models and their validation, model-based simulation of subsequent response to ongoing therapy, and suggestion of potentially more effective patientspecific modified treatment. Using a mathematical model of prostate cancer immunotherapy, we applied our model to data obtained in a clinical investigation of an allogeneic ...

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

Cet article passe en revue les travaux récents sur le rôle des cils cellulaires primaires dans la progression d'un cancer et la réponse à un inhibiteur de la voie Hedgehog

Molecular Pathways: The Role of Primary Cilia in Cancer Progression and Therapeutics with a Focus on Hedgehog Signaling
• Clinical Cancer Research, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le rôle des cils cellulaires primaires dans la progression d'un cancer et la réponse à un inhibiteur de la voie Hedgehog

“Molecular Pathways: The Role of Primary Cilia in Cancer Progression and Therapeutics with a Focus on Hedgehog Signaling”

• Hassounah, Nadia Bassam;Bunch, Thomas Allen;McDermott, Kimberly Marie

Abnormal Hedgehog (Hh) pathway activity has been reported in many cancers including basal cell carcinomas, medulloblastomas, rhabdomyosarcomas, glioblastomas, breast and prostate cancers. For this reason the Hh pathway is a flourishing area for development of anti-cancer drugs such as Hh ligand antagonists (e.g. 5E1, robotnikinin), Smo inhibitors (e.g. GDC-0449, IPI-926) and Gli transcriptional activity inhibitors (e.g. GANT58, GANT61). In vertebrate cells it is now clear that primary cilia are required for activation of the Hh pathway in normal cells. It is in the primary cilium that both positive and negative effectors of the Hh pathway are processed by post-translational modifications. In many cancers, preliminary results suggest that primary cilia are lost. As drugs are developed that inhibit different steps of the Hh pathway, it is important to consider how these drugs will function in the context of primary cilia in the tumor environment. We will discuss why some of the Hh ...

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

Menée sur trois lignées cellulaires de cancer colorectal, cette étude met en évidence la modulation, par un inhibiteur de mTOR, de l'activité d'une combinaison d'inhibiteurs de MEK et PI3K

The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition
• British Journal of Cancer, sous presse, 2012 (résumé)

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Menée sur trois lignées cellulaires de cancer colorectal, cette étude met en évidence la modulation, par un inhibiteur de mTOR, de l'activité d'une combinaison d'inhibiteurs de MEK et PI3K

“The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition”

• Haagensen, E. J.;Kyle, S.;Beale, G. S.;Maxwell, R. J.;Newell, D. R.

Background: Combined targeting of MAPK and PI3K signalling pathways may be necessary for optimal therapeutic activity in cancer. This study evaluated the MEK inhibitors AZD6244 and PD0325901, alone and in combination with the dual mTOR/PI3K inhibitor NVP-BEZ235 or the PI3K inhibitor GDC-0941, in three colorectal cancer cell lines. Methods: Growth inhibition, survival and signal transduction were measured using the Sulforhodamine B assay, clonogenicity and western blotting, respectively, in HCT116, HT29 and DLD1 cell lines. Results: All MEK/PI3K inhibitor combinations exhibited marked synergistic growth inhibition; however, GDC-0941 displayed greater synergy in combination with either MEK inhibitor. NVP-BEZ235 exhibited stronger inhibition of 4EBP1 phosphorylation, and similar inhibition of S6 and AKT phosphorylation, compared with GDC-0941. Both PD0325901 and AZD6244 inhibited ERK phosphorylation, and with MEK/PI3K inhibitor combinations inhibition of S6 phosphorylation was increased. ...

