Menée à l'aide d'une xénogreffe sur un modèle murin, cette étude montre qu'un traitement sonodynamique peut inhiber l'angiogenèse et la croissance tumorale

Sonodynamic therapy inhibits angiogenesis and tumor growth in a xenograft mouse model

Gao-Zhong, Xiuzi ; Zheng, Jinhua ; Yang, Bin ; Wang, Zhu ; Fan, Haixia ; Lv, Yanhong ; Li, Haixia ; Jia, Limin ; Cao, Wenwu

Studies of sonodynamic therapy (SDT) have mainly focused on its direct cytotoxic effect on tumor cells. Its effects on the tumor microenvironment, especially angiogenesis, remain unknown. In this study, we found that SDT significantly inhibited endothelial cell proliferation, migration, invasion, and tube formation. Furthermore, in a tumor xenograft mouse model, SDT was found to remarkably suppress tumor growth, intratumoral vascularity, and expression of vascular endothelial growth factor in [...]

Menée à l'aide d'une xénogreffe de carcinome du côlon, cette étude évalue l'efficacité d'un traitement combinant ultrasons et microbulles administrées par voie intraveineuse pour inhiber la croissance tumorale

A Novel Therapeutic Strategy using Ultrasound Mediated Microbubbles Destruction to Treat Colon Cancer in A Mouse Model

Huang, Pintong ; You, Xiandong ; Pan, Minqiang ; Li, Shiyan ; Zhang, Ying ; Zhao, Yingzhen ; Wang, Minhui ; Hong, Yurong ; Pu, Zhaoxia ; Chen, Lirong ; Yang, Guangen ; Guo, Youmin

The goal of this study was to determine whether ultrasound mediated microbubbles destruction (UMMD) could inhibit colon cancer growth in a mouse model. Six-week-old balb/c female nude mice were subcutaneously inoculated with HT29-GFP cells (HT29 cells labeled with green fluorescent dye) in axilla to establish a xenograft mouse model of colon carcinoma, which were randomly divided into 5 groups (n=10 each): group A (blank group): no treatment; group B (saline only); group C (saline + ultrasound [...]

Mené sur 52 patients atteints d'un cancer de la prostate traité par radiothérapie avec modulation d'intensité, cet essai prospectif multicentrique évalue l'efficacité d'une injection entre le rectum et la prostate d'un hydrogel à base de polyéthylène glycol pour réduire la dose de rayonnement reçue par le rectum

A Multi-institutional Clinical Trial of Rectal Dose Reduction via Injected Polyethylene-Glycol Hydrogel During Intensity Modulated Radiation Therapy for Prostate Cancer: Analysis of Dosimetric Outcomes

Song, Danny Y. ; Herfarth, Klaus K. ; Uhl, Matthias ; Eble, Michael J. ; Pinkawa, Michael ; van Triest, Baukelien ; Kalisvaart, Robin ; Weber, Damien C. ; Miralbell, Raymond ; DeWeese, Theodore L. ; Ford, Eric C.

To characterize the effect of a prostate-rectum spacer on dose to rectum during external beam radiation therapy for prostate cancer and to assess for factors correlated with rectal dose reduction. Fifty-two patients at 4 institutions were enrolled into a prospective pilot clinical trial. Patients underwent baseline scans and then were injected with perirectal spacing hydrogel and rescanned. Intensity modulated radiation therapy plans were created on both scans for comparison. The objectives [...]

Menée à l'aide de quatre modèles murins, cette étude montre que le mécanisme d'action antitumorale de la trabectédine consiste à induire une apoptose dans les phagocytes mononucléés exclusivement

Role of Macrophage Targeting in the Antitumor Activity of Trabectedin

Germano, Giovanni ; Frapolli, Roberta ; Belgiovine, Cristina ; Anselmo, Achille ; Pesce, Samantha ; Liguori, Manuela ; Erba, Eugenio ; Uboldi, Sarah ; Zucchetti, Massimo ; Pasqualini, Fabio ; Nebuloni, Manuela ; van Rooijen, Nico ; Mortarini, Roberta ; Beltrame, Luca ; Marchini, Sergio ; Fuso Nerini, Ilaria ; Sanfilippo, Roberta ; Casali, Paolo G ; Pilotti, Silvana ; Galmarini, Carlos M ; Anichini, Andrea ; Mantovani, Alberto ; D Incalci, Maurizio ; Allavena, Paola

There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we [...]

