Menée sur une lignée cellulaire humaine de cancer du côlon, cette étude montre que l'irradiation des cellules dendritiques par rayonnements gamma améliore la réponse immunitaire antitumorale

Enhanced anti-cancer activity of human dendritic cells sensitized with gamma-irradiation-induced apoptotic colon cancer cells

Kim, Sun Kyung ; Yun, Cheol-Heui ; Han, Seung Hyun

Properly sensitized dendritic cells (DCs) can be an effective immunotherapeutic against cancers. We investigated the phenotypic and functional changes in human DCs sensitized with γ-irradiated colon cancer cell-line HT-29 (GIH). GIH induced maturation and activation of DCs. GIH-sensitized DCs showed increased cytotoxic activity against HT-29 through higher expression of perforin and granzyme B. They further induced expression of effector cytokines, cytotoxic molecules, and mucosal-homing [...]

Menée sur 123 patients atteints d'un rétinoblastome unilatéral intraoculaire (durée médiane de suivi : 71 mois), cette étude prospective multicentrique française évalue, du point de vue de la progression de la maladie, de la récidive, de la présence de métastases distantes et du taux de survie, l'intérêt d'une énucléation avec ou sans chimiothérapie adjuvante

Results of a Multicenter Prospective Study on the Postoperative Treatment of Unilateral Retinoblastoma Following Primary Enucleation

Aerts, Isabelle ; Sastre-Garau, Xavier ; Savignoni, Alexia ; Lumbroso-Le Rouic, Livia ; Thebaud-Leculée, Estelle ; Frappaz, Didier ; Coze, Carole ; Thomas, Caroline ; Gauthier-Villars, Marion ; L’evy-Gabriel, Christine ; Brisse, Herv’e J. ; Desjardins, Laurence ; Doz, Francois

Purpose The objective of this prospective study was to assess overall survival and event-free survival in patients with intraocular unilateral retinoblastoma (Reese-Ellsworth group V) treated by primary enucleation with or without adjuvant therapy depending on histopathologic risk factors. Patients and Methods Patients (n = 123) were divided into three groups on the basis of risk factors for extraocular relapse and metastasis assessed on centralized histologic examination of enucleated eyes. [...]

Cet article analyse les travaux récents sur le rôle de la chirurgie dans le cadre des traitements personnalisés d'un cancer du poumon non à petites cellules

Surgery for NSCLC in the era of personalized medicine

Mitsudomi, Tetsuya ; Suda, Kenichi ; Yatabe, Yasushi

The discovery in 2004 of activating mutations in the EGFR gene opened the era of personalized medicine in thoracic oncology. Treatment with drugs that target EGFR typically results in dramatic tumour response compared with conventional chemotherapy in patients with non-small-cell lung cancer. Subsequently, newer driver oncogenes such as ALK, ROS1 and RET have been discovered. Nevertheless, surgery has become safer and less invasive in the past 10–15 years. In the era of personalized medicine, [...]

A partir d'une revue systématique de la littérature publiée entre 1970 et 2012 (16 études), cette étude évalue, par rapport à une radiothérapie fractionnée conventionnelle, l'efficacité et la toxicité d'une radiothérapie hypofractionnée pour traiter un cancer de la prostate

Systematic review of hypofractionated radiation therapy for prostate cancer

Zaorsky, Nicholas G. ; Ohri, Nitin ; Showalter, Timothy N. ; Dicker, Adam P. ; Den, Robert B.

Prostate cancer is the second most prevalent solid tumor diagnosed in men in the United States and Western Europe. Conventionally fractionated external beam radiation therapy (1.8–2.0Gy/fraction) is an established treatment modality for men in all disease risk groups. Emerging evidence from experimental and clinical studies suggests that the α/β ratio for prostate cancer may be as low as 1.5Gy, which has prompted investigators around the world to explore moderately hypofractionated radiation [...]

A partir de données médicales portant sur 13 patients atteints d'un syndrome de Lynch et d'un carcinome urothélial des voies urinaires supérieures (âge moyen : 56,5 ans ; durée moyenne de suivi : 59 mois), cette étude évalue, du point de vue du taux de conservation rénale et du contrôle de la maladie, l'efficacité d'une résection urétéroscopique par laser

Ureteroscopic management of upper tract urothelial carcinoma (UTUC) in patients with Lynch Syndrome (hereditary nonpolyposis colorectal cancer syndrome)

Hubosky, Scott G. ; Boman, Bruce M. ; Charles, Sarah ; Bibbo, Marluce ; Bagley, Demetrius H.