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

Traitements systémiques : applications cliniques

Cet article passe en revue les travaux récents sur la capécitabine seule en traitement de première ligne pour les patientes atteintes d'un cancer du sein HER2- métastatique

Capecitabine Monotherapy: Review of Studies in First-Line HER-2-Negative Metastatic Breast Cancer
• The Oncologist, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur la capécitabine seule en traitement de première ligne pour les patientes atteintes d'un cancer du sein HER2- métastatique

“Capecitabine Monotherapy: Review of Studies in First-Line HER-2-Negative Metastatic Breast Cancer”

• O'Shaughnessy, Joyce A.;Kaufmann, Manfred;Siedentopf, Friederike;Dalivoust, Philippe;Debled, Marc;Robert, Nicholas J.;Harbeck, Nadia

Abstract The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel ...

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

Mené sur 229 patientes atteintes d'un cancer du sein HER2- localement avancé ou métastatique, cet essai de phase IIB évalue, du point de vue de la survie sans progression, les effets de l'ajout de sorafenib à un traitement à base de capecitabine

Sorafenib in Combination With Capecitabine: An Oral Regimen for Patients With HER2-Negative Locally Advanced or Metastatic Breast Cancer
• Journal of Clinical Oncology, sous presse, 2012 (résumé)

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Mené sur 229 patientes atteintes d'un cancer du sein HER2- localement avancé ou métastatique, cet essai de phase IIB évalue, du point de vue de la survie sans progression, les effets de l'ajout de sorafenib à un traitement à base de capecitabine

“Sorafenib in Combination With Capecitabine: An Oral Regimen for Patients With HER2-Negative Locally Advanced or Metastatic Breast Cancer”

• Baselga, José;Segalla, José Getúlio Martins;Roché, Henri;del Giglio, Auro;Pinczowski, Hélio;Ciruelos, Eva M.;Filho, Sebastião Cabral;Gómez, Patricia;Van Eyll, Brigitte;Bermejo, Begoña;Llombart, Antonio;Garicochea, Bernardo;Durán, Miguel Ángel Climent;Hoff, Paulo Marcelo Gehm;Espié, Marc;de Moraes, Andre Augusto Junior Gemeinder;Ribeiro, Ronaldo Albuquerque;Mathias, Clarissa;Gil Gil, Miguel;Ojeda, Belén;Morales, Josefa;Kwon Ro, Sunhee;Li, Shell;Costa, Frederico

Purpose Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) –negative breast cancer.Patients and Methods Patients were randomly assigned to first- or second-line capecitabine 1,000 mg/m2 orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS).Results In total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement ...

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

Mené sur 202 patients coréens atteints d'un cancer avancé de l'estomac, cet essai de phase III évalue les effets, du point de vue de la survie globale, d'une chimiothérapie de sauvetage à base de docetaxel ou d'irinotecan

Salvage Chemotherapy for Pretreated Gastric Cancer: A Randomized Phase III Trial Comparing Chemotherapy Plus Best Supportive Care With Best Supportive Care Alone
• Journal of Clinical Oncology, sous presse, 2012 (résumé)

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Mené sur 202 patients coréens atteints d'un cancer avancé de l'estomac, cet essai de phase III évalue les effets, du point de vue de la survie globale, d'une chimiothérapie de sauvetage à base de docetaxel ou d'irinotecan

“Salvage Chemotherapy for Pretreated Gastric Cancer: A Randomized Phase III Trial Comparing Chemotherapy Plus Best Supportive Care With Best Supportive Care Alone”

• Kang, Jung Hun;Lee, Soon Il;Lim, Do Hyoung;Park, Keon-Woo;Oh, Sung Yong;Kwon, Hyuk-Chan;Hwang, In Gyu;Lee, Sang-Cheol;Nam, Eunmi;Shin, Dong Bok;Lee, Jeeyun;Park, Joon Oh;Park, Young Suk;Lim, Ho Yeong;Kang, Won Ki;Park, Se Hoon

Purpose When designing this trial, there was no evidence that salvage chemotherapy (SLC) in advanced gastric cancer (AGC) resulted in substantial prolongation of survival when compared with best supportive care (BSC). However, SLC is often offered to pretreated patients with AGC for anecdotal reasons.Patients and Methods Patients with AGC with one or two prior chemotherapy regimens involving both fluoropyrimidines and platinum and with an Eastern Cooperative Oncology Group performance status (PS) 0 or 1 were randomly assigned in a ratio of 2:1 to SLC plus BSC or BSC alone. Choice of SLC—either docetaxel 60 mg/m2 every 3 weeks or irinotecan 150 mg/m2 every 2 weeks—was left to the discretion of investigators. Primary end point was overall survival (OS).Results Median OS was 5.3 months among 133 patients in the SLC arm and 3.8 months among 69 patients in the BSC arm (hazard ratio, 0.657; 95% CI, 0.485 to 0.891; one-sided P = .007). OS benefit for SLC was consistent in most of the ...

