Menée en Allemagne à partir de données portant sur 11 982 patientes atteintes d'un cancer du sein traité entre 1998 et 2008, cette étude met en évidence l'absence d'association entre l'utilisation de la radiothérapie conformationnelle 3D et la mortalité cardiaque à long terme

3D conformal radiotherapy is not associated with the long-term cardiac mortality in breast cancer patients : a retrospective cohort study in Germany (PASSOS-Heart Study)

Merzenich, Hiltrud ; Bartkowiak, Detlef ; Schmidberger, Heinz ; Schmidt, Marcus ; Schwentner, Lukas ; Wiegel, Thomas ; Woeckel, Achim ; Wollschläger, Daniel ; Blettner, Maria

Purpose : In breast cancer patients treated in the 1970s and 1980s, radiation therapy (RT) for left-sided tumors has been associated with an elevated risk of cardiac mortality. In recent years, improved RT techniques have reduced radiation exposure of the heart and major coronary vessels, but some exposure remains unavoidable. In a retrospective cohort study, we investigated the long-term cardiac mortality risk of breast cancer survivors treated with modern RT in Germany. Methods : A total of [...]

Menée à partir de données portant sur 2 456 patientes atteintes d'un cancer du col de l'utérus de stade IA-IVA traité entre 1986 et 2012 par radiothérapie définitive en combinaison ou non avec une chimiothérapie à base de platine (âge médian : 55 ans ; durée médiane de suivi : 65,1 mois), cette étude met en évidence une association entre la présence d'une leucocytose liée à la maladie et une faible réponse tumorale aux rayonnements ionisants ou un pronostic défavorable

Tumor-related leukocytosis is associated with poor radiation response and clinical outcome in uterine cervical cancer patients

Cho, Y. ; Kim, K. H. ; Yoon, H. I. ; Kim, G. E. ; Kim, Y. B.

Background : To evaluate response to radiation and clinical outcome of uterine cervical cancer patients with tumor-related leukocytosis (TRL) at initial diagnosis and during definitive radiotherapy. Patients and methods : We retrospectively analyzed 2 456 patients with stage IA–IVA uterine cervical cancer who received definitive radiotherapy with (37.4%) or without (62.6%) platinum-based chemotherapy between 1986 and 2012. TRL was defined as two or more occurrences of leukocytosis over 9000/  [...]

Menée à l'aide de différents modèles murins de tumeurs stromales gastro-intestinales, cette étude met en évidence l'activité antitumorale du cabozantinib quelle que soit la mutation KIT impliquée

Cabozantinib is active against human gastrointestinal stromal tumor xenografts carrying different KIT mutations

Gebreyohannes, Yemarshet K. ; Schöffski, Patrick ; Van Looy, Thomas ; Wellens, Jasmien ; Vreys, Lise ; Cornillie, Jasmien ; Vanleeuw, Ulla ; Aftab, Dana T. ; Debiec-Rychter, Maria ; Sciot, Raf ; Wozniak, Agnieszka

In the majority of gastrointestinal stromal tumors (GIST) oncogenic signaling is driven by KIT mutations. Advanced GIST is treated with tyrosine kinase inhibitors (TKI) such as imatinib. Acquired resistance to TKI is mainly caused by secondary KIT mutations, but can also be attributed to a switch of KIT dependency to another receptor tyrosine kinase (RTK). We tested the efficacy of cabozantinib, a novel TKI targeting KIT, MET, AXL, and vascular endothelial growth factor receptors (VEGFR), in [...]

Cet article passe en revue les travaux récents sur les mécanismes moléculaires de la signalisation PD-1

Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway

Boussiotis, Vassiliki A.

The PD-1 pathway plays an essential role in maintaining immunologic self-tolerance. However, cancers can subvert the role of this pathway and blind the immune system to their presence. The molecular details of the pathway are discussed.

Menée à l'aide dun modèle murin reproduisant une résistance aux immunothérapies anti PD-1, cette étude met en évidence l'intérêt d'une injection intratumorale d'un agoniste de TRL9 (SD-101) pour augmenter la quantité et la qualité des lymphocytes T CD8+ spécifiques des tumeurs

Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells

Wang, Shu ; Campos, Jose ; Gallotta, Marilena ; Gong, Mei ; Crain, Chad ; Naik, Edwina ; Coffman, Robert L. ; Guiducci, Cristiana

Despite the impressive rates of clinical response to programmed death 1 (PD-1) blockade in multiple cancers, the majority of patients still fail to respond to this therapy. The CT26 tumor in mice showed similar heterogeneity, with most tumors unaffected by anti–PD-1. As in humans, response of CT26 to anti–PD-1 correlated with increased T- and B-cell infiltration and IFN expression. We show that intratumoral injection of a highly interferogenic TLR9 agonist, SD-101, in anti–PD-1 nonresponders [...]

