Menée à l'aide d'un modèle murin de glioblastome proneural, cette étude met en évidence l'induction d'un processus protégeant la transcription du gène p53 ainsi que l'évolution du glioblastome proneural vers une forme mésenchymateuse après exposition de la tumeur aux rayonnements ionisants

In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift

Halliday, John ; Helmy, Karim ; Pattwell, Siobhan S. ; Pitter, Kenneth L. ; LaPlant, Quincey ; Ozawa, Tatsuya ; Holland, Eric C.

Glioblastoma is the most common adult primary brain tumor and has a dismal median survival. Radiation is a mainstay of treatment and significantly improves survival, yet recurrence is nearly inevitable. Better understanding the radiation response of glioblastoma will help improve strategies to treat this devastating disease. Here, we present a comprehensive study of the in vivo radiation response of glioma cells in a mouse model of proneural glioblastoma. These tumors are a heterogeneous mix of [...]

Menée sur une cohorte de 1 822 patients atteints d'un cancer de l'œsophage traité par résection entre 1987 et 2010, cette étude rétrospective évalue, du point de vue de la mortalité spécifique et de la mortalité toutes causes confondues à 5 ans, l'intérêt d'une seconde intervention chirurgicale dans les 30 jours suivant la première opération

Reoperation after oesophageal cancer surgery in relation to long-term survival: a population-based cohort study

van der Schaaf, Maartje ; Derogar, Maryam ; Johar, Asif ; Rutegård, Martin ; Gossage, James ; Mason, Robert ; Lagergren, Pernilla ; Lagergren, Jesper

Objectives : The influence of reoperation on long-term prognosis is unknown. In this large population-based cohort study, it was aimed to investigate the influence of a reoperation within 30 days of oesophageal cancer resection on survival even after excluding the initial postoperative period. Design : This was a nationwide population-based retrospective cohort study.Setting All hospitals performing oesophageal cancer resections during the study period (1987–2010) in Sweden. Participants : [...]

A partir d'une revue de la littérature (7 essais de phase I-II, 413 patients), cette étude évalue la faisabilité d'une radiothérapie corporelle stéréotaxique avec hypofractionnement poussé à l'extrême et utilisation d'un accélérateur linéaire non robotisé pour traiter un cancer localisé de la prostate

A Clinical Review on Extreme Hypofractionated Stereotactic Body Radiation Therapy for Localized Prostate Cancer Using Nonrobotic Linear Accelerators

Macias, Victor A. ; Perez-Romasanta, Luis A.

Seven phase I–II studies fell within the inclusion criteria. Details on the radiotherapy technique, patient selection, fractionation scheme, exclusion criteria, treatment toxicity, quality-of-life, and tumor control were collected. The studies provide encouraging results of acute and late toxicity, with rare grade 3 events, that seem comparable to robotic SBRT. The biochemical disease-free survival rates look promising, but most patients belong to the low-risk group. The trials are limited by a [...]

Mené sur 388 patients atteints d'un cancer de la prostate de stade pT3pN0 traité par prostatectomie radicale, cet essai évalue, du point de vue de la survie sans progression et par rapport à un simple suivi médical, l'intérêt d'une radiothérapie adjuvante (durée médiane de suivi : 111 mois)

Adjuvant Radiotherapy Versus Wait-and-See After Radical Prostatectomy : 10-year Follow-up of the ARO 96–02/AUO AP 09/95 Trial

Thomas Wiegel, ; Detlef Bartkowiak, ; Dirk Bottke, ; Claudia Bronner, ; Ursula Steiner, ; Aless, ; ra Siegmann, ; Reinhard Golz, ; Stephan Störkel, ; Normann Willich, ; Axel Semjonow, ; Michael Stöckle, ; Christian Rübe, ; Udo Rebmann, ; Tilman Kälble, ; Horst Jürgen Feldmann, ; Manfred Wirth, ; Rainer Hofmann, ; Rita Engenhart-Cabillic, ; Axel Hinke, ; Wolfgang Hinkelbein c and Kurt Miller b

Background : Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Three prospectively randomized trials demonstrated an advantage for adjuvant radiotherapy (ART) compared with a wait-and-see (WS) policy. Objective : To determine the efficiency of ART after a 10-yr follow-up in the ARO 96–02 study. Design, setting, and participants : After RP, 388 patients with pT3 pN0 prostate cancer (PCa) were randomized to WS or three-dimensional [...]