Cet article passe en revue les perspectives offertes par les connaissances relatives à la voie de signalisation du facteur de croissance des fibroblastes et de son récepteur pour le développement de thérapies ciblées du cancer

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

Dieci, Maria Vittoria ; Arnedos, Monica ; Andre, Fabrice ; Soria, Jean Charles

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifications, tumor neoangiogenesis, and targeted [...]

Menée sur 17 lignées cellulaires de mélanome et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un mimétique de Smac, le birinapant, seul ou en combinaison avec TNF-α

The novel SMAC mimetic Birinapant exhibits potent activity against human melanoma cells

Krepler, Clemens ; Chunduru, Srinivas K. ; Halloran, Molly B. ; He, Xu ; Xiao, Min ; Vultur, Adina M. ; Villanueva, Jessie ; Mitsuuchi, Yasuhiro ; Neiman, Eric M. ; Benetatos, Christopher ; Nathanson, Katherine L. ; Amaravadi, Ravi ; Pehamberger, Hubert ; McKinlay, Mark ; Herlyn, Meenhard

Purpose: Inhibitor of apoptosis proteins (IAPs) promote cancer cell survival and confer resistance to therapy. We report on the ability of second mitochondria-derived activator of caspases (SMAC) mimetic, birinapant, which acts as antagonist to cIAP1 and cIAP2, to restore the sensitivity to apoptotic stimuli such as tumor necrosis factor (TNF) -α in melanomas Experimental Design: Seventeen melanoma cell lines, representing five major genetic subgroups of cutaneous melanoma, were treated with [...]

Cet article passe en revue les travaux récents sur des vaccins thérapeutiques pour le cancer de la prostate

Proposed mechanisms of action for prostate cancer vaccines

Geary, Sean M. ; Lemke, Caitlin D. ; Lubaroff, David M. ; Salem, Aliasger K.

Prostate cancer is responsible for the deaths of more than 33,000 American men every year. Once this disease has become metastatic, there is no curative treatment. Alternative therapies to chemotherapy and radical prostatectomy are being increasingly explored. Prostate cancer vaccines—which trigger a tumour-specific cytotoxic-T-lymphocyte-mediated immune attack by the patient's immune system—have been investigated in clinical trials with modest, yet encouraging, results. When developing and [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude suggère l'intérêt d'un composé appelé LY2157299, un inhibiteur de l'activité tyrosine kinase du récepteur TGF-β de type I, en combinaison avec le paclitaxel pour le traitement d'un cancer du sein triplement négatif

TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer

Bhola, Neil E. ; Balko, Justin M. ; Dugger, Teresa C. ; Kuba, Mar ; xEd, ; a, Gabriela ; xE, ; nchez, Violeta ; Sanders, Melinda ; Stanford, Jamie ; Cook, Rebecca S. ; Arteaga, Carlos L.

After an initial response to chemotherapy, many patients with triple-negative breast cancer (TNBC) have recurrence of drug-resistant metastatic disease. Studies with TNBC cells suggest that chemotherapy-resistant populations of cancer stem-like cells (CSCs) with self-renewing and tumor-initiating capacities are responsible for these relapses. TGF-β has been shown to increase stem-like properties in human breast cancer cells. We analyzed RNA expression in matched pairs of primary breast cancer [...]

Mené sur 58 patients atteints d'une tumeur solide, cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale d'un composé appelé OSI-930, une petite molécule par voie orale inhibant l'activité tyrosine kinase de divers récepteurs

First-in-Human Phase I Trial of Two Schedules of OSI-930, a Novel Multikinase Inhibitor, Incorporating Translational Proof-of-Mechanism Studies

Yap, Timothy A. ; Arkenau, Hendrik-Tobias ; Camidge, D. Ross ; George, Suzanne ; Serkova, Natalie J. ; Gwyther, Stephen J. ; Spratlin, Jennifer L. ; Lal, Rohit ; Spicer, James ; Desouza, Nandita M. ; Leach, Martin O. ; Chick, Jon ; Poondru, Srinivasu ; Boinpally, Ramesh ; Gedrich, Richard ; Brock, Katie ; Stephens, Andrew ; Eckhardt, S. Gail ; Kaye, Stan B. ; Demetri, George ; Scurr, Michelle

Purpose: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors. Experimental Design: OSI-930 was administered once or twice a day using a modified accelerated titration design. [...]