Menée à l'aide de modèles murins de leucémie myéloïde aiguë, cette étude met en évidence des mécanismes suggérant l'intérêt de développer des thérapies ciblées à base d'anticorps anti CD98

CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia

Bajaj, Jeevisha ; Konuma, Takaaki ; Lytle, Nikki K ; Kwon, Hyog Young ; Ablack, Jailal N ; Cantor, Joseph M ; Rizzieri, David ; Chuah, Charles ; Oehler, Vivian G ; Broome, Elizabeth H ; Ball, Edward D ; van der Horst, Edward H ; Ginsberg, Mark H ; Reya, Tannishtha

Acute myelogenous leukemia (AML) is an aggressive disease associated with drug resistance and relapse. To improve therapeutic strategies, it is critical to better understand the mechanisms that underlie AML progression. Here we show that the integrin binding glycoprotein CD98 plays a central role in AML. CD98 promotes AML propagation and lethality by driving engagement of leukemia cells with their microenvironment and maintaining leukemic stem cells. Further, delivery of a humanized anti-CD98 [...]

Cet article passe en revue les travaux récents sur le développement d'immunothérapies anti PD-1 et anti PD-L1 pour le traitement des patients atteints d'un lymphome B

PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas

Goodman, Aaron ; Patel, Sandip P. ; Kurzrock, Razelle

Cancer cells can escape T-cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immune checkpoint. Indeed, therapeutic antibodies that block the PD-1-PD-L1 axis induce durable clinical responses against a growing list of solid tumours. B-cell lymphomas also leverage this checkpoint to escape immune recognition, although the outcomes of PD-1-PD-L1 blockade, and the correlations between PD-L1 expression and [...]

Menée sur des lignées cellulaires de mélanome avec mutation du gène BRAF puis à l'aide de biopsies et d'échantillons sériques prélevés sur des patients atteints de la maladie, cette étude montre que des inhibiteurs de la voie des kinases MAPK peuvent sensibiliser les cellules tumorales au CDX-011, un conjugué anticorps-médicament ciblant la glycoprotéine GPNMB

MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB

Rose, April A.N. ; Annis, Matthew G. ; Frederick, Dennie T. ; Biondini, Marco ; Dong, Zhifeng ; Kwong, Lawrence ; Chin, Lynda ; Keler, Tibor ; Hawthorne, Thomas ; Watson, Ian R. ; Flaherty, Keith T. ; Siegel, Peter M.

Purpose : To determine if BRAF and/or MEK inhibitor–induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB. Experimental Design : The Cancer Genome Atlas melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF-mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot, and FACS analyses. Transient siRNA-mediated [...]

Menée sur des lignées cellulaires de myélome multiple et à l'aide de xénogreffes sur un modèle murin, cette étude met en évidence l'activité antitumorale d'un traitement combinant un inhibiteur de l'histone déacétylase HDAC6 (WT161) et le bortézomib

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

Hideshima, Teru ; Qi, Jun ; Paranal, Ronald M. ; Tang, Weiping ; Greenberg, Edward ; West, Nathan ; Colling, Meaghan E. ; Estiu, Guillermina ; Mazitschek, Ralph ; Perry, Jennifer A. ; Ohguchi, Hiroto ; Cottini, Francesca ; Mimura, Naoya ; Gorgun, Gullu ; Tai, Yu-Tzu ; Richardson, Paul G. ; Carrasco, Ruben D. ; Wiest, Olaf ; Schreiber, Stuart L. ; Anderson, Kenneth C. ; Bradner, James E.

Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the [...]

Menée sur des lignées cellulaires de neuroblastome et à l'aide de xénogreffes sur des modèles murins, cette étude suggère l'intérêt thérapeutique de développer des inhibiteurs de STAT3 en combinaison avec une chimiothérapie à base de cisplatine

Inhibition of STAT3 with the generation 2.5 antisense oligonucleotide, AZD9150, decreases neuroblastoma tumorigenicity and increases chemosensitivity

Odate, Seiichi ; Veschi, Veronica ; Yan, Shuang ; Lam, Norris ; Woessner, Richard ; Thiele, Carol J.

Purpose:Neuroblastoma (NB) is a pediatric tumor of peripheral sympathoadrenal neuroblasts. The long-term event-free survival of children with high-risk NB is still poor despite the improvements with current multimodality treatment protocols. Activated JAK/STAT3 pathway plays an important role in many human cancers, suggesting that targeting STAT3 is a promising strategy for treating high-risk NB. Experimental Design:To evaluate the biologic consequences of specific targeting of STAT3 in NB, we [...]

Cet article passe en revue les perspectives thérapeutiques offertes par les travaux récents sur la voie de signalisation KRAS dans le cancer du poumon non à petites cellules

Targeting the KRAS Pathway in Non-Small Cell Lung Cancer

Tomasini, Pascale ; Walia, Preet ; Labbe, Catherine ; Jao, Kevin ; Leighl, Natasha B.