Cet article passe en revue les travaux récents suggérant différentes approches pour améliorer l'efficacité du sorafenib dans le traiement d'un carcinome hépatocellulaire

New biological perspectives for the improvement of the efficacy of sorafenib in hepatocellular carcinoma

Galmiche, Antoine ; Chauffert, Bruno ; Barbare, Jean-Claude

Sorafenib, an orally-available kinase inhibitor, is the only medical treatment with a proven efficacy against Hepatocellular Carcinoma (HCC). Although the overall clinical efficacy of sorafenib is modest, recent experimental results have uncovered new potential strategies that may increase its clinical benefits. The potential implication of Receptor Tyrosine Kinases (RTKs), such as the Epidermal Growth Factor Receptor (EGFR), in the development of resistance to sorafenib highlights the [...]

Cet article passe en revue les travaux récents sur le développement de thérapies ciblées anti-HER2 dans diverses localisations tumorales

HER2 aberrations in cancer: Implications for therapy

Yan, Min ; Parker, Barbara A. ; Schwab, Richard ; Kurzrock, Razelle

Although anti-HER2 (human epidermal growth factor receptor 2) therapy is currently approved for breast, gastric, and gastroesophageal cancers overexpressing the HER2 protein or amplified for the HER2 gene, HER2 aberrations (gene amplification, gene mutations, and protein overexpression) are reported in other diverse malignancies. Indeed, about 1–37% of tumors of the following types harbor HER2 aberrations: bladder, cervix, colon, endometrium, germ cell, glioblastoma, head and neck, liver, lung, [...]

Menée à l'aide de modèles murins, cette étude suggère l'intérêt de développer des immunothérapies ciblant la protéine TEM1 pour perturber le réseau vasculaire tumoral

Tumor endothelial marker 1–specific DNA vaccination targets tumor vasculature

Facciponte, John G. ; Ugel, Stefano ; De Sanctis, Francesco ; Li, Chunsheng ; Wang, Liping ; Nair, Gautham ; Sehgal, Sandy ; Raj, Arjun ; Matthaiou, Efthymia ; Coukos, George ; Facciabene, Andrea

Tumor endothelial marker 1 (TEM1; also known as endosialin or CD248) is a protein found on tumor vasculature and in tumor stroma. Here, we tested whether TEM1 has potential as a therapeutic target for cancer immunotherapy by immunizing immunocompetent mice with Tem1 cDNA fused to the minimal domain of the C fragment of tetanus toxoid (referred to herein as Tem1-TT vaccine). Tem1-TT vaccination elicited CD8+ and/or CD4+ T cell responses against immunodominant TEM1 protein sequences. Prophylactic [...]

Menée in vivo, cette étude met en évidence des mécanismes par lesquels l'ibrutinib, un inhibiteur de BTK, agit sur la prolifération des cellules de leucémie lymphocytaire chronique

Ibrutinib inhibits B-cell receptor and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with chronic lymphocytic leukemia

Herman, Sarah E. M. ; Mustafa, Rashida Z. ; Gyamfi, Jennifer A. ; Pittaluga, Stefania ; Chang, Stella ; Chang, Betty ; Farooqui, Mohammed ; Wiestner, Adrian

Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, tissue-resident CLL cells show prominent activation of both B-cell receptor (BCR) and NF-κB pathways. We evaluated the in vivo effects of ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor on tumor cell activation and proliferation in blood, lymph node, and bone marrow of patients with CLL. Applying validated pathway specific gene signatures, we detected a rapid and [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels des inhibiteurs de BRAF sont susceptibles de favoriser les processus invasif et métastatique dans les tumeurs de mélanome ayant acquis une résistance à ces médicaments

BRAF Inhibitors Induce Metastasis in RAS Mutant or Inhibitor-Resistant Melanoma Cells by Reactivating MEK and ERK Signaling