Objectives * To report our experience with ureteroscopic laser ablation of upper tract urothelial carcinoma (UTUC) in patients with Lynch Syndrome (LS), as defined by a documented germline mutation in the MSH-2 gene. * To increase awareness among urologists about UTUC in this unique patient population and refer to genetic counselling when appropriate. Patients and Methods * Demographic, clinical and pathological data on 13 consecutive patients with UTUC and documented MSH-2 mutation comprising [...]

Menée in vitro et sur des échantillons prélevés sur 111 patients atteints d'un cancer de l'estomac, cette étude met en évidence le rôle joué par la protéine YB-1 dans la régulation de l'expression de HER2 et la réponse au lapatinib

Y-box binding protein-1 (YB-1) contributes to both HER2/ErbB2 expression and lapatinib sensitivity in human gastric cancer cells

Shibata, Tomohiro ; Kan, Hitoshi ; Murakami, Yuichi ; Ureshino, Hiroki ; Watari, Kosuke ; Kawahara, Akihiko ; Kage, Masayoshi ; Hattori, Satoshi ; Ono, Mayumi ; Kuwano, Michihiko

Gene amplification of HER2/ErbB2 occurs in gastric cancer, and the therapeutic efficacy of the HER2-targeted antibody, trastuzumab, has recently been improved against HER2-positive advanced stomach cancer. Here we examined whether Y-box-binding protein-1 (YB-1) could selectively control HER2 gene expression and cellular sensitivity to epidermal growth factor receptor (EGFR) family protein-targeted drugs in human gastric cancer cells. HER2 expression was specifically downregulated by YB-1 [...]

Cet article passe en revue les perspectives thérapeutiques offertes par les connaissances récentes sur le rôle de l'ubiquitine ligase Siah dans la progression tumorale

Siah - a promising anti-cancer target

Wong, Christina SF ; Moeller, Andreas

Siah ubiquitin ligases play important roles in a number of signaling pathways involved in the progression and spread of cancer in cell-based models but their role in tumor progression remains controversial. Siah proteins have been described to be both oncogenic as well as tumor-suppressive in a variety of patient cohort studies and animal cancer models. This review collates the current knowledge of Siah in cancer progression and identifies potential methods of translation of these findings into [...]

Cet article passe en revue les perspectives thérapeutiques offertes par les travaux récents sur les mécanismes de résistance aux agents cytotoxiques et aux thérapies ciblées

A Tale of Two Approaches: Complementary Mechanisms of Cytotoxic and Targeted Therapy Resistance May Inform Next Generation Cancer Treatments

Masui, Kenta ; Gini, Beatrice ; Wykosky, Jill ; Zanca, Ciro ; Mischel, Paul S. ; Furnari, Frank ; Cavenee, Webster

Chemotherapy and molecularly targeted approaches represent two very different modes of cancer treatment and each is associated with unique benefits and limitations. Both types of therapy share the overarching limitation of the emergence of drug resistance, which prevents these drugs from eliciting lasting clinical benefit. This review will provide an overview of the various mechanisms of resistance to each of these classes of drugs and examples of drug combinations that have been tested [...]

Cette étude passe en revue les travaux récents sur le rôle du facteur de croissance de l'endothélium vasculaire dans le micro-environnement immunitaire des tumeurs et suggère une stratégie basée sur de faibles doses d'agents antiangiogéniques pour renforcer les effets des immunothérapies

Vascular normalization as an emerging strategy to enhance cancer immunotherapy

Huang, Yuhui ; Goel, Shom ; Duda, Dan G ; Fukumura, Dai ; Jain, Rakesh K.

The recent approval of Provenge has brought new hope for anti-cancer vaccine therapies. However, the immunosuppressive tumor microenvironment seems to impair the efficacy of vaccine therapies. The abnormal tumor vasculature creates a hypoxic microenvironment that polarizes inflammatory cells toward immune suppression. Moreover, tumors systemically alter immune cells' differentiation and their function via secretion of growth factors and cytokines. For example, vascular endothelial growth factor [...]