Cet article passe en revue les travaux récents sur le développement de traitements anticancéreux basés sur l'inhibition de la voie de signalisation PI3K

Development of PI3K inhibitors: lessons learned from early clinical trials

Rodon, Jordi ; Dienstmann, Rodrigo ; Serra, Violeta ; Tabernero, Josep

The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metabolism, growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumour formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clinical trials. This Review focuses on [...]

Mené sur 21 patients atteints d'une leucémie myéloïde aiguë récidivante ou réfractaire, cet essai de phase I évalue la dose maximale tolérée du vorinostat, un inhibiteur d'histone désacétylase, avant un traitement combinant cytarabine et étoposide

Translational phase I trial of vorinostat combined with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia

Gojo, Ivana ; Tan, Ming T ; Fang, Hong-Bin ; Sadowska, Mariola ; Lapidus, Rena G ; Baer, Maria R. ; Carrier, France ; Beumer, Jan H ; Anyang, Bean N ; Srivastava, Rakesh K ; Espinoza-Delgado, Igor ; Ross, Douglas D

PURPOSE. To determine the maximum tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine and etoposide in patients with poor-risk or advanced acute leukemia; to obtain preliminary efficacy data, describe pharmacokinetics and in vivo pharmacodynamic effects of vorinostat in leukemia blasts. EXPERIMENTAL DESIGN. In this open-label phase I study vorinostat was given orally on days 1-7 at 3 escalating dose levels: 200 mg BID, 200 mg TID, and 300 [...]

Mené sur 40 patients atteints d'un lymphome non hodgkinien à cellules du manteau récidivant ou réfractaire (âge médian : 70 ans), cet essai de phase II évalue, du point de vue du taux de réponse globale observé à l'aide d'une tomographie par émission de positrons, un traitement combinant bendamustine, rituximab et cytarabine

Combination of Rituximab, Bendamustine, and Cytarabine for Patients With Mantle-Cell Non-Hodgkin Lymphoma Ineligible for Intensive Regimens or Autologous Transplantation

Visco, Carlo ; Finotto, Silvia ; Zambello, Renato ; Paolini, Rossella ; Menin, Andrea ; Zanotti, Roberta ; Zaja, Francesco ; Semenzato, Gianpietro ; Pizzolo, Giovanni ; D’Amore, Emanuele S.G. ; Rodeghiero, Francesco

Purpose The combination of bendamustine (B) and rituximab (R) is efficacious, with favorable toxicity in mantle-cell lymphoma (MCL). In this phase II study, we combined cytarabine with R and B (R-BAC) in patients with MCL age ≥ 65 years who were previously untreated or relapsed or refractory (R/R) after one prior immunochemotherapy treatment. Patients and Methods In stage one, we established the maximum-tolerated dose (MTD) of cytarabine in R-BAC. In stage two, patients received R (375 mg/m2 [...]

Mené sur 172 patients atteints d'un lymphome folliculaire transformé, cet essai multicentrique évalue, du point de vue de la survie globale après transformation, l'efficacité d'une greffe autologue ou allogénique de cellules souches en complément d'une chimiothérapie comprenant du rituximab

Autologous and Allogeneic Stem-Cell Transplantation for Transformed Follicular Lymphoma: A Report of the Canadian Blood and Marrow Transplant Group

Villa, Diego ; Crump, Michael ; Panzarella, Tony ; Savage, Kerry J. ; Toze, Cynthia L. ; Stewart, Douglas A. ; MacDonald, David A. ; Buckstein, Rena ; Lee, Christina ; Alzahrani, Mohsen ; Rubinger, Morel ; Foley, Ronan ; Xenocostas, Anargyros ; Sabloff, Mitchell ; Muccilli, Alexandra ; Chua, Neil ; Couture, Felix ; Larouche, Jean-François ; Cohen, Sandra ; Connors, Joseph M. ; Ambler, Kimberley ; Al-Tourah, Abdulwahab ; Ramadan, Khaled M. ; Kuruvilla, John

Purpose To determine whether autologous (auto) or allogeneic (allo) stem-cell transplantation (SCT) improves outcome in patients with transformed follicular lymphoma compared with rituximab-containing chemotherapy alone. Patients and Methods This was a multicenter cohort study of patients with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patient, treatment, and outcome data were collected from each transplantation center and combined for analysis. A [...]