Lung cancer remains the leading cause of cancer-related deaths worldwide. However, significant progress has been made individualizing therapy based on molecular aberrations (e.g., EGFR, ALK) and pathologic subtype. KRAS is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC), found in approximately 30% of lung adenocarcinomas, and is thus an appealing target for new therapies. Although no targeted therapy has yet been approved for the treatment of KRAS-mutant NSCLC, [...]

Menée in vitro et in vivo, cette étude suggère l'intérêt de l'indométacine, un anti-inflammatoire non stéroïdien, pour surmonter l'apparition d'une résistance à l'abiratérone chez les patients atteints d'un cancer avancé de la prostate

Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer

Liu, Chengfei ; Armstrong, Cameron M. ; Lou, Wei ; Lombard, Alan ; Evans, Christopher P. ; Gao, Allen C.

Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a critical mechanism driving resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. We found that [...]

Menée sur 122 lignées cellulaires de cancer colorectal et à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence l'activité antitumorale d'un inhibiteur de la signalisation NEDD8, le pévonédistat, dans les adénocarcinomes mucineux de haut grade faiblement différenciés

Efficacy of NEDD8 Pathway Inhibition in Preclinical Models of Poorly Differentiated, Clinically Aggressive Colorectal Cancer

Picco, Gabriele ; Petti, Consalvo ; Sassi, Francesco ; Grillone, Katia ; Migliardi, Giorgia ; Rossi, Teresa ; Isella, Claudio ; Di Nicolantonio, Federica ; Sarotto, Ivana ; Sapino, Anna ; Bardelli, Alberto ; Trusolino, Livio ; Bertotti, Andrea ; Medico, Enzo

Background: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing. Methods: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based [...]

Menée sur un modèle murin de cancer du sein triplement négatif, cette étude met en évidence l'intérêt d'un inhibiteur de p53 pour préserver la fonction auditive des patientes traitées à l'aide de cisplatine

Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy

Benkafadar, Nesrine ; Menardo, Julien ; Bourien, Jérôme ; Nouvian, Régis ; François, Florence ; Decaudin, Didier ; Maiorano, Domenico ; Puel, Jean-Luc ; Wang, Jing

Cisplatin is a widely used chemotherapy drug, despite its significant ototoxic side effects. To date, the mechanism of cisplatin-induced ototoxicity remains unclear, and hearing preservation during cisplatin-based chemotherapy in patients is lacking. We found activation of the ATM-Chk2-p53 pathway to be a major determinant of cisplatin ototoxicity. However, prevention of cisplatin-induced ototoxicity is hampered by opposite effects of ATM activation upon sensory hair cells: promoting both outer [...]

Menée in vitro et in vivo sur des modèles de cancer du sein triplement négatif, cette étude met en évidence l'activité antitumorale d'un nouvel inhibiteur des kinases RSK

Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer

Ludwik, Katarzyna A. ; Campbell, J. Preston ; Li, Mingzong ; Li, Yu ; Sandusky, Zachary M. ; Pasic, Lejla ; Sowder, Miranda E. ; Brenin, David R. ; Pietenpol, Jennifer A. ; Doherty, George A. ; Lannigan, Deborah A.

Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple-negative breast cancer (TNBC) frequently metastasizes and high levels of activated p90RSK (RSK), a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate, using direct pharmacologic and genetic inhibition of RSK1/2, that these kinases contribute to the TNBC metastatic process in vivo. Kinase profiling showed that RSK1 and RSK2 are the predominant kinases targeted by [...]

A partir d'une revue de la littérature publiée jusqu'en février 2016 (5 études incluant au total 1 815 participants), cette méta-analyse évalue, du point de vue de la survie globale, l'efficacité de nouvelles thérapies ciblées (axitinib, brivanib, tivatinib, évérolimus et ramucirumab) en traitement de seconde ligne dans le cancer hépatocellulaire de stade avancé

New molecular therapies in patients with advanced Hepatocellular Cancer in second line of treatment : is a real defeat? : Results from a literature based meta-analysis of randomized trials

Roviello, Giandomenico ; Zanotti, Laura ; Cappelletti, Maria Rosa ; Gobbi, Angela ; Borsella, Giulia ; Pacifico, Chiara ; Multari, Andrea Giovanni ; Generali, Daniele

Several new biological agents have been investigated as second line of treatment in advanced Hepatocellular Cancer (HCC). We performed a meta-analysis to assess the effect of targeted therapies in advanced HCC patients beyond the first line of treatment. A literature-based metaanalysis of randomized controlled trials was undertaken. The primary outcome was the overall survival. The secondary endpoints were the progression-free survival (PFS), the response rate (RR) and disease control rate [...]

