Menée in vitro, cette étude montre que la différenciation mésenchymateuse dépendant du facteur nucléaire

Mesenchymal Differentiation Mediated by NF-

Bhat, Krishna P L. ; Balasubramaniyan, Veerakumar ; Vaillant, Brian ; Ezhilarasan, Ravesanker ; Hummelink, Karlijn ; Hollingsworth, Faith ; Wani, Khalida ; Heathcock, Lindsey ; James, Johanna D ; Goodman, Lindsey D ; Conroy, Siobhan ; Long, Lihong ; Lelic, Nina ; Wang, Suzhen ; Gumin, Joy ; Raj, Divya ; Kodama, Yoshinori ; Raghunathan, Aditya ; Olar, Adriana ; Joshi, Kaushal ; Pelloski, Christopher E ; Heimberger, Amy ; Kim, Se Hoon ; Cahill, Daniel P ; Rao, Ganesh ; Den Dunnen, Wilfred F A. ; Boddeke, Hendrikus W G. M. ; Phillips, Heidi S ; Nakano, Ichiro ; Lang, Frederick F ; Colman, Howard ; Sulman, Erik P ; Aldape, Kenneth

Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-

Menée sur 575 patients atteints d'un cancer de la prostate localisé traité entre 2006 et 2012 (âge : 40 à 76 ans ; durée moyenne de suivi : 30 mois), cette étude évalue l'efficacité, du point de vue du taux de marges de résection positives et de la survie globale sans récidive biochimique à 5 ans, d'une prostatectomie radicale endoscopique extrapéritonéale

Five-year oncological outcomes of endoscopic extraperitoneal radical prostatectomy (EERPE) for prostate cancer: results from a medium-volume UK centre

McNeill, S. Alan ; Good, Daniel W. ; Stewart, Grant D. ; Stolzenburg, Jens-Uwe

Objective : To determine the 5-year oncological outcomes of endoscopic extraperitoneal radical prostatectomy (EERPE) from a medium-volume centre, thereby providing much needed data on outcomes from the UK. Patients and Methods : From January 2006 to January 2012, 575 patients underwent EERPE for localized prostate cancer, performed by a single surgeon who had completed a modular training programme. Follow-up was as per local hospital policy and data were collected in our prospective database. A [...]

Menée sur 387 patients atteints d'un cancer rectal traité par résection entre janvier 2000 et décembre 2009, cette étude évalue, du point de vue de la régression tumorale, de la récidive locale et de la survie sans maladie, l'efficacité d'une chimioradiothérapie intensifiée (106 cas)

Prognosis of rectal cancer patients improves with downstaging by intensified neoadjuvant radiochemotherapy - a matched pair analysis

Schiffmann, Leif ; Klautke, Gunther ; Wedermann, Nicole ; Gock, Michael ; Prall, Friedrich ; Fietkau, Rainer ; Rau, Bettina ; Klar, Ernst

BACKGROUND : Neoadjuvant radiochemotherapy has been proven superior to adjuvant treatment in reducing the rate of local recurrence without impairing cancer related survival or the incidence of distant metastases in standard protocols of neoadjuvant radiochemotherapy. The present study aimed at addressing the effects of an intensified neoadjuvant radiochemotherapy on long term cancer related and disease free survival. METHODS : A total of 387 patients underwent oncologic resection for rectal [...]

Cet article passe en revue les perspectives offertes par des combinaisons de deux thérapies ciblant un membre de la famille des récepteurs à activité tyrosine kinase ERBB pour le traitement des cancers

Targeting the ERBB family in cancer: couples therapy

Tebbutt, Niall ; Pedersen, Mikkel W. ; Johns, Terrance G.

The ERBB family of receptor tyrosine kinases has a central role in the tumorigenesis of many types of solid tumour. Various therapeutics targeting these receptors have been approved for the treatment of several cancers. Considerable preclinical data have shown that the administration of two inhibitors against an individual ERBB family member — particularly epidermal growth factor receptor (EGFR) or ERBB2 — leads to markedly higher antitumour activity than the administration of single agents. [...]