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

Menée sur des lignées cellulaires et 50 patients atteints d'un cancer colorectal métastatique, cette étude préclinique suivie par un essai de phase II évalue l'efficacité et la toxicité d'un traitement combinant cetuximab et erlotinib

Dual Targeting of the Epidermal Growth Factor Receptor Using the Combination of Cetuximab and Erlotinib: Preclinical Evaluation and Results of the Phase II DUX Study in Chemotherapy-Refractory, Advanced Colorectal Cancer
• Journal of Clinical Oncology, sous presse, 2012 (résumé)

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Menée sur des lignées cellulaires et 50 patients atteints d'un cancer colorectal métastatique, cette étude préclinique suivie par un essai de phase II évalue l'efficacité et la toxicité d'un traitement combinant cetuximab et erlotinib

“Dual Targeting of the Epidermal Growth Factor Receptor Using the Combination of Cetuximab and Erlotinib: Preclinical Evaluation and Results of the Phase II DUX Study in Chemotherapy-Refractory, Advanced Colorectal Cancer”

• Weickhardt, Andrew J.;Price, Tim J.;Chong, Geoff;Gebski, Val;Pavlakis, Nick;Johns, Terrance G.;Azad, Arun;Skrinos, Effie;Fluck, Kate;Dobrovic, Alexander;Salemi, Renato;Scott, Andrew M.;Mariadason, John M.;Tebbutt, Niall C.

Purpose This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC).Patients and Methods The activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m2 as a loading dose and then weekly cetuximab 250 mg/m2 with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design.Results Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the ...
Dual Blockade of Epidermal Growth Factor Receptor–Induced Pathways: A New Avenue to Treat Metastatic Colorectal Cancer
• Journal of Clinical Oncology, sous presse, 2012 (commentaire)

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Menée sur des lignées cellulaires et 50 patients atteints d'un cancer colorectal métastatique, cette étude préclinique suivie par un essai de phase II évalue l'efficacité et la toxicité d'un traitement combinant cetuximab et erlotinib

“Dual Blockade of Epidermal Growth Factor Receptor–Induced Pathways: A New Avenue to Treat Metastatic Colorectal Cancer”

• Laurent-Puig, Pierre ; Manceau, Gilles ; Zucman-Rossi, Jessica ; Blons, Hélène

Mots clés : Colon-rectum; Traitements (Traitements systémiques : applications cliniques)

A partir d'une revue de la littérature, cette méta-analyse (6 essais, 3 060 patients) évalue l'efficacité du bevacizumab en traitement de première ligne d'un cancer colorectal métastatique

Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups
• BMC Cancer, Vol. 12 (1), pp. 89, 2012 (article en libre accès)

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A partir d'une revue de la littérature, cette méta-analyse (6 essais, 3 060 patients) évalue l'efficacité du bevacizumab en traitement de première ligne d'un cancer colorectal métastatique

“Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups”

• Macedo, Ligia;Lima, Andre;Sasse, Andre

BACKGROUND:Bevacizumab has an important role in first-line treatment of metastatic colorectal cancer. However, clinical trials studying its effect have involved distinct chemotherapy regimens with divergent results. The aim of this meta-analysis is to gather current data and evaluate not only the efficacy of bevacizumab, but also the impact of divergent backbone regimens.METHODS:A wide search of randomized clinical trials using bevacizumab in first-line metastatic colorectal cancer was performed in Embase, MEDLINE, LILACS and Cochrane databases. Meeting presentations and abstracts were also investigated. The resulting data were examined and included in the meta-analysis according to the type of regimen.RESULTS:Six trials, totaling 3060 patients, were analyzed. There was an advantage to using bevacizumab for overall survival (OS) and progression-free survival (PFS) (HR = 0.84; CI: 0.77-0.91; P < 0.00001 and HR = 0.72; CI: 0.66-0.78; P < 0.00001, respectively). However, heterogeneity of ...