Mené sur des patients asiatiques atteints d'un carcinome hépatocellulaire de stade avancé, cet essai de phase I/II évalue les caractéristiques pharmacocinétiques et pharmacodynamiques, l'activité antitumorale, la dose maximale tolérée, la toxicité et l'efficacité, du point de vue du taux de réponse objective, du forétinib, un inhibiteur multikinase, en traitement de première ligne

A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

Yau, Thomas CC ; Lencioni, Riccardo ; Sukeepaisarnjaroen, Wattana ; Chao, Yee ; Yen, Chia-Jui ; Lausoontornsiri, Wirote ; Chen, Pei-Jer ; Sanpajit, Theeranun ; Camp, Aaron ; Cox, Donna S ; Gagnon, Robert C. ; Liu, Yuan ; Raffensperger, Kristen E ; Kulkarni, Diptee A ; Kallender, Howard ; Ottesen, Lone Harild ; Poon, Ronnie TP ; Bottaro, Donald P.

Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma (HCC) patients. Experimental Design: In the phase I part, advanced HCC patients were dose-escalated on foretinib (30-60 mg) once daily (QD) using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an [...]

Cette étude passe en revue les mécanismes de la cancérogenèse virale et évalue l'intéret de l'immunothérapie pour traiter les cancers liés à une infection virale

Harnessing the immune system as a therapeutic tool in virus-associated cancers

Santana-Davila, R. ; Bhatia, S. ; Chow, L. M.

Importance : There are at least 7 viruses implicated in the pathogenesis of 10% to 15% of all human cancers worldwide. Despite a high prevalence of infection with these viruses, only a minority of infected individuals develop a subsequent malignant tumor, underscoring the important role that host and environmental factors have in cancer development. This article reviews the mechanisms of viral carcinogenesis, with an emphasis on the viral evasion of the host immune system, and discusses how to [...]

A partir d'une revue systématique de la littérature publiée entre 1990 et 2016, cette étude évalue l'association entre une chimiothérapie et le risque de réactivation du virus de l'hépatite B chez les patients atteints de tumeurs solides

Hepatitis B virus reactivation in patients with solid tumors receiving systemic anticancer treatment

Voican, C. S. ; Mir, O. ; Loulergue, P. ; Dhooge, M. ; Brezault, C. ; Dréanic, J. ; Chaussade, S. ; Pol, S. ; Coriat, R.

Background : Hepatitis B virus (HBV) reactivation is a well-known risk during chemotherapy for hematological malignancies with reported rates ranging between 14% and 72%. However, there is a paucity of data regarding HBV infection management and reactivation risk in patients receiving systemic treatments for solid tumors. Design : We conducted a PubMed search for publications from January 1990 until May 2016 related to HBV reactivation. The search terms were ‘hepatitis B reactivation’, [...]

Mené sur 27 patients atteints d'une leucémie lymphocytaire chronique récidivante ou réfractaire, cet essai évalue l'efficacité, du point de vue de la survie globale et de la survie sans progression, et la toxicité de l'ibrutinib, après une greffe allogénique de cellules souches

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

Ryan, Christine E. ; Sahaf, Bita ; Logan, Aaron C. ; O'Brien, Susan ; Byrd, John C. ; Hillmen, Peter ; Brown, Jennifer R. ; Dyer, Martin J.S. ; Mato, Anthony R. ; Keating, Michael J. ; Jaglowski, Samantha ; Clow, Fong ; Rezvani, Andrew R. ; Styles, Lori ; Coutre, Steven E. ; Miklos, David B.

Ibrutinib provided effective salvage therapy in CLL relapse post-alloHCT, resulting in sustained MRD negativity without GVHD development.Ibrutinib selectively depleted pre-germinal B cells and Th2 helper cells, and may enhance donor Th1 T cell-mediated GVL effects. Ibrutinib, a potent and irreversible small molecule inhibitor of both Bruton's tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with [...]

A partir de données portant sur 889 patients atteints d'un mélanome des muqueuses et inclus dans des essais cliniques, cette étude évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du nivolumab, seul ou en combinaison avec l'ipilimumab

Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis

Sandra P. D’Angelo ; James Larkin ; Jeffrey A. Sosman ; Celeste Lebbé ; Benjamin Brady ; Bart Neyns ; Henrik Schmidt ; Jessica C. Hassel ; F. Stephen Hodi ; Paul Lorigan ; Kerry J. Savage ; Wilson H. Miller Jr ; Peter Mohr ; Ivan Marquez-Rodas ; Julie Charles ; Martin Kaatz ; Mario Sznol ; Jeffrey S. Weber ; Alexander N. Shoushtari ; Mary Ruisi ; Joel Jiang ; Jedd D. Wolchok

Purpose : Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods : Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal [...]