Sanchez-Laorden, Berta ; Viros, Amaya ; Girotti, Maria Romina ; Pedersen, Malin ; Saturno, Grazia ; Zambon, Alfonso ; Niculescu-Duvaz, Dan ; Turajlic, Samra ; Hayes, Andrew ; Gore, Martin ; Larkin, James ; Lorigan, Paul ; Cook, Martin ; Springer, Caroline ; Marais, Richard

Melanoma is a highly metastatic and lethal form of skin cancer. The protein kinase BRAF is mutated in about 40% of melanomas, and BRAF inhibitors improve progression-free and overall survival in these patients. However, after a relatively short period of disease control, most patients develop resistance because of reactivation of the RAF–ERK (extracellular signal–regulated kinase) pathway, mediated in many cases by mutations in RAS. We found that BRAF inhibition induces invasion and metastasis [...]

A partir d'une analyse de la structure cristalline de la protéine EML1, cette étude suggère l'intérêt du ganestespib, un inhibiteur de la protéine de choc thermique Hsp90, pour le traitement de certains patients atteints d'un cancer du poumon non à petites cellules présentant une fusion des gènes ALK et EML4

Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain

Richards, Mark W. ; Law, Edward W. P. ; Rennalls, La’Verne P. ; Busacca, Sara ; O’Regan, Laura ; Fry, Andrew M. ; Fennell, Dean A. ; Bayliss, Richard

Proteins of the echinoderm microtubule-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-Å crystal structure of the representative [...]

Menée sur des cellules tumorales issues de prélèvements sur des patients atteints d'un cancer de la prostate et inclus dans un essai clinique, cette étude met en évidence une surexpression de divers gènes impliqués dans la transition épithélio-mésenchymateuse en association avec l'apparition d'une résistance au docétaxel

Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer

Marín-Aguilera, Mercedes ; Codony-Servat, Jordi ; Reig, Òscar ; Lozano, Juan Jose ; Fernandez, Pedro L. ; Pereira, María Verónica ; Jiménez, Natalia ; Donovan, Michael ; Puig, Pere ; Mengual, Lourdes ; Bermudo, Raquel ; Font, Albert ; Gallardo, Enrique ; Ribal, Maria Jose ; Alcaraz, Antonio ; Gascón, Pere ; Mellado, Begoña

Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer (PC) participating in a phase-II neoadjuvant docetaxel (D) and androgen deprivation (AD) trial to identify mediators of resistance. Transcriptional level of 93 genes from a D-resistant PC cell lines microarray study was analyzed by Taqman low-density arrays in tumors from patients [...]

Cet article passe en revue les travaux récents sur le développement de nouveaux agents pour le traitement des patients atteints d'un cancer de la prostate métastatique résistant à la castration

New agents for prostate cancer

Agarwal, N. ; Di Lorenzo, G. ; Sonpavde, G. ; Bellmunt, J.

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en agissant sur la voie de signalisation WNT/β-caténine, des inhibiteurs de la glycogène synthase kinase sont susceptibles d'agir sur la croissance d'un rhadbdomyosarcome embryonnaire

Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

Chen, Eleanor Y. ; DeRan, Michael T. ; Ignatius, Myron S. ; Grandinetti, Kathryn Brooke ; Clagg, Ryan ; McCarthy, Karin M. ; Lobbardi, Riadh M. ; Brockmann, Jillian ; Keller, Charles ; Wu, Xu ; Langenau, David M.

Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle, with relapse being the major clinical challenge. Self-renewing tumor-propagating cells (TPCs) drive cancer relapse and are confined to a molecularly definable subset of ERMS cells. To identify drugs that suppress ERMS self-renewal and induce differentiation of TPCs, a large-scale chemical screen was completed. Glycogen synthase kinase 3 (GSK3) inhibitors were identified as potent suppressors of ERMS growth through [...]

Menée à l'aide d'un modèle murin, cette étude évalue l'activité de nanoparticules inorganiques comportant du méthotrexate pour le traitement d'un cancer du sein

Inorganic Nanovehicle Targets Tumor in an Orthotopic Breast Cancer Model

Choi, Goeun ; Kwon, Oh-Joon ; Oh, Yeonji ; Yun, Chae-Ok ; Choy, Jin-Ho

The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average [...]