Mots clés : Colon-rectum; Traitements (Traitements systémiques : applications cliniques)

Cet article passe en revue les travaux récents sur le diagnostic et le traitement des cancers d'origine primitive inconnue

Cancer of unknown primary site
• The Lancet, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le diagnostic et le traitement des cancers d'origine primitive inconnue

“Cancer of unknown primary site”

• Pavlidis, Nicholas;Pentheroudakis, George

Cancer of unknown primary site (CUP) is a well recognised clinical disorder, accounting for 3?5% of all malignant epithelial tumours. CUP is clinically characterised as an aggressive disease with early dissemination. Diagnostic approaches to identify the primary site include detailed histopathological examination with specific immunohistochemistry and radiological assessment. Gene-profiling microarray diagnosis has high sensitivity, but further prospective study is necessary to establish whether patients' outcomes are improved by its clinical use. Metastatic adenocarcinoma is the most common CUP histopathology (80%). CUP patients are divided into subsets of favourable (20%) and unfavourable (80%) prognosis. Favourable subsets are mostly given locoregional treatment or systemic platinum-based chemotherapy. Responses and survival are similar to those of patients with relevant known primary tumours. Patients in unfavourable subsets are treated with empirical chemotherapy based on ...

Mots clés : Autres organes; Traitements (Traitements systémiques : applications cliniques)

Cet article passe en revue les travaux récents sur le diagnostic et les traitements du rétinoblastome

Retinoblastoma
• The Lancet, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le diagnostic et les traitements du rétinoblastome

“Retinoblastoma”

• Dimaras, Helen;Kimani, Kahaki;Dimba, Elizabeth A. O.;Gronsdahl, Peggy;White, Abby;Chan, Helen S. L.;Gallie, Brenda L.

Retinoblastoma is an aggressive eye cancer of infancy and childhood. Survival and the chance of saving vision depend on severity of disease at presentation. Retinoblastoma was the first tumour to draw attention to the genetic aetiology of cancer. Despite good understanding of its aetiology, mortality from retinoblastoma is about 70% in countries of low and middle income, where most affected children live. Poor public and medical awareness, and an absence of rigorous clinical trials to assess innovative treatments impede progress. Worldwide, most of the estimated 9000 newly diagnosed patients every year will die. However, global digital communications present opportunities to optimise standards of care for children and families affected by this rare and often devastating cancer. Parents are now leading the effort for widespread awareness of the danger of leucocoria. Genome-level technologies could make genetic testing a reality for every family affected by retinoblastoma. Best-practice ...

Mots clés : Autres organes; Traitements (Traitements systémiques : applications cliniques)

Combinaison de traitements localisés et systémiques

Menée sur 163 patients atteints d'un carcinome épidermoïde oropharyngé de stade avancé (durée médiane de suivi : 36 mois), cette étude rétrospective évalue, du point de vue de la survie globale, du contrôle loco-régional et de l'absence de métastases distantes, l'efficacité d'un traitement combinant une radiothérapie avec modulation d'intensité et une chimiothérapie concomitante ou séquentielle

Treatment of oropharyngeal squamous cell carcinoma with IMRT: patterns of failure after concurrent chemoradiotherapy and sequential therapy
• Annals of Oncology, sous presse, 2012 (résumé)

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Menée sur 163 patients atteints d'un carcinome épidermoïde oropharyngé de stade avancé (durée médiane de suivi : 36 mois), cette étude rétrospective évalue, du point de vue de la survie globale, du contrôle loco-régional et de l'absence de métastases distantes, l'efficacité d'un traitement combinant une radiothérapie avec modulation d'intensité et une chimiothérapie concomitante ou séquentielle

“Treatment of oropharyngeal squamous cell carcinoma with IMRT: patterns of failure after concurrent chemoradiotherapy and sequential therapy”

• Sher, D. J.;Thotakura, V.;Balboni, T. A.;Norris, C. M.;Haddad, R. I.;Posner, M. R.;Lorch, J.;Goguen, L. A.;Annino, D. J.;Tishler, R. B.