A partir des données portant 2 patients atteints d'un mélanome et décédés d'une myocardite fulminante, cette étude met en avant le risque d'événements indésirables fatals liés à une immunothérapie à base d'ipilimumab combiné au nivolumab

Fulminant Myocarditis with Combination Immune Checkpoint Blockade

Johnson, Douglas B. ; Balko, Justin M. ; Compton, Margaret L. ; Chalkias, Spyridon ; Gorham, Joshua ; Xu, Yaomin ; Hicks, Mellissa ; Puzanov, Igor ; Alexander, Matthew R. ; Bloomer, Tyler L. ; Becker, Jason R. ; Slosky, David A. ; Phillips, Elizabeth J. ; Pilkinton, Mark A. ; Craig-Owens, Laura ; Kola, Nina ; Plautz, Gregory ; Reshef, Daniel S. ; Deutsch, Jonathan S. ; Deering, Raquel P. ; Olenchock, Benjamin A. ; Lichtman, Andrew H. ; Roden, Dan M. ; Seidman, Christine E. ; Koralnik, Igor J. ; Seidman, Jonathan G. ; Hoffman, Robert D. ; Taube, Janis M. ; Diaz, Luis A. Jr. ; Anders, Robert A. ; Sosman, Jeffrey A. ; Moslehi, Javid J.

Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust [...]

Mené sur 18 patients atteints d'un cancer du poumon non à petites cellules de stade avancé avec réarrangement du gène RET, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du vandétanib après l'échec d'une chimiothérapie à base de sels de platine

Vandetanib in Pretreated Patients with Advanced Non-Small Cell Lung Cancer Harboring RET Rearrangement: A Phase II Clinical Trial

Lee, S.-H. ; Lee, J.-K. ; Ahn, M.-J. ; Kim, D.-W. ; Sun, J.-M. ; Keam, B. ; Kim, T. M. ; Heo, D. S. ; Ahn, J. S. ; Choi, Y.-L. ; Min, H.-S. ; Jeon, Y. K. ; Park, K.

Background: Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and safety of vandetanib 300 mg daily in this patient population. Patients and Methods: This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ [...]

Mené sur 125 patients atteints d'un cancer du poumon non à petites cellules de stade avancé sans mutation du gène EGFR, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité d'un traitement de deuxième ou troisième ligne à base d'erlotinib ou de cabozantinib, puis évalue l'efficacité du cabozantinib seul ou en combinaison avec l'erlotinib

Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial

Neal, Joel W. ; Dahlberg, Suzanne E. ; Wakelee, Heather A. ; Aisner, Seena C. ; Bowden, Michaela ; Huang, Ying ; Carbone, David P. ; Gerstner, Gregory J. ; Lerner, Rachel E. ; Rubin, Jerome L. ; Owonikoko, Taofeek K. ; Stella, Philip J. ; Steen, Preston D. ; Khalid, Ahmed Ali ; Ramalingam, Suresh S.

Background : Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC. Methods : This three group, [...]

Mené en France sur des patients atteints d'un cancer colorectal métastatique et âgés de plus de 75 ans, cet essai de phase III évalue l'efficacité, du point de vue du taux de réponse objective, de l'ajout de l'irinotécan à un traitement de première ligne à base de 5-fluorouracile, en fonction des résultats d'une évaluation gériatrique

Geriatric factors analyses from FFCD 2001-02 phase III study of first-line chemotherapy for elderly metastatic colorectal cancer patients

Aparicio, Thomas ; Gargot, Dany ; Teillet, Laurent ; Maillard, Emilie ; Genet, Dominique ; Cretin, Jacques ; Locher, Christophe ; Bouche, Olivier ; breysacher, gilles ; Seitz, Jean-François ; Gasmi, Mohamed ; Stefani, Laetitia ; Ramdani, Mohamed ; Lecomte, Thierry ; Auby, Dominique ; Faroux, Roger ; Bachet, Jean-Baptiste ; Lepere, Celine ; khemissa, faiza ; Sobhani, Iradj ; Boulat, Olivier ; mitry, emmanuel ; Jouve, Jean-Louis

Highlights : •Addition of irinotecan to 5-fluorouracil in the treatment of elderly did not improve progression-free survival and overall survival. •Normal autonomy was independently associated with better overall survival (OS). •Some patient's subgroup might benefit from doublet chemotherapy with regard to progression free survival (PFS) and overall survival (OS). •These sub-group are: age <80, unresected primary tumour, leucocytes >11,000 and carcinoembryonic antigen >2N for PFS. •And patients [...]

Cette étude passe en revue les essais évaluant l'efficacité du sunitinib dans la prise en charge des patients atteints d'un carcinome à cellules rénales de stade avancé

Sunitinib: Ten Years of Successful Clinical Use and Study in Advanced Renal Cell Carcinoma

Motzer, Robert J. ; Escudier, Bernard ; Gannon, Andrew ; Figlin, Robert A.