Cet article passe en revue les perspectives offertes par le ciblage de la survivine pour le développement de traitements anticancéreux

Treat cancers by targeting survivin: Just a dream or future reality?

Coumar, Mohane Selvaraj ; Tsai, Fang-Ying ; Kanwar, Jagat Rakesh ; Sarvagalla, Sailu ; Cheung, Chun Hei Antonio

Since the discovery of survivin (BIRC5) as a cancer-related molecule by Grazia Ambrosini and Dario C. Altieri at 1997, our knowledge related to the function of this molecule has been extended from simple apoptosis inhibition to complicated, interlinked processes that involve interference of mitosis, apoptosis, autophagy, and even DNA repair recently. However, despite the growing amount of knowledge related to survivin in the last ten years, the development of survivin inhibitors or [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes justifiant l'intérêt de développer des thérapies ciblées sur le facteur de croissance des tissus conjonctifs, CTGF, pour le traitement d'un mélanome de stade avancé

CTGF is a therapeutic target for metastatic melanoma

Finger, E. C. ; Cheng, C. F. ; Williams, T. R. ; Rankin, E. B. ; Bedogni, B. ; Tachiki, L. ; Spong, S. ; Giaccia, A. J. ; Powell, M. B.

Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude évalue les effets d'inhibiteurs du micro-ARN 21 sur la croissance des cellules de myélome multiple

Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth

Leone, Emanuela ; Morelli, Eugenio ; Di Martino, Maria T. ; Amodio, Nicola ; Foresta, Umberto ; Gulla', Annamaria ; Rossi, Marco ; Neri, Antonino ; Giordano, Antonio ; Munshi, Nikhil C. ; Anderson, Kenneth C. ; Tagliaferri, Pierosandro ; Tassone, Pierfrancesco

Purpose: Deregulated expression of microRNAs (miRNAs) plays a role in the pathogenesis and progression of multiple myeloma (MM). Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of MM. Experimental design: Here, we investigated the in vitro and in vivo anti-MM activity of miR-21 inhibitors. Results: Either transient enforced expression or lentivirus-based constitutive expression of miR-21 inhibitors triggered significant [...]

Cet article passe en revue les perspectives offertes par différents inhibiteurs de mTOR (temsirolimus, everolimus et nouveaux agents en développement) pour le traitement d'un carcinome à cellules rénales

Differentiating mTOR inhibitors in renal cell carcinoma

Pal, Sumanta K. ; Quinn, David I.

PI3K/Akt/mTOR signalling is dysregulated in many cancers, including renal cell carcinoma (RCC), and activation of this pathway has been suggested to correlate with aggressive behavior and poor prognosis in RCC tumors. mTOR inhibition plays a principal role in the targeted treatment of many cancer types, including RCC. Although mTOR inhibitors share the same mechanism of action, differences in metabolism, formulation and dosing schedule underpin distinct PK/PD profiles such that they may be [...]

Menée in vitro et in vivo, cette étude identifie des mécanismes justifiant l'intérêt de cibler la signalisation Wnt, via l'un de ses récepteurs FZD8, pour surmonter une résistance au cisplatine dans le traitement d'un cancer du sein triplement négatif

Tumor Initiating Cells and FZD8 play a major role in drug resistance in Triple- Negative Breast Cancer

Yin, Shuping ; Xu, Liping ; Bonfil, R. Daniel ; Banerjee, Sanjeev ; Sarkar, Fazlul H. ; Sethi, Seema ; Reddy, Kaladhar B

Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority who had residual tumor had a relatively poor outcome. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially performed gene expression profiling using the CRL2335 TNBC cell line derived from a squamous breast carcinoma before and after treatment with cisplatin plus TRAIL. We found a significant [...]