Background: The optimal management of oropharyngeal squamous cell carcinoma (OPSCC) is controversial. Modern radiotherapy typically employs intensity-modulated radiation therapy (IMRT), and herein, we report the Dana-Farber Cancer Institute (DFCI) experience with IMRT-based treatment of OPSCC.Design: Retrospective study of all patients treated at DFCI for OPSCC with definitive or adjuvant IMRT between 8/04 and 8/09. The primary end point was overall survival (OS); secondary end points were locoregional control (LRC) and freedom from distant metastases (FFDM). Propensity score matching was used to create concurrent chemoradiotherapy (CCRT) and sequential therapy (ST) cohorts equally balanced for patient and disease characteristics.Results: One hundred and sixty-three patients were included with 75% presenting with stage IV disease. Fifty-six patients (34%) were treated with ST. The three-year actuarial OS, LRC, and FFDM rates for the entire cohort/ST subset were 86%/89%, 86%/87%, and ...

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

A partir des données de l'essai randomisé "UKW3" portant sur 718 patients pédiatriques présentant une tumeur de Wilms, cette étude évalue, en fonction des traitements et des caractéristiques clinicopathologiques de la maladie, la survie sans événement et la survie globale à 5 ans des patients

Treatment and outcome of Wilms’ tumour patients: an analysis of all cases registered in the UKW3 trial
• Annals of Oncology, sous presse, 2012 (résumé)

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A partir des données de l'essai randomisé "UKW3" portant sur 718 patients pédiatriques présentant une tumeur de Wilms, cette étude évalue, en fonction des traitements et des caractéristiques clinicopathologiques de la maladie, la survie sans événement et la survie globale à 5 ans des patients

“Treatment and outcome of Wilms’ tumour patients: an analysis of all cases registered in the UKW3 trial”

• Pritchard-Jones, K.;Moroz, V.;Vujanić, G.;Powis, M.;Walker, J.;Messahel, B.;Hobson, R.;Levitt, G.;Kelsey, A.;Mitchell, C.

Background: The randomised findings of the UKW3 trial were that preoperative chemotherapy was associated with a more advantageous stage distribution and reduction in therapy burden versus immediate nephrectomy without compromising outcome in localised Wilms’ tumour (WT). We analysed outcome in all WT registered in UKW3.Patients and methods: Seven hundred and eighteen WT cases (7% anaplastic) were registered in UKW3. We assigned a treatment stage and conducted survival analysis.Results: Five-year event-free survival (EFS) and overall survival (OS) were 77.2% [95% confidence interval (CI) 73.9–80.2] and 87.5% (95% CI 84.8–89.7) after median follow-up of 9.5 years and 10.0 years, respectively. Five-year OS in localised non-anaplastic cases was 92.9% (95% CI 90.2–94.9). Anaplasia was associated with adverse outcome compared with non-anaplastic cases: 5-year EFS of 42.0% (95% CI 28.3–55.1) versus 79.8% (95% CI 76.5–82.7) and 5-year OS of 60% (95% CI 45.1–72.0) versus 89.6% ...