The oral multikinase inhibitor sunitinib malate was approved by the U.S. Food and Drug Administration in January 2006 for use in patients with advanced renal cell carcinoma (RCC). Since then, it has been approved globally for this indication and for patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors and advanced pancreatic neuroendocrine tumors. As we mark the 10-year anniversary of the beginning of the era of targeted therapy, and specifically the approval of [...]

Mené sur 416 patientes atteintes d'un cancer du sein HER2- métastatique ou localement avancé, cet essai international de phase I/III évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout du buparlisib à une chimiothérapie à base de paclitaxel en traitement de première ligne

A randomized adaptive phase II/III study of buparlisib, a pan-Class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2– advanced breast cancer (BELLE-4)

Martín, M. ; Chan, A. ; Dirix, L. ; O’Shaughnessy, J. ; Hegg, R. ; Manikhas, A. ; Shtivelband, M. ; Krivorotko, P. ; Batista López, N. ; Campone, M. ; Ruiz Borrego, M. ; Khan, Q. J. ; Beck, J. T. ; Ramos Vázquez, M. ; Urban, P. ; Goteti, S. ; Di Tomaso, E. ; Massacesi, C. ; Delaloge, S.

Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or [...]

Mené sur 1 095 patientes atteintes d'un cancer du sein HER2+ de stade avancé, cet essai de phase III compare l'efficacité, du point de vue de la survie sans progression, d'un traitement de première ligne à base de trastuzumab emtansine (T-DM1), seul ou en combinaison avec du pertuzumab, avec un traitement combinant trastuzumab et taxane

Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2–Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study

Edith A. Perez ; Carlos Barrios ; Wolfgang Eiermann ; Masakazu Toi ; Young-Hyuck Im ; Pierfranco Conte ; Miguel Martin ; Tadeusz Pienkowski ; Xavier Pivot ; Howard Burris III ; Jennifer A. Petersen ; Sven Stanzel ; Alexander Strasak ; Monika Patre ; Paul Ellis

Purpose : Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models [...]

Mené sur 13 patients atteints d'un carcinome épidermoïde de la tête et du cou de stade métastatique ou récidivant, cet essai de phase Ib évalue l'activité antitumorale, la dose maximale tolérée et l'efficacité, du point de vue du taux de réponse globale, du motolimod, un agoniste du récepteur TLR8, en combinaison avec le cétuximab

Phase 1b Trial of the Toll-Like Receptor 8 Agonist, Motolimod (VTX-2337), Combined with Cetuximab in Patients with Recurrent or Metastatic SCCHN

Chow, Laura Q.M. ; Morishima, Chihiro ; Eaton, Keith D ; Baik, Christina S. ; Goulart, Bernardo H ; Anderson, Leslie N. ; Manjarrez, Kristi L ; Dietsch, Gregory N. ; Bryan, James Kyle ; Hershberg, Robert M. ; Disis, Mary L ; Martins, Renato G

Purpose: As toll-like receptors (TLRs) are key mediators of immune responses, TLR agonists may be important for augmenting the efficacy of therapies for squamous cell carcinoma of the head and neck (SCCHN). Motolimod (VTX-2337), a selective small-molecule agonist of TLR8, stimulates NK cells, dendritic cells, and monocytes. A Phase 1b clinical trial assessed the safety and anti-tumor activity of motolimod in combination with cetuximab in patients with SCCHN. Correlative biomarkers of immune [...]

Menée sur des lignées cellulaires de glioblastome multiforme et de cancer du poumon non à petites cellules puis à l'aide de xénogreffes sur des modèles murins, cette étude montre qu'un anticorps ciblant la protéine GRP78 peut augmenter l'efficacité d'une radiothérapie

Antibody targeting GRP78 enhances the efficacy of radiation therapy in human glioblastoma and non-small-cell lung cancer cell lines and tumor models

Dadey, David YA ; Kapoor, Vaishali ; Hoye, Kelly ; Khudanyan, Arpine ; Collins, Andrea ; Thotala, Dinesh ; Hallahan, Dennis E

Purpose : Non-small-cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) have poor median survival. NSCLC and GBM overexpress glucose regulated protein 78 (GRP78), which has a role in radioresistance and recurrence. In this study, we determined the effect of anti-GRP78 antibody and the combined effect of the anti-GRP78 antibody with ionizing radiation (XRT) on NSCLC and GBM cell lines both in vitro and in vivo. Experimental Design : NSCLC and GBM cancer cell lines were treated with [...]

