Menée sur un modèle murin de cancer du sein, cette étude évalue l'efficacité antitumorale d'un protocole thérapeutique comportant une faible dose de cyclophosphamide, un traitement topique à base d'un agoniste du récepteur TLR 7 et une radiothérapie

Synergy of topical Toll-Like Receptor 7 agonist with radiation and low dose cyclophosphamide in a mouse model of cutaneous breast cancer

Dewan, Zahidunnabi ; Vanpouille-Box, Claire ; Kawashima, Noriko ; DiNapoli, Sara ; Babb, James S ; Formenti, Silvia C. ; Adams, Sylvia ; Demaria, Sandra

Purpose: This study tested the hypothesis that topical Toll-Like Receptor (TLR) 7 agonist imiquimod promotes anti-tumor immunity and synergizes with other treatments in a model of skin-involving breast cancer. Experimental Design: TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice. Imiquimod 5% or placebo cream was applied topically on the shaved skin overlying tumors three times/week. In some experiments, local ionizing radiation therapy (RT) was delivered to the tumor in [...]

A partir des données du registre américain des cancers portant sur 7 684 patients atteints d'un cancer du poumon non à petites cellules avec métastases cérébrales diagnostiquées entre 2000 et 2007, cette étude analyse, par rapport à la radiothérapie, le taux d'utilisation annuelle d'une radiochirurgie stéréotaxique ainsi que le coût et les facteurs prédictifs associés

Use of Stereotactic Radiosurgery for Brain Metastases From Non-Small Cell Lung Cancer in the United States

Halasz, Lia M. ; Weeks, Jane C. ; Neville, Bridget A. ; Taback, Nathan ; Punglia, Rinaa S.

The indications for treatment of brain metastases from non-small cell lung cancer (NSCLC) with stereotactic radiosurgery (SRS) remain controversial. We studied patterns, predictors, and cost of SRS use in elderly patients with NSCLC. Using the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we identified patients with NSCLC who were diagnosed with brain metastases between 2000 and 2007. Our cohort included patients treated with radiation therapy and not surgical [...]

Mené sur 151 patientes atteintes d'un cancer du sein de stade Tis-T2 traité par chirurgie conservatrice et curiethérapie interstitielle à haut débit de dose, cet essai de phase II analyse les résultats esthétiques post-opératoires (durée médiane de suivi : 55 mois) et identifie les facteurs prédictifs associés

Cosmetic Analysis Following Breast-Conserving Surgery and Adjuvant High-Dose-Rate Interstitial Brachytherapy for Early-Stage Breast Cancer: A Prospective Clinical Study

Garsa, Adam A. ; Ferraro, Daniel J. ; DeWees, Todd ; Margenthaler, Julie A. ; Naughton, Michael ; Aft, Rebecca ; Gillanders, William E. ; Eberlein, Timothy ; Matesa, Melissa A. ; Zoberi, Imran

To prospectively evaluate cosmetic outcomes in women treated with accelerated partial breast irradiation using high-dose-rate interstitial brachytherapy for early-stage breast cancer. Between 2004 and 2008, 151 patients with early-stage breast cancer were enrolled in a phase 2 prospective clinical trial. Eligible patients had stage Tis-T2 tumors of ≤3 cm that were excised with negative margins and with no nodal involvement. Patients received 3.4 Gy twice daily to a total dose of 34 Gy. Both the [...]

Cette étude met en évidence la structure cristalline d'une oncoprotéine adénovirale, E4-ORF3 , un polymère nucléaire susceptible d'inactiver plusieurs suppresseurs de tumeurs de façon simultanée

A Structural Basis for the Assembly and Functions of a Viral Polymer that Inactivates Multiple Tumor Suppressors

Ou, Horng D ; Kwiatkowski, Witek ; Deerinck, Thomas J ; Noske, Andrew ; Blain, Katie Y ; Land, Hannah S ; Soria, Conrado ; Powers, Colin J ; May, Andrew P ; Shu, Xiaokun ; Tsien, Roger Y ; Fitzpatrick, James A J. ; Long, Jeff A ; Ellisman, Mark H ; Choe, Senyon ; O'Shea, Clodagh C

Evolution of minimal DNA tumor virus' genomes has selected for small viral oncoproteins that hijack critical cellular protein interaction networks. The structural basis for the multiple and dominant functions of adenovirus oncoproteins has remained elusive. E4-ORF3 forms a nuclear polymer and simultaneously inactivates p53, PML, TRIM24, and MRE11/RAD50/NBS1 (MRN) tumor suppressors. We identify oligomerization mutants and solve the crystal structure of E4-ORF3. E4-ORF3 forms a dimer with a [...]