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

Mené sur 13 patients atteints d'un cancer du poumon non à petites cellules de stade avancé, cet essai de phase I évalue la dose maximale tolérable de fludarabine, un analogue de l'adénosine, en combinaison avec une radiothérapie concomitante

Fludarabine combined with radiotherapy in patients with locally advanced NSCLC lung carcinoma: a phase I study
• Journal of Cancer Research and Clinical Oncology, sous presse, 2012 (résumé)

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Mené sur 13 patients atteints d'un cancer du poumon non à petites cellules de stade avancé, cet essai de phase I évalue la dose maximale tolérable de fludarabine, un analogue de l'adénosine, en combinaison avec une radiothérapie concomitante

“Fludarabine combined with radiotherapy in patients with locally advanced NSCLC lung carcinoma: a phase I study”

• Nitsche, Mirko;Christiansen, Hans;Lederer, Katinka;Griesinger, Frank;Schmidberger, Heinz;Pradier, Olivier

Background and purpose Fludarabine is an adenine nucleoside analogue that has significant activity in hematological malignancies and has shown promising activity in combination with radiation in preclinical solid tumor models. We designed a phase I trial exploring concurrent fludarabine and radiotherapy in patients with advanced non-small cell lung cancer (NSCLC) to determine the maximum tolerated dose (MTD) of fludarabine given with concurrent irradiation. Materials and methods Thirteen patients with stage IIIB NSCLC received thoracic irradiation of 60 Gy. Fludarabine was administered during the 5th and 6th week of radiotherapy. Doses started at 10 mg/m 2 per day and increased by steps of 3 mg/m 2 per day. Results At a daily dose of 16 mg/m 2 , one out of six patients developed a grade 4 leukopenia, and one a grad 3 pneumonitis. Further grade III toxicity was not observed. The dose of 13 mg/m 2 was identified as the MTD. All patients developed a fludarabine dose-dependent ...

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

Menée à partir de lignées cellulaires de cancer du pancréas et à l'aide de xénogreffes, cette étude évalue l'intérêt d'associer à une radiothérapie un traitement ciblant la voie de signalisation des protéines kinases MAPK et PI3K

Co-Targeting MAPK and PI3K Signaling with Concurrent Radiotherapy as a Strategy for the Treatment of Pancreatic Cancer
• Molecular Cancer Therapeutics, sous presse, 2012 (résumé)

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Menée à partir de lignées cellulaires de cancer du pancréas et à l'aide de xénogreffes, cette étude évalue l'intérêt d'associer à une radiothérapie un traitement ciblant la voie de signalisation des protéines kinases MAPK et PI3K

“Co-Targeting MAPK and PI3K Signaling with Concurrent Radiotherapy as a Strategy for the Treatment of Pancreatic Cancer”

• Williams, Terence M;Flecha, Athena R;Keller, Paul;Ram, Ashwin;Karnak, David;Galban, Stefanie;Galban, Craig J;Ross, Brian D;Lawrence, Theodore S;Rehemtulla, Alnawaz;Sebolt-Leopold, Judith

There is an urgent need for the development of novel therapies to treat pancreatic cancer, which is among the most lethal of all cancers. KRAS activating mutations, which are found in >90% of pancreatic adenocarcinomas, drive tumor dependency on the Ras/MAPK and Akt signaling pathways. Radiation is currently being explored as a component of the standard treatment regimen for pancreatic cancer. This study's purpose was to test the hypothesis that MEK inhibitors will offer clear therapeutic benefit when integrated into radiotherapy treatment regimens for treatment of this disease. We explored the activation of the MAPK and Akt pathways in response to radiation in multiple pancreatic tumor cell lines. Small molecule inhibitors of MEK (PD0325901) and Akt (API-2) were subsequently evaluated for their radiosensitizing potential alone and in combination. In vivo efficacy was tested in subcutaneous MiaPaCa2 xenografts. Phosphorylated levels of ERK-1/2 and Akt were found to increase in ...