Menée sur un modèle murin de glioblastome multiforme, cette étude évalue les mécanismes d'activité antitumorale d'une molécule appelée Vacquinol-1

Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule

Kitambi, Satish Srinivas ; Toledo, Enrique M ; Usoskin, Dmitry ; Wee, Shimei ; Harisankar, Aditya ; Svensson, Richard ; Sigmundsson, Kristmundur ; Kalderén, Christina ; Niklasson, Mia ; Kundu, Soumi ; Aranda, Sergi ; Westermark, Bengt ; Uhrbom, Lene ; Andäng, Michael ; Damberg, Peter ; Nelander, Sven ; Arenas, Ernest ; Artursson, Per ; Walfridsson, Julian ; Forsberg Nilsson, Karin ; Hammarström, Lars G J. ; Ernfors, Patrik

Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with marginal life expectancy. Based on the assumption that GBM cells gain functions not necessarily involved in the cancerous process, patient-derived glioblastoma cells (GCs) were screened to identify cellular processes amenable for development of targeted treatments. The quinine-derivative NSC13316 reliably and selectively compromised viability. Synthetic chemical expansion reveals delicate structure-activity [...]

Mené sur 149 patients (97 atteints d'un syndrome myélodysplasique à haut risque, 52 atteints d'une leucémie myéloïde aiguë), cet essai de phase II évalue l'activité clinique d'un traitement combinant azacitidine et entinostat, un inhibiteur d'histone désacétylase

Prolonged Administration of Azacitidine With or Without Entinostat for Myelodysplastic Syndrome and Acute Myeloid Leukemia With Myelodysplasia-Related Changes: Results of the US Leukemia Intergroup Trial E1905

Prebet, Thomas ; Sun, Zhuoxin ; Figueroa, Maria E. ; Ketterling, Rhett ; Melnick, Ari ; Greenberg, Peter L. ; Herman, James ; Juckett, Mark ; Smith, Mitchell R. ; Malick, Lisa ; Paietta, Elisabeth ; Czader, Magdalena ; Litzow, Mark ; Gabrilove, Janice ; Erba, Harry P. ; Gore, Steven D. ; Tallman, Martin S.

Purpose : Although azacitidine (AZA) improves survival in patients with high-risk myelodysplastic syndrome, the overall response remains approximately 50%. Entinostat is a histone deacetylase inhibitor that has been combined with AZA with significant clinical activity in a previous phase I dose finding study. Design : Open label phase II randomized trial comparing AZA 50 mg/m2/d given for 10 days ± entinostat 4 mg/m2/d day 3 and day 10. All subtypes of myelodysplasia, chronic myelomonocytic [...]

Mené sur 35 patients atteints d'un lymphome T périphérique CD30+ récidivant et/ou réfractaire, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du brentuximab vendotin

Objective responses in relapsed T-cell lymphomas with single agent brentuximab vedotin

Horwitz, Steven M. ; Advani, Ranjana H. ; Bartlett, Nancy L. ; Jacobsen, Eric D. ; Sharman, Jeff P. ; O'Connor, Owen A. ; Siddiqi, Tanya ; Kennedy, Dana A. ; Oki, Yasuhiro

This phase 2, open-label, multicenter study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in relapsed/refractory CD30+ non-Hodgkin lymphomas (NCT01421667). The primary endpoint was objective response rate (ORR). Key secondary endpoints included safety, correlation of CD30 expression with response, response duration, and progression-free survival (PFS). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks until disease progression or [...]