Cet article passe en revue les perspectives offertes par le développement de traitements anticancéreux visant à moduler l'autophagie

Autophagy as a target for cancer therapy: new developments

Jennifer S Carew, ; Kevin R Kelly, S ; teffan T Nawrocki

Autophagy is an evolutionarily conserved lysosomal degradation pathway that eliminates cytosolic proteins, macromolecules, organelles, and protein aggregates. Activation of autophagy may function as a tumor suppressor by degrading defective organelles and other cellular components. However, this pathway may also be exploited by cancer cells to generate nutrients and energy during periods of starvation, hypoxia, and stress induced by chemotherapy. Therefore, induction of autophagy has emerged as [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé GSK126 pour le traitement de patients atteints d'un lymphome diffus à grandes cellules B présentant des mutations du gène EZH2

EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations

McCabe, Michael T. ; Ott, Heidi M. ; Ganji, Gopinath ; Korenchuk, Susan ; Thompson, Christine ; Van Aller, Glenn S. ; Liu, Yan ; Graves, Alan P. ; Iii, Anthony Della Pietra ; Diaz, Elsie ; LaFrance, Louis V. ; Mellinger, Mark ; Duquenne, Celine ; Tian, Xinrong ; Kruger, Ryan G. ; McHugh, Charles F. ; Brandt, Martin ; Miller, William H. ; Dhanak, Dashyant ; Verma, Sharad K. ; Tummino, Peter J. ; Creasy, Caretha L.

In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types. Additionally, somatic heterozygous mutations of Y641 and A677 residues within the [...]

Mené sur un modèle murin, cette étude suggère qu'une thérapie ciblée sur le récepteur bêta du facteur de croissance dérivé des plaquettes, PDGFRB, serait efficace pour le traitement de patients atteints d'un lymphome anaplasique à grandes cellules NPM-ALK

PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas

Laimer, Daniela ; Dolznig, Helmut ; Kollmann, Karoline ; Vesely, Paul W. ; Schlederer, Michaela ; Merkel, Olaf ; Schiefer, Ana-Iris ; Hassler, Melanie R. ; Heider, Susi ; Amenitsch, Lena ; Thallinger, Christiane ; Staber, Philipp B. ; Simonitsch-Klupp, Ingrid ; Artaker, Matthias ; Lagger, Sabine ; Turner, Suzanne D. ; Pileri, Stefano ; Piccaluga, Pier Paolo ; Valent, Peter ; Messana, Katia ; Landra, Indira ; Weichhart, Thomas ; Knapp, Sylvia ; Shehata, Medhat ; Todaro, Maria ; Sexl, Veronika ; Hofler, Gerald ; Piva, Roberto ; Medico, Enzo ; Ruggeri, Bruce A. ; Cheng, Mangeng ; Eferl, Robert ; Egger, Gerda ; Penninger, Josef M. ; Jaeger, Ulrich ; Moriggl, Richard ; Inghirami, Giorgio ; Kenner, Lukas

Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK–triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor [...]

Menée sur des lignées cellulaires d'adénocarcinome canalaire du pancréas et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé BMS-754807, un inhibiteur des récepteurs de l'insuline et de IGF-1, en combinaison avec la gemcitabine

BMS-754807, a Small Molecule Inhibitor of Insulin-like Growth Factor-1 Receptor / Insulin Receptor, Enhances Gemcitabine Response in Pancreatic Cancer

Awasthi, Niranjan ; Zhang, Changhua ; Ruan, Winston ; Schwarz, Margaret A ; Schwarz, Roderich E

Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). Insulin-like growth factor (IGF) signaling proteins are frequently over-expressed in PDAC. The therapeutic potential of BMS-754807, a small molecule inhibitor of IGF-type 1 receptor (IGF-1R) and insulin receptor (IR), and gemcitabine was evaluated in experimental PDAC. Cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and survival studies were performed in [...]