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

Menée sur 62 patients atteints d'un cancer de l'œsophage (âge : 38 à 86 ans ; durée médiane de suivi : 20,1 mois), cette étude prospective évalue la toxicité et l'efficacité d'un traitement combinant protonthérapie et chimiothérapie concomitante

Proton Beam Therapy and Concurrent Chemotherapy for Esophageal Cancer
• International journal of radiation oncology, biology, physics, sous presse, 2012 (résumé)

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Menée sur 62 patients atteints d'un cancer de l'œsophage (âge : 38 à 86 ans ; durée médiane de suivi : 20,1 mois), cette étude prospective évalue la toxicité et l'efficacité d'un traitement combinant protonthérapie et chimiothérapie concomitante

“Proton Beam Therapy and Concurrent Chemotherapy for Esophageal Cancer”

• Lin, Steven H.;Komaki, Ritsuko;Liao, Zhongxing;Wei, Caimiao;Myles, Bevan;Guo, Xiaomao;Palmer, Matthew;Mohan, Radhe;Swisher, Stephen G.;Hofstetter, Wayne L.;Ajani, Jaffer A.;Cox, James D.

Proton beam therapy (PBT) is a promising modality for the management of thoracic malignancies. We report our preliminary experience of treating esophageal cancer patients with concurrent chemotherapy (CChT) and PBT (CChT/PBT) at MD Anderson Cancer Center. This is an analysis of 62 esophageal cancer patients enrolled on a prospective study evaluating normal tissue toxicity from CChT/PBT from 2006 to 2010. Patients were treated with passive scattering PBT with two- or three-field beam arrangement using 180 to 250 MV protons. We used the Kaplan-Meier method to assess time-to-event outcomes and compared the distributions between groups using the log–rank test. The median follow-up time was 20.1 months for survivors. The median age was 68 years (range, 38–86). Most patients were males (82%) who had adenocarcinomas (76%) and Stage II-III disease (84%). The median radiation dose was 50.4 Gy (RBE [relative biologic equivalence]) (range, 36–57.6). The most common grade 2 to 3 acute ...

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

Ressources et infrastructures (Traitements)

Cet article analyse la controverse relative à la réforme du système des essais cliniques à l'ère des traitements personnalisés du cancer

Redefining Clinical Trials: The Age of Personalized Medicine
• Cell, Vol. 148 (6), pp. 1079-1080, 2012 (résumé)

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Cet article analyse la controverse relative à la réforme du système des essais cliniques à l'ère des traitements personnalisés du cancer

“Redefining Clinical Trials: The Age of Personalized Medicine”

• Vaidyanathan, Gayathri

The triumph of personalized cancer therapeutics in recent years is prompting some oncologists to rethink clinical trial design; other researchers have different priorities for trial reform.

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

Cet article évalue les perspectives offertes par l'intégration d'informations de nature pharmacogénomique dans les essais cliniques de phase II

Pharmacogenomics in Early Phase Oncology Clinical Trials: Is There a Sweet Spot in Phase II?
• Clinical Cancer Research, sous presse, 2012 (résumé)

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Cet article évalue les perspectives offertes par l'intégration d'informations de nature pharmacogénomique dans les essais cliniques de phase II

“Pharmacogenomics in Early Phase Oncology Clinical Trials: Is There a Sweet Spot in Phase II?”

• O'Donnell, Peter H;Stadler, Walter M

Many clinical trials of oncology drugs now include at least a consideration of pharmacogenomics, the study of germline or acquired genetic factors governing a drug's response and toxicity. Besides the potential benefit to patients from the consideration of personalized pharmacogenomic information when making treatment decisions, there is a clear incentive for oncology drug developers to incorporate pharmacogenomic factors in the drug development process since pharmacogenomic biomarkers may allow predictive characterization of sub-populations within a disease that may particularly respond, or may allow pre-identification of patients at highest risk for adverse events. There is, however, a lack of agreement in actual practice as to where in the oncology clinical drug development process pharmacogenomic studies should be incorporated. In this article, we examine the recent growth of pharmacogenomics in oncology clinical trials, especially in early phase studies, and examine several ...