Menée in vitro et in vivo sur des modèles de cancer du sein et du poumon, cette étude suggère l'intérêt thérapeutique d'une stratégie basée sur l'inhibition de l'hexokinase 2

Hexokinase 2 Is Required for Tumor Initiation and Maintenance and Its Systemic Deletion Is Therapeutic in Mouse Models of Cancer

Patra, Krushna C ; Wang, Qi ; Bhaskar, Prashanth T ; Miller, Luke ; Wang, Zebin ; Wheaton, Will ; Chandel, Navdeep ; Laakso, Markku ; Muller, William J ; Allen, Eric L ; Jha, Abhishek K ; Smolen, Gromoslaw A ; Clasquin, Michelle F ; Robey, R.  Brooks ; Hay, Nissim

Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, but only in a limited number of normal adult tissues. Using Hk2 conditional knockout mice, we showed that HK2 is required for tumor initiation and maintenance in mouse models of KRas-driven lung cancer, and ErbB2-driven breast cancer, despite continued HK1 expression. Similarly, HK2 ablation [...]

Cet article passe en revue les perspectives offertes par les connaissances récentes sur le métabolisme tumoral pour développer des stratégies thérapeutiques basées sur l'induction d'une "catastrophe métabolique" dans les cellules des tumeurs en expansion rapide

Disrupting proton dynamics and energy metabolism for cancer therapy

Parks, Scott K. ; Chiche, Johanna ; Pouyssegur, Jacques

Intense interest in the 'Warburg effect' has been revived by the discovery that hypoxia-inducible factor 1 (HIF1) reprogrammes pyruvate oxidation to lactic acid conversion; lactic acid is the end product of fermentative glycolysis. The most aggressive and invasive cancers, which are often hypoxic, rely on exacerbated glycolysis to meet the increased demand for ATP and biosynthetic precursors and also rely on robust pH-regulating systems to combat the excessive generation of lactic and carbonic [...]

Menée sur des lignées cellulaires de glioblastome et de mélanome, cette étude suggère que l'inhibition des kinases ATM et ATR augmente la sensibilité des cellules cancéreuses au témolozomide

Contribution of ATM and ATR to the resistance of glioblastoma and malignant melanoma cells to the methylating anticancer drug temozolomide

Eich, Marcus ; Roos, Wynand Paul ; Nikolova, Theodora ; Kaina, Bernd

The major cytotoxic DNA adduct induced by temozolomide and other methylating agents used in malignant glioma and metastasized melanoma therapy is O6-methylguanine. This primary DNA damage is converted by mismatch repair into secondary lesions, which block replication and in turn induce DNA double-strand breaks that trigger the DNA damage response (DDR). Key upstream players in the DDR are the PI3 kinases ATM and ATR. Here we addressed the question of the importance of ATM and ATR in the cell [...]

Cet article passe en revue les travaux récents sur le développement d'inhibiteurs sélectifs de protéines méthyltransférases pour le traitement des cancers

Molecular Pathways: Protein methyltransferases in cancer

Copeland, Robert A

The protein methyltransferases (PMTs) constitute a large and important class of enzymes that catalyze site-specific methylation of lysine or arginine residues on histones and other proteins. Site-specific histone methylation is a critical component of chromatin regulation of gene transcription - a pathway that is often genetically altered in human cancers. Oncogenic alterations (e.g., mutations, chromosomal translocations and others) of PMTs, or of associated proteins, have been found to confer [...]

Cet article passe en revue les travaux récents sur le développement de molécules mimétiques de BH3 pour le traitement des cancers

BH3 Mimetics: Status of the Field and New Developments

Billard, Christian

Targeting apoptosis is an attractive approach in cancer therapy. The BH3-only proteins of the BCL-2 family (having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this family and neutralizing their functional activity (sequestration of the proapoptotic Bcl-2 family members). The “BH3 mimetic” concept has prompted the development of small molecules capable of mimicking BH3-only proteins and thus inducing apoptosis. The prototype BH3 mimetic [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels un blocage ciblé de CD73 renforce l'activité antitumorale d'un anticorps monoclonal anti¨PD-1 ou anti CTLA-4

Targeting CD73 enhances the anti-tumor activity of anti-PD-1 and anti-CTLA-4 mAbs

Allard, Bertrand ; Pommey, Sandra ; Smyth, Mark J. ; Stagg, John

Purpose: Monoclonal antibodies (mAb) that block programmed death (PD)-1 or cytotoxic T lymphocyte antigen (CTLA-4) receptors have been associated with durable clinical responses against a variety of cancer types and hold great potential as novel cancer therapeutics. Recent evidence suggest that targeted blockade of multiple immunosuppressive pathways can induce synergistic anti-tumor responses. Experimental Design: In this study, we investigated whether targeted blockade of CD73, an [...]