A partir d'un modèle numérique évolutionniste paramétré par des expériences in vitro, cette étude évalue l'intérêt d'une stratégie thérapeutique adaptative basée sur des faibles doses de chimiothérapie pour minimiser l'apparition de clones résistants et augmenter la survie sans progression d'un cancer du sein

Evolutionary approaches to prolong progression-free survival in breast cancer

Silva, Ariosto S ; Kam, Yoonseok ; Khin, Zayar P. ; Minton, Susan E. ; Gillies, Robert J. ; Gatenby, Robert A

Many cancers adapt to chemotherapeutic agents by upregulating membrane efflux pumps that export drugs from the cytoplasm, but this response comes at an energetic cost. In breast cancer patients, expression of these pumps is low in tumors before therapy but increases after treatment. While the evolution of therapeutic resistance is virtually inevitable, proliferation of resistant clones is not, suggesting strategies of adaptive therapy. Chemoresistant cells must consume excess resources to [...]

Menée à l'aide de modèles murins de cancer du sein, cette étude suggère qu'un traitement antiangiogénique à faible dose est susceptible de reprogrammer le microenvironnement tumoral de façon à augmenter l'effet d'une immunothérapie

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy

Huang, Yuhui ; Yuan, Jianping ; Righi, Elda ; Kamoun, Walid S. ; Ancukiewicz, Marek ; Nezivar, Jean ; Santosuosso, Michael ; Martin, John D. ; Martin, Margaret R. ; Vianello, Fabrizio ; Leblanc, Pierre ; Munn, Lance L. ; Huang, Peigen ; Duda, Dan G. ; Fukumura, Dai ; Jain, Rakesh K. ; Poznansky, Mark C.

The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature [...]

Mené sur 171 patients âgés atteints d'une leucémie myéloïde aiguë, cet essai de phase II évalue, du point de vue du taux de réponse complète, l'ajout de bevacizumab à une chimiothérapie de référence

Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase II trial of HOVON/SAKK

Ossenkoppele, Gert J. ; Stussi, Georg ; Maertens, Johan ; van Montfort, Kees ; Biemond, Bart J. ; Breems, Dimitri M. ; Ferrant, August ; Graux, Carlos ; de Greef, Georgine E. ; Halkes, C. J.M. ; Hoogendoorn, Mels ; Hollestein, Rene M. ; Jongen-Lavrencic, Mojca ; Levin, Mark D. ; van de Loosdrecht, Arjan A. ; van Marwijk Kooij, Marinus ; van Norden, Yvette ; Pabst, Thomas ; Schouten, Harry C. ; Vellenga, Edo ; Verhoef, Gregor E.G. ; de Weerdt, Okke ; Wijermans, Pierre ; Passweg, Jakob R. ; Löwenberg, Bob

An urgent need for new treatment modalities is emerging in patients with elderly AML. We hypothesized that targeting VEGF might furnish an effective treatment modality in AML. Elderly patients with AML or RAEB and an IPSS of 1.5 or higher were randomly assigned in this Phase II study (n=171) to receive standard chemotherapy (3+7) with or without bevacizumab at adose of 10 mg/kg iv in 60 minutes at days 1 and 15. In the second cycle patients received cytarabine 1000 mg/m2 twice daily on days 1- [...]

Mené sur 105 patients atteints d'une leucémie myéloïde aiguë et d'âge supérieur ou égal à 70 ans, cet essai de phase II évalue l'efficacité, du point de vue du taux de survie globale à 1 an, et la toxicité de la sapacitabine

Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study

Kantarjian, Hagop ; Faderl, Stefan ; Garcia-Manero, Guillermo ; Luger, Selina ; Venugopal, Parameswaran ; Maness, Lori ; Wetzler, Meir ; Coutre, Steven ; Stock, Wendy ; Claxton, David ; Goldberg, Stuart L. ; Arellano, Martha ; Strickland, Stephen A. ; Seiter, Karen ; Schiller, Gary ; Jabbour, Elias ; Chiao, Judy ; Plunkett, William

Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation [...]