Menée sur des lignées cellulaires, à l'aide de xénogreffes et sur des échantillons de tissus de tumeurs primitives et de métastases prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence le rôle joué par le récepteur HER2 dans les cellules souches de cancer du sein HER2- de type luminal et en tire des conséquences pour améliorer l'efficacité du trastuzumab en traitement adjuvant

HER2 Drives Luminal Breast Cancer Stem Cells in the Absence of HER2 Amplification: Implications for Efficacy of Adjuvant Trastuzumab

Ithimakin, Suthinee ; Day, Kathleen C. ; Malik, Fayaz ; Zen, Qin ; Dawsey, Scott J. ; Bersano-Begey, Tom F. ; Quraishi, Ahmed A. ; Ignatoski, Kathleen Woods ; Daignault, Stephanie ; Davis, April ; Hall, Christopher L. ; Palanisamy, Nallasivam ; Heath, Amber N. ; Tawakkol, Nader ; Luther, Tahra K. ; Clouthier, Shawn G. ; Chadwick, Whitney A. ; Day, Mark L. ; Kleer, Celina G. ; Thomas, Dafydd G. ; Hayes, Daniel F. ; Korkaya, Hasan ; Wicha, Max S.

Although current breast cancer treatment guidelines limit the use of HER2-blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Using breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we show that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell (CSC) population in estrogen receptor-positive (ER+), HER2− luminal [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes suggérant l'intérêt de développer des inhibiteurs du facteur de croissance placentaire pour le traitement des médulloblastomes

Targeting Placental Growth Factor/Neuropilin 1 Pathway Inhibits Growth and Spread of Medulloblastoma

Snuderl, Matija ; Batista, Ana ; Kirkpatrick, Nathaniel D ; Ruiz de Almodovar, Carmen ; Riedemann, Lars ; Walsh, Elisa C ; Anolik, Rachel ; Huang, Yuhui ; Martin, John D ; Kamoun, Walid ; Knevels, Ellen ; Schmidt, Thomas ; Farrar, Christian T ; Vakoc, Benjamin J ; Mohan, Nishant ; Chung, Euiheon ; Roberge, Sylvie ; Peterson, Teresa ; Bais, Carlos ; Zhelyazkova, Boryana H ; Yip, Stephen ; Hasselblatt, Martin ; Rossig, Claudia ; Niemeyer, Elisabeth ; Ferrara, Napoleone ; Klagsbrun, Michael ; Duda, Dan G ; Fukumura, Dai ; Xu, Lei ; Carmeliet, Peter ; Jain, Rakesh K

Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth [...]

Menée in vitro, in vivo et sur des échantillons tumoraux prélevés sur des patients atteints d'un glioblastome et inclus dans des essais de phase I, cette étude met en évidence le rôle joué par le gène PML dans la résistance à un traitement à base d'inhibiteurs de mTOR et EGFR

PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies

Iwanami, Akio ; Gini, Beatrice ; Zanca, Ciro ; Matsutani, Tomoo ; Assuncao, Alvaro ; Nael, Ali ; Dang, Julie ; Yang, Huijun ; Zhu, Shaojun ; Kohyama, Jun ; Kitabayashi, Issay ; Cavenee, Webster K. ; Cloughesy, Timothy F. ; Furnari, Frank B. ; Nakamura, Masaya ; Toyama, Yoshiaki ; Okano, Hideyuki ; Mischel, Paul S.

Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote [...]

Cet artcle passe en revue les développements cliniques récents de thérapies ciblées sur le récepteur à activité tyrosine kinase MET et son ligand, le facteur de croissance des hépatocytes HGF

The emerging role of MET/HGF inhibitors in oncology

Scagliotti, Giorgio V. ; Novello, Silvia ; von Pawel, Joachim

The N-methyl-N′-nitroso-guanidine human osteosarcoma transforming gene (MET) receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) control cellular signaling cascades that direct cell growth, proliferation, survival, and motility. Aberrant MET/HGF activation has been observed in many tumor types, can occur by multiple mechanisms, and promotes cellular proliferation and metastasis via growth factor receptors and other oncogenic receptor pathways. Thus, MET/HGF inhibition has [...]

A partir d'une revue systématique de la littérature (60 essais, 8 526 patients), cette méta-analyse évalue les risques de développer une neutropénie, une thrombocytopénie ou une anémie en association avec un traitement par sunitinib

Risk of hematologic toxicities in cancer patients treated with sunitinib: A systematic review and meta-analysis

Funakoshi, Tomohiro ; Latif, Asma ; Galsky, Matthew D.