Menée in vitro, cette étude suggère l'intérêt d'anticorps anti CD62L, en combinaison avec une chimiothérapie standard, pour le traitement des patients atteints d'une leucémie lymphocytaire chronique

CD62L as a therapeutic target in chronic lymphocytic leukemia

Burgess, Melinda ; Gill, Devinder S. ; Singhania, Richa ; Cheung, Catherine ; Chambers, Lynne ; Reynolds, Brent A. ; Smith, Louise ; Mollee, Peter ; Saunders, Nicholas A. ; McMillan, Nigel A.

Purpose: Despite advances in the treatment of chronic lymphocytic leukemia (CLL), the disease remains incurable with standard therapies and relapse is inevitable. A growing body of evidence indicates that alterations in the adhesion properties of neoplastic cells play a pivotal role in the development and progression of CLL. Experimental Design: The expression of 71 cell surface molecules was examined on CLL PBMCs over 3 weeks in culture. The most highly up-regulated marker, CD62L, was examined [...]

Menée à l'aide d'un modèle murin de cancer épithélial de l'ovaire, cette étude met en évidence des mécanismes par lesquels des anticorps anti PD1 ou PD-L1 renforcent l'efficacité de mécanismes immunitaires antitumoraux

Therapeutic PD-1 Pathway Blockade Augments with other Modalities of Immunotherapy to Prevent Immune Decline in Ovarian Cancer

Duraiswamy, Jaikumar ; Freeman, Gordon J ; Coukos, George

The tumor microenvironment mediates induction of the immunosuppressive programmed death-1 (PD-1) pathway, targeted interventions against which can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1) expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence l'intérêt du sorafenib pour surmonter une résistance à l'irinotecan chez les patients atteints d'un cancer colorectal, notamment pour les tumeurs présentant des mutations du gène KRAS

Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump

Mazard, Thibault ; Causse, Annick ; Simony, Joelle ; Leconet, Wilhem ; Vezzio-Vie, Nadia ; Torro, Adeline ; Jarlier, Marta ; Evrard, Alexandre ; Del Rio, Maguy ; Assenat, Eric ; Martineau, Pierre ; Ychou, Marc ; Robert, Bruno ; Gongora, Celine

Despite recent advances in the treatment of colorectal cancer, tumor resistance is a frequent cause of chemotherapy failure. Thus, new treatment options are needed to improve survival of patients with irinotecan-refractory colorectal cancers, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based [...]

Menée à l'aide de modèles murins de cancer du sein "basal-like" triplement négatif, cette étude évalue l'intérêt de l'inhibition du protéasome pour réduire la croissance tumorale et prévenir le processus métastatique

A Genome-wide siRNA Screen Identifies Proteasome Addiction as a Vulnerability of Basal-like Triple-Negative Breast Cancer Cells

Petrocca, Fabio ; Altschuler, Gabriel ; Tan, Shen Mynn ; Mendillo, Marc L ; Yan, Haoheng ; Jerry, D.  Joseph ; Kung, Andrew L ; Hide, Winston ; Ince, Tan A ; Lieberman, Judy

Basal-like triple-negative breast cancers (TNBCs) have poor prognosis. To identify basal-like TNBC dependencies, a genome-wide siRNA lethality screen compared two human breast epithelial cell lines transformed with the same genes: basal-like BPLER and myoepithelial HMLER. Expression of the screen s 154 BPLER dependency genes correlated with poor prognosis in breast, but not lung or colon, cancer. Proteasome genes were overrepresented hits. Basal-like TNBC lines were selectively sensitive to [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes de cancer du sein triplement négatif, cette étude évalue l'activité antitumorale d'un composé par voie orale appelé AMG 900, seul ou en combinaison avec un inhibiteur de la fonction des microtubules (taxane ou épothilone)