Mené sur 651 patients atteints d'un mélanome de stade avancé, cet essai de phase III évalue, du point de vue de la survie sans progression, l'efficacité de l'elesclomol, un inducteur d'apoptose, en combinaison avec le paclitaxel

Final Results of Phase III SYMMETRY Study: Randomized, Double-Blind Trial of Elesclomol Plus Paclitaxel Versus Paclitaxel Alone As Treatment for Chemotherapy-Naive Patients With Advanced Melanoma

O’Day, Steven J. ; Eggermont, Alexander M.M. ; Chiarion-Sileni, Vanna ; Kefford, Richard ; Grob, Jean Jacques ; Mortier, Laurent ; Robert, Caroline ; Schachter, Jacob ; Testori, Alessandro ; Mackiewicz, Jacek ; Friedlander, Philip ; Garbe, Claus ; Ugurel, Selma ; Collichio, Frances ; Guo, Wei ; Lufkin, Joelle ; Bahcall, Safi ; Vukovic, Vojo ; Hauschild, Axel

Purpose Elesclomol, an investigational first-in-class compound, induces oxidative stress, triggers mitochondrial-induced apoptosis in cancer cells, and shows synergy with taxanes in tumor models. Following completion of a phase II trial of elesclomol in combination with paclitaxel that met its primary end point of progression-free survival (PFS), this randomized, double-blind, controlled phase III study was conducted to confirm the efficacy and tolerability of elesclomol in combination with [...]

Cet article passe en revue les travaux récents sur les inhibiteurs de BRAF pour le traitement d'un mélanome métastatique

Targeting BRAF in melanoma: Biological and clinical challenges

Mandalà, Mario ; Voit, Christiane

Melanoma is an aggressive form of skin cancer that causes the greatest number of skin cancer-related deaths worldwide. In its early stages malignant melanoma can be cured by surgical resection, but once it has progressed to the metastatic stage it is extremely difficult to treat and does not respond to current therapies. A majority of cutaneous melanomas show activating mutations in the NRAS or BRAF proto-oncogenes, components of the Ras-Raf-Mek-Erk (MAPK) signal transduction pathway. The [...]

Mené sur 260 patients atteints d'un mélanome avancé, cet essai de phase III évalue, du point de vue de la survie globale et de la survie sans progression, l'ajout de fotemustine ou d'interféron-alpha 2b à un traitement de référence à base de dacarbazine

Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-alpha in advanced malignant melanoma

Daponte, Antonio ; Signoriello, Simona ; Maiorino, Luigi ; Massidda, Bruno ; Simeone, Ester ; Grimaldi, Antonio ; Caracò, Corrado ; Palmieri, Giuseppe ; Cossu, Antonio ; Botti, Gerardo ; Petrillo, Antonella ; Lastoria, Secondo ; Cavalcanti, Ernesta ; Aprea, Pasquale ; Mozzillo, Nicola ; Gallo, Ciro ; Comella, Giuseppe ; Ascierto, Paolo

BACKGROUND:The effect of the addition of fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial. METHODS:A total of 260 patients were randomly assigned to one of four treatment groups: (A) fotemustine and dacarbazine repeated on 3-week cycle; (B) same treatment as (A) plus IFN-alpha2b three times per week; (C) dacarbazine alone repeated on 3-week cycle; [...]

Mené sur 95 patients atteints d'un adénocarcinome pancréatique localement avancé, cet essai de phase II évalue l'efficacité et la toxicité de l'upamostat, un inhibiteur de l'activateur du plasminogène de type urokinase, en combinaison avec la gemcitabine

Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer

Heinemann, V. ; Ebert, M. P. ; Laubender, R. P. ; Bevan, P. ; Mala, C. ; Boeck, S.

Background: To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma (LAPC). Methods: Within a prospective multicenter study, LAPC patients were randomly assigned to receive 1000 mg m−2 of gemcitabine IV weekly either alone (arm A) or in combination with 200 mg (arm B) or 400 mg (arm C) oral upamostat daily. Efficacy endpoints of this proof-of-concept study included [...]

Cet article passe en revue les travaux récents sur le développement de thérapies ciblées, notamment le crizotinib, pour le traitement des cancers du poumon non à petites cellules avec réarrangements du gène ALK

ALK in Lung Cancer: Past, Present, and Future

Shaw, Alice T. ; Engelman, Jeffrey A.