Background : The incidence and risk of unique toxicities associated with a multi-targeted tyrosine kinase inhibitor sunitinib, such as hypertension and thromboembolic events, have been previously reported. However, the incidence and risk of hematologic toxicities have been less well characterized. We performed an up-to-date meta-analysis of trials to evaluate the risk of sunitinib-related hematologic toxicities. Methods : We searched Medline and the American Society of Clinical Oncology online [...]

Mené sur 73 patients atteints d'une leucémie myéloïde aiguë récidivante ou réfractaire (âge supérieur à 60 ans), cet essai de phase II évalue, du point de vue du pourcentage de patients en rémission complète, deux protocoles d'administration du tosedostat, un inhibiteur d'aminopeptidase par voie orale

Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study

Cortes, Jorge ; Feldman, Eric ; Yee, Karen ; Rizzieri, David ; Advani, Anjali S. ; Charman, Anthony ; Spruyt, Richard ; Toal, Martin ; Kantarjian, Hagop

Bacjground : Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1-2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat. Methods : In this randomised phase 2 study, patients aged 60 years or older with AML that had relapsed after a first complete remission lasting less than 12 months, or had achieved no previous complete remission, were randomly assigned (1:1) to [...]

Menée sur 11 patients atteints d'une leucémie à pronostic défavorable et ayant reçu une greffe de moelle osseuse, cette étude évalue la faisabilité et l'intérêt d'un protocole utilisant des lymphocytes T du donneur sélectionnés pour leur capacité à reconnaître WT1

Transferred WT1-Reactive CD8+ T Cells Can Mediate Antileukemic Activity and Persist in Post-Transplant Patients

Chapuis, Aude G. ; Ragnarsson, Gunnar B. ; Nguyen, Hieu N. ; Chaney, Colette N. ; Pufnock, Jeffrey S. ; Schmitt, Thomas M. ; Duerkopp, Natalie ; Roberts, Ilana M. ; Pogosov, Galina L. ; Ho, William Y. ; Ochsenreither, Sebastian ; Wölfl, Matthias ; Bar, Merav ; Radich, Jerald P. ; Yee, Cassian ; Greenberg, Philip D.

Relapse remains a leading cause of death after allogeneic hematopoietic cell transplantation (HCT) for patients with high-risk leukemias. The potentially beneficial donor T cell–mediated graft-versus-leukemia (GVL) effect is often mitigated by concurrent graft-versus-host disease (GVHD). Providing T cells that can selectively target Wilms tumor antigen 1 (WT1), a transcription factor overexpressed in leukemias that contributes to the malignant phenotype, represents an opportunity to promote [...]

Mené sur 196 patients atteints d'un cancer métastatique du pancréas, cet essai de phase II évalue, du point de vue du taux de survie à six mois, l'ajout d'un composé appelé AGS-1C4D4, un anticorps monoclonal anti PSCA, à la gemcitabine

Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer

Wolpin, B. M. ; O'Reilly, E. M. ; Ko, Y. J. ; Blaszkowsky, L. S. ; Rarick, M. ; Rocha-Lima, C. M. ; Ritch, P. ; Chan, E. ; Spratlin, J. ; Macarulla, T. ; McWhirter, E. ; Pezet, D. ; Lichinitser, M. ; Roman, L. ; Hartford, A. ; Morrison, K. ; Jackson, L. ; Vincent, M. ; Reyno, L. ; Hidalgo, M.

Background We evaluated AGS-1C4D4, a fully human monoclonal antibody to prostate stem cell antigen (PSCA), with gemcitabine in a randomized, phase II study of metastatic pancreatic cancer. Patients and methods Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and previously untreated, metastatic pancreatic adenocarcinoma were randomly assigned 1:2 to gemcitabine (1000 mg/m2 weekly seven times, 1 week rest, weekly three times q4weeks) or gemcitabine plus AGS-1C4D4 [...]