AMG 900, a small molecule inhibitor of aurora kinases, potentiates the activity of microtubule-targeting agents in human metastatic breast cancer models

Bush, Tammy L. ; Payton, Marc ; Heller, Scott ; Chung, Grace ; Hanestad, Kelly ; Rottman, James B ; Loberg, Robert ; Friberg, Gregory ; Kendall, Richard L. ; Saffran, Douglas ; Radinsky, Robert

Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer deaths, where death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubule-targeting agents (MTAs) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent and highly selective pan-aurora kinase inhibitor that is active [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels un dérivé de l'indirubine, 6BIO, inhibe le processus métastatique d'un cancer du sein

Indirubin derivative 6BIO suppresses metastasis

Braig, Simone ; Kressirer, Christine A. ; Liebl, Johanna ; Bischoff, Fabian ; Zahler, Stefan ; Meijer, Laurent ; Vollmar, Angelika M.

While metastasis is the chief cause of cancer mortality, there nonetheless remains a lack of anti-metastatic therapies that are clinically available. In this study, we present the indirubin derivative 6-bromo-indirubin-3'-oxime (6BIO) as a promising antimetastatic agent. 6BIO strongly reduced formation of lung metastasis in the well-established 4T1 mouse model of aggressive breast cancer. Several major hallmarks of the metastatic process were affected by subtoxic concentrations of 6BIO, which [...]

Mené sur 15 patients atteints d'un cancer et présentant une hypercalcémie, cet essai de preuve de concept évalue l'intérêt du dénosumab pour réduire le niveau de calcium sérique corrigé en fonction du niveau d'albumine

Denosumab for Patients With Persistent or Relapsed Hypercalcemia of Malignancy Despite Recent Bisphosphonate Treatment

Hu, Mimi I. ; Glezerman, Ilya ; Leboulleux, Sophie ; Insogna, Karl ; Gucalp, Rasim ; Misiorowski, Waldemar ; Yu, Bennett ; Ying, Wendy ; Jain, Rajul K.

Hypercalcemia of malignancy (HCM), caused primarily by tumor-induced bone resorption, may lead to renal failure, coma, and death. Although HCM can be treated with intravenous bisphosphonates, patients may not respond or may relapse on therapy. Denosumab binds the bone resorption mediator RANKL. In this single-arm, open-label, proof-of-concept study, HCM patients with albumin-corrected serum calcium (CSC) levels greater than 12.5mg/dL (Common Terminology Criteria for Adverse Events grade ≥3) [...]

Mené sur 20 patients atteints d'un cancer du poumon non à petites cellules de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale d'un traitement combinant erlotinib et cetuximab

Combining Erlotinib and Cetuximab is Associated with Activity in Patients with Non Small Cell Lung Cancer (including Squamous Cell Carcinomas) and Wild-Type EGFR or Resistant Mutations

Wheler, Jennifer J. ; Tsimberidou, Apostolia M. ; Falchook, Gerald S. ; Zinner, Ralph G. ; Hong, David S. ; Fok, Jansina Y. ; Fu, Siqing ; Piha-Paul, Sarina A. ; Naing, Aung ; Kurzrock, Razelle

Preclinical data suggest that combined epidermal growth factor receptor (EGFR) targeting with an EGFR tyrosine kinase inhibitor and an anti-EGFR monoclonal antibody may be superior over single-agent targeting. Therefore, as part of a phase I study, we analyzed the outcome of 20 patients with non-small cell lung cancer treated with the combination of erlotinib and cetuximab. EGFR mutation status was ascertained in a CLIA-approved lab. There were 10 men; median number of prior therapies, 5. [...]