Menée sur 90 patientes atteintes d'un cancer du sein triplement négatif, cette étude rétrospective évalue l'efficacité, du point de vue de la survie sans maladie et de la survie globale, d'un traitement adjuvant séquentiel comprenant une immunothérapie à base de lymphocytes tueurs et une chimiothérapie

Clinical activity of adjuvant cytokine-induced killer cell (CIK) immunotherapy in post-mastectomy triple-negative breast cancer patients

Pan, Ke ; Guan, Xunxing ; Li, Yong-qiang ; Zhao, Jing-jing ; Li, Jian-jun ; Oiu, Hui-Juan ; Weng, De-sheng ; Wang, Qi-jing ; Liu, Qing ; Huang, Li-Xi ; He, Jia ; Chen, Shi-ping ; Ke, Miao-La ; Zeng, Yi-Xin ; Xia, Jian-chuan

Purpose: Triple-negative breast cancer (TNBC) is a high risk form of this disease, even after surgery, due to the absence of targets for hormone treatment and anti-Her-2 therapy. Chemotherapy is the main therapeutic strategy for such breast cancer patients although the outcome is often unsatisfactory. Thus, the development of combination adjuvant therapies is essential for improved prognosis in TNBC patients. In this study, we investigated the efficacy of a sequential combination of [...]

Mené sur 51 patientes atteintes d'un cancer du sein métastatique ER+, cet essai de phase IIb évalue la toxicité et l'activité clinique du buparlisib en combinaison avec du létrozole, en fonction de la présence de mutations du gène PIK3CA

Stand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer

Mayer, Ingrid A. ; Abramson, Vandana G. ; Isakoff, Steven J. ; Forero, Andres ; Balko, Justin M. ; Kuba, María Gabriela ; Sanders, Melinda E. ; Yap, Jeffrey T. ; Van den Abbeele, Annick D. ; Li, Yisheng ; Cantley, Lewis C. ; Winer, Eric ; Arteaga, Carlos L.

Purpose : Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole’s safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy. Patients and Methods : Patients received letrozole and buparlisib [...]

Mené sur 130 patients atteints d'un cancer de la vessie de stade T2-4aN0M0, cet essai japonais de phase III évalue, du point de vue de la survie globale, l'intérêt d'ajouter une chimiothérapie néoadjuvante de type MVAC à une cystectomie radicale

Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group study JCOG0209

Kitamura, H. ; Tsukamoto, T. ; Shibata, T. ; Masumori, N. ; Fujimoto, H. ; Hirao, Y. ; Fujimoto, K. ; Kitamura, Y. ; Tomita, Y. ; Tobisu, K. ; Niwakawa, M. ; Naito, S. ; Eto, M. ; Kakehi, Y. ; on behalf of Urologic Oncology Study Group of the Japan Clinical Oncology Group

Background : This study aimed to determine the clinical benefit of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. Patients and methods : Patients with MIBC (T2-4aN0M0) were randomised to receive 2 cycles of neoadjuvant MVAC followed by radical cystectomy (NAC arm) or radical cystectomy alone (RC arm). The primary endpoint was overall survival (OS). Secondary endpoints were [...]

Cet article passe en revue les enjeux associés à la détermination de la dose optimale dans les essais de thérapies ciblées des cancers

Determining the optimal dose in the development of anticancer agents

Mathijssen, Ron H. J. ; Sparreboom, Alex ; Verweij, Jaap

Identification of the optimal dose remains a key challenge in drug development. For cytotoxic drugs, the standard approach is based on identifying the maximum tolerated dose (MTD) in phase I trials and incorporating this to subsequent trials. However, this strategy does not take into account important aspects of clinical pharmacology. For targeted agents, the dose-effect relationships from preclinical studies are less obvious, and it is important to change the way these agents are developed to [...]

A partir de données portant sur 108 essais inclus dans la base ClinicalTrials.gov et portant sur des traitements d'un carcinome à cellules rénales, cette étude évalue la qualité des informations relatives au recrutement des patients

Lack of timely accrual information in oncology clinical trials: a cross-sectional analysis

Mitchell, Aaron ; Hirsch, Bradford ; Abernethy, Amy

BACKGROUND:Poor accrual is a significant barrier to the successful completion of oncology clinical trials; half of all phase 3 oncology trials close due to insufficient accrual. Timely access to accrual data fosters an understanding of successful trial design and can be used to inform the design of new clinical trials prospectively. Accrual statistics are available within research networks, such as the cancer cooperative groups, but comprehensive data reflecting the overall portfolio of cancer [...]