Menée à partir de données portant sur 74 patients atteints d'un cancer du poumon à petites cellules de stade T1-T2N0M0 (âge médian : 72 ans ; taille médiane de la tumeur : 2,5 cm ; durée médiane de suivi : 18 mois), cette étude multicentrique analyse, du point de vue du contrôle de la maladie, de la survie globale et de la toxicité, l'intérêt d'une radiothérapie stéréotaxique ablative, puis identifie les formes de récidive

Multi-Institutional Experience of Stereotactic Ablative Radiotherapy for Stage I Small Cell Lung Cancer

Verma, Vivek ; Simone, Charles B., II ; Allen, Pamela K. ; Gajjar, Sameer R. ; Shah, Chirag ; Zhen, Weining ; Harkenrider, Matthew M. ; Hallemeier, Christopher L. ; Jabbour, Salma K. ; Matthiesen, Chance L. ; Braunstein, Steve E. ; Lee, Percy ; Dilling, Thomas J. ; Allen, Bryan G. ; Nichols, Elizabeth M. ; Attia, Albert ; Zeng, Jing ; Biswas, Tithi ; Paximadis, Peter ; Wang, Fen ; Walker, Joshua M. ; Stahl, John M. ; Daly, Megan E. ; Decker, Roy H. ; Hales, Russell K. ; Willers, Henning ; Videtic, Gregory M. M. ; Mehta, Minesh P. ; Lin, Steven H.

Purpose : For inoperable stage I (T1-2N0) small cell lung cancer (SCLC), national guidelines recommend chemotherapy with/without conventionally-fractionated radiotherapy. This multi-institutional cohort study investigated the role of stereotactic ablative radiotherapy (SABR) for this population. Methods : Clinical/treatment characteristics, toxicities, outcomes, and patterns of failure were assessed in patients with histologically-confirmed T1-T2N0M0 SCLC. Kaplan-Meier analysis evaluated [...]

Menée à l'aide d'un modèle murin de cancer du poumon résistant aux traitements anti-PD-1, cette étude montre que cette résistance, induite par la suppression de la voie de signalisation de l'interféron de type I dans les cellules tumorales, peut être levée par les rayonnements ionisants

Suppression of type I IFN signaling in tumors mediates resistance to anti-PD-1 treatment that can be overcome by radiotherapy

Wang, Xiaohong ; Schoenhals, Jonathan E. ; Li, Ailin ; Valdecanas, David R. ; Ye, Huiping ; Zhang, Fenglin ; Tang, Chad ; Tang, Ming ; Liu, Chang-Gong ; Liu, Xiuping ; Krishnan, Sunil ; Allison, James P. ; Sharma, Padmanee ; Hwu, Patrick ; Komaki, Ritsuko ; Overwijk, Willem W. ; Gomez, Daniel R. ; Chang, Joe Y. ; Hahn, Stephen M. ; Cortez, Maria Angelica ; Welsh, James W.

Immune checkpoint therapies exhibit impressive efficacy in some patients with melanoma or lung cancer, but the lack of response in most cases presses the question of how general efficacy can be improved. In addressing this question, we generated a preclinical tumor model to study anti-PD-1 resistance by in vivo passaging of Kras-mutated, p53-deficient murine lung cancer cells (p53R172H

Menée sur des lignées cellulaires de cancer du poumon non à petites cellules et à l'aide de xénogreffes, cette étude montre que le ganetespib, un inhibiteur de la protéine HSP90, peut sensibiliser les cellules tumorales aux rayonnements ionisants et s'avérer moins efficace lorsqu'une chimiothérapie est ajoutée à la radiothérapie

Hsp90 Inhibitor Ganetespib Sensitizes Non–Small Cell Lung Cancer to Radiation but Has Variable Effects with Chemoradiation

Wang, Yifan ; Liu, Hui ; Diao, Lixia ; Potter, Adam ; Zhang, Jianhu ; Qiao, Yawei ; Wang, Jing ; Proia, David A. ; Tailor, Ramesh ; Komaki, Ritsuko ; Lin, Steven H.

Purpose : HSP90 inhibition is well known to sensitize cancer cells to radiation. However, it is currently unknown whether additional radiosensitization could occur in the more clinically relevant setting of chemoradiation (CRT). We used the potent HSP90 inhibitor ganetespib to determine whether it can enhance CRT effects in NSCLC. Experimental Design : We first performed in vitro experiments in various NSCLC cell lines combining radiation with or without ganetespib. Some of these experiments [...]