Mené sur 138 patients atteints d'un lymphome anaplasique à grandes cellules, cette étude évalue les résultats à long terme (durée médiane de suivi : 8 ans) de trois essais du Groupe d’Étude des Lymphomes de l’Adulte selon la présence de mutations ALK et l'âge des patients

Long-Term Outcome of Adults With Systemic Anaplastic Large-Cell Lymphoma Treated Within the Groupe d’Étude des Lymphomes de l’Adulte Trials

Sibon, David ; Fournier, Marion ; Briere, Josette ; Lamant, Laurence ; Haioun, Corinne ; Coiffier, Bertrand ; Bologna, Serge ; Morel, Pierre ; Gabarre, Jean ; Hermine, Olivier ; Sonet, Anne ; Gisselbrecht, Christian ; Delsol, Georges ; Gaulard, Philippe ; Tilly, Herve

Purpose Systemic anaplastic large-cell lymphoma (ALCL) is a T-cell lymphoma, whose anaplastic lymphoma kinase (ALK) expression varies according to age. Long-term outcomes of chemotherapy-treated adults are not definitively established and should be evaluated.Patients and Methods Patients treated in three Groupe d’Étude des Lymphomes de l’Adulte prospective clinical trials with confirmed systemic ALCL after immunohistopathologic review and defined ALK expression status were analyzed.Results [...]

Mené sur 68 patients atteints d'un carcinome métastatique à cellules rénales (âge médian : 74 ans), cet essai italien évalue l'efficacité, du point de vue de la survie globale, du sunitinib et la tolérance au traitement de ces patients âgés

Safety and activity of sunitinib in elderly patients (≥70 years) with metastatic renal cell carcinoma: a multicenter study

Brunello, A. ; Basso, U. ; Sacco, C. ; Sava, T. ; De Vivo, R. ; Camerini, A. ; Barile, C. ; Roma, A. ; Maruzzo, M. ; Falci, C. ; Zagonel, V.

Background Actual tolerability of sunitinib is still poorly documented in elderly patients with metastatic renal cell carcinoma (mRCC).Patients and methods Charts of elderly patients treated with sunitinib for mRCC were reviewed in six Italian centers to assess safety (primary objective), efficacy and correlation of toxicity with comprehensive geriatric assessment (CGA) (secondary objectives).Results Sixty-eight patients were eligible, and the median age was 74 years. MGA was carried out in 34 [...]

Mené sur 18 patientes ayant été traitées pour une néoplasie cervicale intra-épithéliale de grade 2 ou 3, cet essai de phase I évalue la réponse du système immunitaire à un vaccin thérapeutique anti HPV 16/18

Immunotherapy Against HPV16/18 Generates Potent TH1 and Cytotoxic Cellular Immune Responses

Bagarazzi, Mark L. ; Yan, Jian ; Morrow, Matthew P. ; Shen, Xuefei ; Parker, R. Lamar ; Lee, Jessica C. ; Giffear, Mary ; Pankhong, Panyupa ; Khan, Amir S. ; Broderick, Kate E. ; Knott, Christine ; Lin, Feng ; Boyer, Jean D. ; Draghia-Akli, Ruxandra ; White, C. Jo ; Kim, J. Joseph ; Weiner, David B. ; Sardesai, Niranjan Y.

Despite the development of highly effective prophylactic vaccines against human papillomavirus (HPV) serotypes 16 and 18, prevention of cervical dysplasia and cancer in women infected with high-risk HPV serotypes remains an unmet medical need. We report encouraging phase 1 safety, tolerability, and immunogenicity results for a therapeutic HPV16/18 candidate vaccine, VGX-3100, delivered by in vivo electroporation (EP). Eighteen women previously treated for cervical intraepithelial neoplasia [...]