Menée sur 136 patients atteints d'un lymphome primitif cutané à cellules B sans métastase extra-cutanée ou ganglionnaire distante et traités dans un centre canadien de lutte contre le cancer entre 1981 et 2011 (âge médian au diagnostic : 62 ans), cette étude analyse les caractéristiques cliniques de la maladie, les traitements utilisés ainsi que leur efficacité du point de vue du contrôle de la maladie et de la survie à 5 ans

Treatment and Outcomes in Patients With Primary Cutaneous B-cell Lymphoma : The BC Cancer Agency Experience

Hamilton, Sarah N. ; Wai, Elaine S. ; Tan, King ; Alexander, Cheryl ; Gascoyne, Randy D. ; Connors, Joseph M.

To review the treatment and outcomes of patients with primary cutaneous B-cell lymphoma (CBCL). Clinical characteristics, treatment, and outcomes were analyzed for all patients referred to our institution from 1981 through 2011 with primary CBCL without extracutaneous or distant nodal spread at diagnosis (n=136). Hematopathologists classified 99% of cases using the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) guidelines. Median age at [...]

Mené sur 126 patients atteints d'un cancer de l'œsophage, cet essai randomisé de phase II évalue l'intérêt d'ajouter une chimiothérapie d'induction par oxaliplatine-5-fluorouracile à une chimioradiothérapie pré-opératoire pour améliorer le taux de réponse pathologique complète et prolonger la survie des patients

A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer

Ajani, J. A. ; Xiao, L. ; Roth, J. A. ; Hofstetter, W. L. ; Walsh, G. ; Komaki, R. ; Liao, Z. ; Rice, D. C. ; Vaporciyan, A. A. ; Maru, D. M. ; Lee, J. H. ; Bhutani, M. S. ; Eid, A. ; Yao, J. C. ; Phan, A. P. ; Halpin, A. ; Suzuki, A. ; Taketa, T. ; Thall, P. F. ; Swisher, S. G.

Background : The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR). Methods : Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted 5–6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), [...]

Menée sur 453 patients atteints d'un cancer de la prostate avec risque intermédiaire ou élevé de récidive et traités entre 1990 et 2011, cette étude identifie les facteurs associés à la réponse à un traitement néoadjuvant anti-androgénique combiné à une radiothérapie définitive

Factors associated with improved biochemical response to neoadjuvant androgen deprivation therapy before definitive radiation therapy in prostate cancer patients

Cerne, J. Z. ; McGuire, S. E. ; Grant, S. R. ; Munsell, M. F. ; Lee, A. K. ; Kudchadker, R. J. ; Choi, S. L. ; Mahmood, U. ; Hoffman, K. E. ; Pugh, T. J. ; Frank, S. J. ; Kuban, D. A.

Background : In prostate cancer patients treated with androgen deprivation therapy (ADT) and radiation therapy (RT), a pre-RT PSA level greater than or equal to 0.5 ng ml−1, determined after neoadjuvant ADT and before RT, predicts for worse survival measures. The present study sought to identify patient, tumor and treatment characteristics associated with the pre-RT PSA in prostate cancer patients. Methods : We reviewed the charts of all patients diagnosed with intermediate- and high-risk [...]

Cet article présente un portail de données qui, pour plus de 200 lignées cellulaires cancéreuses, dresse un catalogue de leur sensibilité à 345 petites molécules

An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies Targeted by Small Molecules

Basu, Amrita ; Bodycombe, Nicole E ; Cheah, Jaime H ; Price, Edmund V ; Liu, Ke ; Schaefer, Giannina I ; Ebright, Richard Y ; Stewart, Michelle L ; Ito, Daisuke ; Wang, Stephanie ; Bracha, Abigail L ; Liefeld, Ted ; Wawer, Mathias ; Gilbert, Joshua C ; Wilson, Andrew J ; Stransky, Nicolas ; Kryukov, Gregory V ; Dancik, Vlado ; Barretina, Jordi ; Garraway, Levi A ; Hon, C.  Suk-Yee ; Munoz, Benito ; Bittker, Joshua A ; Stockwell, Brent R ; Khabele, Dineo ; Stern, Andrew M ; Clemons, Paul A ; Shamji, Alykhan F ; Schreiber, Stuart L

The high rate of clinical response to protein-kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell line (CCL) profiling to identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: (1) associate with specific [...]