Menée sur 19 patientes atteintes d'un cancer du sein de stade précoce et devant subir une mastectomie, cette étude évalue la tolérabilité, la sécurité et l'efficacité, du point de vue de la réponse immunitaire intratumorale et systémique, d'un traitement pré-opératoire comportant une dose d'ipilimumab et/ou une cryoablation percutanée guidée par IRM

A Pilot Study of Preoperative Single-Dose Ipilimumab and/or Cryoablation in Women with Early-Stage Breast Cancer with Comprehensive Immune Profiling

McArthur, Heather L. ; Diab, Adi ; Page, David B. ; Yuan, Jianda ; Solomon, Stephen B. ; Sacchini, Virgilio ; Comstock, Christopher ; Durack, Jeremy C. ; Maybody, Majid ; Sung, Janice ; Ginsberg, Arielle ; Wong, Phillip ; Barlas, Afsar ; Dong, Zhiwan ; Zhao, Chunjun ; Blum, Brian ; Patil, Sujata ; Neville, Deirdre ; Comen, Elizabeth A. ; Morris, Elizabeth A. ; Kotin, Alan ; Brogi, Edi ; Wen, Y. Hannah ; Morrow, Monica ; Lacouture, Mario E. ; Sharma, Padmanee ; Allison, James P. ; Hudis, Clifford A. ; Wolchok, Jedd D. ; Norton, Larry

Purpose : To assess the safety and tolerability of preoperative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer. Experimental Design : In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with preoperative tumor cryoablation (n = 7), single-dose ipilimumab at 10 mg/kg (n = 6), or both (n = 6). The primary outcome for this pilot study was safety/tolerability as defined as [...]

Cet article passe en revue les études pré-cliniques et cliniques concernant l'intérêt des traitements anticancéreux combinant inhibiteurs de PARP et autres agents thérapeutiques (témozolomide, gemcitabine, inhibiteurs PI3K/mTOR, ...), puis analyse les perspectives futures de ces stratégies thérapeutiques ainsi que les défis associés à leur développement

PARP inhibitor combination therapy

Drean, Amy ; Lord, Christopher J. ; Ashworth, Alan

In 2014, olaparib (Lynparza) became the first PARP (Poly(ADP-ribose) polymerase) inhibitor to be approved for the treatment of cancer. When used as single agents, PARP inhibitors can selectively target tumour cells with BRCA1 or BRCA2 tumour suppressor gene mutations through synthetic lethality. However, PARP inhibition also shows considerable promise when used together with other therapeutic agents. Here, we summarise both the pre-clinical and clinical evidence for the utility of such [...]

A partir d'une revue systématique des données de la base "PharmaProject" portant sur 42 médicaments anticancéreux dont le développement a été abandonné entre 2009 et 2014, cette étude analyse les facteurs associés au taux d'échecs survenus lors des essais de phase III

Factors Associated with Failure of Oncology Drugs in Late-Stage Clinical Development: a Systematic Review

Fontes Jardim, Denis L. ; Groves, Eric S. ; Breitfeld, Philip P. ; Kurzrock, Razelle

Highlights : •Drug development in oncology is characterized by a high rate of failure at the stage of phase III trials. •Achieving proof of concept based on drug activity after a phase II trial increases the likelihood of later approval. •Drugs developed under a biomarker-based selection strategy are less likely to fail at late stages of development. Abstract : Background : We aimed to describe the reasons for failure of experimental anticancer drugs in late-stage clinical development. Material [...]

Menée avec l'aide d'un groupe de travail composé de différents spécialistes (radiothérapeutes, radiophysiciens et techniciens), cette étude identifie de nouveaux indicateurs de qualité (indicateurs de structure, de processus et de résultats) spécifiques des techniques de radiothérapie avec modulation d'intensité et des techniques de radiothérapie guidée par l'imagerie

Quality indicators in the Intensity Modulated/Image-Guided Radiotherapy era

Gabriele, P. ; Maggio, A. ; Garibaldi, E. ; Bracco, C. ; Delmastro, E. ; Gabriele, D. ; Rosi, A. ; Munoz, F. ; Di Muzio, N. ; Corvò, R. ; Stasi, M.

Purpose : To propose new Quality Indicators (QIs) for the Intensity Modulated(IMRT)/Image-Guided(IGRT) Radiotherapy techniques. Materials and methods : Two structure, 10 process and 2 outcome QIs were elaborated. A working group including Radiation Oncologist, Medical Physicist and Radiation Technologists was made up. A preliminary set of indicators was selected on the basis of evidenced critical issues; the criteria to identify more relevant and specific QIs for IMRT/IGRT were defined; [...]

Cet article passe en revue les avancées et les controverses dans le traitement d'un carcinome médullaire de la thyroïde

Advances and controversies in the management of medullary thyroid carcinoma

Maia, Ana Luiza ; Wajner, Simone Magagnin ; Vargas, Carla Vaz Ferreira

Purpose of review : Medullary thyroid carcinoma (MTC) comprises approximately 4% of all malignant thyroid neoplasms. Although the majority of patients have a good prognosis, a subgroup of patients develops progressive disease and requires systemic therapy. Here, we focused on the current MTC therapeutic approaches and discussed the advantages and disadvantages of molecular targeted therapies. Recent findings : Targeted molecular therapies that inhibit REarranged during Transfection and other [...]