In 2007, scientists discovered that anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non–small-cell lung cancers. ALK-positive cancers are highly sensitive to small-molecule ALK kinase inhibitors, such as crizotinib. Phase I and II studies of crizotinib in ALK-positive lung cancer demonstrated impressive activity and clinical benefit, leading to rapid US Food and Drug Administration approval in 2011. Although crizotinib induces remissions and extends the [...]

A partir d'une revue de la littérature (15 essais identifiés), cette méta-analyse évalue l'impact, sur la survie et le taux de fractures, de l'usage d'acide zolédronique en traitement adjuvant chez les patientes atteintes d'un cancer du sein de stade précoce

Adjuvant Therapy With Zoledronic Acid in Patients With Breast Cancer: A Systematic Review and Meta-Analysis

Valachis, Antonis ; Polyzos, Nikolaos P. ; Coleman, Robert E. ; Gnant, Michael ; Eidtmann, Holger ; Brufsky, Adam M. ; Aft, Rebecca ; Tevaarwerk, Amye J. ; Swenson, Karen ; Lind, Pehr ; Mauri, Davide

Background. The purpose of the study was to estimate the impact on survival and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of patients with early-stage (stages I–III) breast cancer. Materials and Methods. We performed a systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meeting searches. All trials that randomized patients with primary [...]

Mené sur 52 patientes atteintes d'un cancer du sein de stade avancé, cet essai de phase I évalue la dose maximale tolérée du dasatinib, en combinaison avec la capécitabine, et ses effets sur des biomarqueurs de l'angiogenèse

Dasatinib Plus Capecitabine for Advanced Breast Cancer: Safety and Preliminary Efficacy in Phase I Study CA180004

Somlo, George ; Atzori, Francesco ; Strauss, Lewis C ; Geese, William ; Specht, Jennifer M. ; Gradishar, William J ; Rybicki, Alissa ; Sy, Oumar ; Vahdat, Linda T ; Cortés, Javier

Purpose: Dasatinib is a Src-family kinase inhibitor with modest activity in advanced breast cancer (ABC). We aimed to assess toxicity and maximum tolerated dose (MTD) for dasatinib plus capecitabine, estimate efficacy,and explore effects on angiogenesis. Experimental Design: Dose levels (DL) were: dasatinib 50 mg twice daily (BID; DL1), 70 mg BID (DL2 and DL3), or 100 mg daily (QD; DL3a), plus capecitabine on days 1-14 of a 21-day cycle, at 825 mg/m2 BID (DL1 and DL2) or 1000 mg/m2 BID (DL3 and [...]

Mené sur 45 patientes atteintes d'un cancer avancé de l'endomètre, cet essai de phase II évalue l'efficacité et la toxicité du ridaforolimus, un inhibiteur de la signalisation mTOR

Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial

Colombo, N. ; McMeekin, D. S. ; Schwartz, P. E. ; Sessa, C. ; Gehrig, P. A. ; Holloway, R. ; Braly, P. ; Matei, D. ; Morosky, A. ; Dodion, P. F. ; Einstein, M. H. ; Haluska, F.

Background: This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer. Methods: Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary end point was clinical benefit response, defined as an [...]

Menée in vitro et à l'aide de modèles murins de cancer de la prostate, cette étude montre que l'inhibition de la voie de signalisation du récepteur du facteur CSF-1 abroge l'effet pro-tumorigène des cellules myéloïdes infiltrant les tumeurs et améliore l'efficacité de la radiothérapie

Abrogating the protumorigenic influences of tumor-infiltrating myeloid cells by CSF1R signaling blockade improves the efficacy of radiotherapy in prostate cancer

Xu, Jingying ; Escamilla, Jemima ; Mok, Stephen ; David, John ; Priceman, Saul J ; West, Brian L ; Bollag, Gideon ; McBride, William H ; Wu, Lily

Radiotherapy is a major frontline treatment for prostate cancer patients, yet, a large portion of these patients suffer from local tumor recurrence. Tumor-infiltrating myeloid cells (TIMs), including CD11b+F4/80+ tumor-associated macrophages (TAMs) and CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), play critical roles in promoting tumor angiogenesis, tissue remodeling and immunosuppression. Here, we show enhanced recruitment of TAMs and MDSCs after local irradiation. Although treatment [...]