A partir d'une revue de la littérature publiée jusqu'en décembre 2011 (4 essais cliniques randomisés ; 3 863 patients), cette méta-analyse évalue l'efficacité à court terme et la toxicité d'une chimioradiothérapie néoadjuvante à base de fluoropyrimidine combinée ou non à l'oxaliplatine chez les patients atteints d'un cancer rectal localement avancé

Short term results of neoadjuvant chemoradiotherapy with fluoropyrimidine alone or in combination with oxaliplatin in locally advanced rectal cancer: A meta analysis

An, Xin ; Lin, Xi ; Wang, Feng-Hua ; Goodman, Karyn ; Cai, Pei-Qiang ; Kong, Ling-Heng ; Fang, Yu-Jing ; Gao, Yuan-Hong ; Lin, Jun-Zhong ; Wan, De-Sen ; Pan, Zhi-Zhong ; Ding, Pei-Rong

Background Oxaliplatin (OX), in combination with fluoropyrimidine (5-fluorouracil or Capecitabine, FU)-based regimens and radiation, has been expected to both enhance primary tumour shrinkage and reduce micrometastases at distant sites in the neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). However, results in terms of pathologic complete response (pCR) and toxicities were inconsistent. The aim of this meta analysis was to evaluate the short term efficacy and [...]

Menée sur 409 patientes atteintes d'un cancer du sein localement avancé, cette étude évalue, du point de vue de la survie sans récidive ou de la survie globale et en fonction du type tumoral, les résultats à long terme d'un traitement systémique néoadjuvant standard suivi d'une intervention chirurgicale combinée à un traitement adjuvant et à une radiothérapie (durée médiane de suivi : 42 mois)

Long-term outcome of neoadjuvant systemic therapy for locally advanced breast cancer in routine clinical practice

Angelucci, Domenico ; Tinari, Nicola ; Grassadonia, Antonino ; Cianchetti, Ettore ; Ausili-Cefaro, Giampiero ; Iezzi, Laura ; Zilli, Marinella ; Grossi, Simona ; Ursini, Lucia ; Scognamiglio, Maria ; Castrilli, Graziella ; De Tursi, Michele ; Noccioli, Paolo ; Cioffi, Pasquale ; Iacobelli, Stefano ; Natoli, Clara

Purpose The aim of this study is to evaluate the long-term outcome of patients with locally advanced breast cancer treated with neoadjuvant systemic chemotherapy (NST) in routine clinical practice. Methods Four hundred and nine patients were identified between January 1999 and December 2011. All patients received NST followed by surgery, adjuvant treatments and radiotherapy, as appropriate. Results At Kaplan–Meier analysis, patients with surgical stage III disease were more likely to develop [...]

Cet article passe en revue les enjeux associés au développement de thérapies ciblées pour le traitement des cancers pédiatriques

Challenges and opportunities in childhood cancer drug development

Norris, Robin E. ; Adamson, Peter C.

Advances made in the treatment of childhood malignancies over the past four decades have resulted in overall 5-year survival rates of approximately 80%. However, despite these advances, several childhood cancers still have unacceptably low cure rates, and, even when treatment is successful, the acute and long-term morbidity of current therapy can be substantial. The development of molecularly targeted anticancer drugs offers the prospect of more effective therapy with fewer side effects, but [...]

Cet article présente les conclusions d'un colloque américain autour du développement de traitements anticancéreux en combinaison

Accelerating Cancer Therapy Development: The Importance of Combination Strategies and Collaboration. Summary of an Institute of Medicine Workshop

LoRusso, Patricia M. ; Canetta, Renzo M ; Wagner, John A ; Balogh, Erin ; Nass, Sharyl J ; Boerner, Scott A. ; Hohneker, John

Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways - even if demonstrating an initial response - often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple [...]

Cet article passe en revue les travaux ayant servi de base à l'autorisation de mise sur le marché, aux Etats-unis et en Europe, du vémurafenib pour le traitement de patients atteints d'un mélanome métastatique

Vemurafenib: the first drug approved for BRAF-mutant cancer

Bollag, Gideon ; Tsai, James ; Zhang, Jiazhong ; Zhang, Chao ; Ibrahim, Prabha ; Nolop, Keith ; Hirth, Peter

The identification of driver oncogenes has provided important targets for drugs that can change the landscape of cancer therapies. One such example is the BRAF oncogene, which is found in about half of all melanomas as well as several other cancers. As a druggable kinase, oncogenic BRAF has become a crucial target of small-molecule drug discovery efforts. Following a rapid clinical development path, vemurafenib (Zelboraf; Plexxikon/Roche) was approved for the treatment of BRAF-mutated [...]