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

En mettant en parallèle les mécanismes de résistance thérapeutique dans les maladies infectieuses et dans le cancer, cet article analyse les défis posés au développement de traitements anticancéreux efficaces à long terme

Converting Cancer Therapies into Cures: Lessons from Infectious Diseases
• Cell, Vol. 148 (6), pp. 1089-1098, 2012 (article en libre accès)

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En mettant en parallèle les mécanismes de résistance thérapeutique dans les maladies infectieuses et dans le cancer, cet article analyse les défis posés au développement de traitements anticancéreux efficaces à long terme

“Converting Cancer Therapies into Cures: Lessons from Infectious Diseases”

• Glickman, Michael S;Sawyers, Charles L

During the past decade, cancer drug development has shifted from a focus on cytotoxic chemotherapies to drugs that target specific molecular alterations in tumors. Although these drugs dramatically shrink tumors, the responses are temporary. Research is now focused on overcoming drug resistance, a frequent cause of treatment failure. Here we reflect on analogous challenges faced by researchers in infectious diseases. We compare and contrast the resistance mechanisms arising in cancer and infectious diseases and discuss how approaches for overcoming viral and bacterial infections, such as HIV and tuberculosis, are instructive for developing a more rational approach for cancer therapy. In particular, maximizing the effect of the initial treatment response, which often requires synergistic combination therapy, is foremost among these approaches. A remaining challenge in both fields is identifying drugs that eliminate drug-tolerant persister cells (infectious disease) or ...

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

Cet article passe en revue les diverses techniques permettant d'évaluer l'activité antitumorale d'un agent thérapeutique au cours d'un essai de phase II

A paradigm shift in tumour response evaluation of targeted therapy: the assessment of novel drugs in exploratory clinical trials
• Current Opinion in Oncology, sous presse, 2012 (résumé)

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Cet article passe en revue les diverses techniques permettant d'évaluer l'activité antitumorale d'un agent thérapeutique au cours d'un essai de phase II

“A paradigm shift in tumour response evaluation of targeted therapy: the assessment of novel drugs in exploratory clinical trials”

• Cousin, Sophie;Taieb, Sophie;Penel, Nicolas

Purpose of review: To describe the difficulty in assessing the biological activity of a novel agent in phase II trials. Recent findings: Two major fields of research provide interesting new potential endpoints: endpoints based on new imaging techniques (e.g. PET or spectral imaging that explore tumour metabolism, dynamic contrast enhanced (DCE) ultrasonography or DCE-MRI that explore tumour vascularization and tumour growth inhibition) and endpoints integrating assessment of tumour burden across time, such as the growth modulation index. Summary: Most of the recently described techniques appear attractive, but require formal validation. (C) 2012 Lippincott Williams & Wilkins, Inc.

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

Cet article passe en revue les travaux en cours à l'Institut Gustave Roussy pour transférer en pratique clinique les résultats d'essais de traitements personnalisés du cancer

The challenge to bring personalized cancer medicine from clinical trials into routine clinical practice: the case of the Institut Gustave Roussy
• Molecular Oncology, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux en cours à l'Institut Gustave Roussy pour transférer en pratique clinique les résultats d'essais de traitements personnalisés du cancer

“The challenge to bring personalized cancer medicine from clinical trials into routine clinical practice: the case of the Institut Gustave Roussy”

• Arnedos, Monica;André, Fabrice;Farace, Françoise;Lacroix, Ludovic;Besse, Benjamin;Robert, Caroline;Soria, Jean Charles;Eggermont, Alexander M. M.

Research with high throughput technologies has propitiated the segmentation of different types of tumors into very small subgroups characterized by the presence of very rare molecular alterations. The identification of these subgroups and the apparition of new agents targeting these infrequent alterations are already affecting the way in which clinical trials are being conducted with an increased need to identify those patients harboring specific molecular alterations. In this review we describe some of the currently ongoing and future studies at the Institut Gustave Roussy that aim for the identification of potential therapeutic targets for cancer patients with the incorporation of high throughput technologies into daily practice including aCGH, next generation sequencing and the creation of a software that allows for target identification specific for each tumor. The initial intention is to enrich clinical trials with cancer patients carrying certain molecular alterations in order ...