Menée sur 31 patients atteints d'un mélanome avancé, cette étude évalue l'intérêt de traiter à nouveau les patients dont les tumeurs avaient initialement répondu à l'ipilimumab puis avaient progressé

Efficacy and Safety of Retreatment with Ipilimumab in Patients with Pretreated Advanced Melanoma who Progressed after Initially Achieving Disease Control

Robert, Caroline ; Schadendorf, Dirk ; Messina, Marianne ; Hodi, F. Stephen ; O'Day, Steven

Purpose:Ipilimumab is a fully human monoclonal antibody against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) that has been shown to improve survival in patients with pretreated, advanced melanoma in a phase III trial. Some patients in this study who initially responded to ipilimumab treatment but later progressed were eligible for retreatment with their original randomized regimen. Here, outcomes for these patients concerning baseline characteristics, best overall response, and disease [...]

A partir de données portant sur 520 patients atteints d'un mélanome métastatique, cette étude analyse les caractéristiques des événements indésirables de nature dermatologique associés à un traitement par vemurafenib

Analysis of Dermatologic Events in Vemurafenib-Treated Patients With Melanoma

Lacouture, Mario E. ; Duvic, Madeleine ; Hauschild, Axel ; Prieto, Victor G. ; Robert, Caroline ; Schadendorf, Dirk ; Kim, Caroline C. ; McCormack, Christopher J. ; Myskowski, Patricia L. ; Spleiss, Olivia ; Trunzer, Kerstin ; Su, Fei ; Nelson, Betty ; Nolop, Keith B. ; Grippo, Joseph F. ; Lee, Richard J. ; Klimek, Matthew J. ; Troy, James L. ; Joe, Andrew K.

Background. Vemurafenib has been approved for the treatment of patients with advanced BRAFV600E-mutant melanoma. This report by the Vemurafenib Dermatology Working Group presents the characteristics of dermatologic adverse events (AEs) that occur in vemurafenib-treated patients, including cutaneous squamous cell carcinoma (cuSCC). Methods. Dermatologic AEs were assessed from three ongoing trials of BRAFV600E mutation-positive advanced melanoma. Histologic central review and genetic [...]

Mené sur 10 patients atteints d'un mélanome présentant une mutation V600E/K du gène BRAF, cet essai de phase II évalue la réponse au selemutinib, un inhibiteur de MEK, en fonction de l'activation de la voie de signalisation PI3K/AKT

Phase II trial of MEK inhibitor selumetinib (AZD6244) in patients with BRAFV600E/K-mutated melanoma

Catalanotti, Federica ; Solit, David B. ; Pulitzer, Melissa P. ; Berger, Michael ; Scott, Sasinya N. ; Iyriboz, Tunc ; Lacouture, Mario E. ; Panageas, Katherine ; Wolchok, Jedd D. ; Carvajal, Richard D. ; Schwartz, Gary K. ; Rosen, Neal ; Chapman, Paul B.

Purpose: Test the hypothesis that in BRAF-mutated melanomas, clinical responses to selumetinib, a MEK inhibitor, will be restricted to tumors in which the PI3K/AKT pathway is not activated. Experimental Design: We conducted a phase II trial in patients with BRAF-mutated melanoma. Patients were stratified by phosphorylated-AKT (pAKT) expression (high vs. low) and treated with selumetinib 75 mg po bid. Pre-treatment tumors were also analyzed for genetic changes in 230 genes of interest using an [...]

Mené sur 40 patients atteints d'un myélome multiple ayant récidivé ou progressé, cet essai de phase I évalue la dose maximale tolérée du carfilzomib, un inhibiteur sélectif du protéasome, en combinaison avec du lénalidomide et de la dexaméthasone à faible dose

Phase Ib Dose-escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Progressive Multiple Myeloma

Niesvizky, Ruben ; Martin, Thomas G. ; Bensinger, William ; Alsina, Melissa ; Siegel, David S. ; Kunkel, Lori A. ; Wong, Alvin F. ; Lee, Susan J ; Orlowski, Robert Z ; Wang, Michael

Purpose: Carfilzomib, a selective proteasome inhibitor, has demonstrated safety and efficacy in relapsed and/or refractory multiple myeloma. This Phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a Phase II expansion study. Experimental Design: Patients with multiple myeloma who relapsed after 1-3 prior regimens [...]

Mené sur 160 patientes atteintes d'un cancer du sein HER- de stade avancé ayant progressé pendant ou après un traitement à l'aide de bevacizumab, cet essai de phase IIb évalue, du point de vue de la survie sans progression, l'ajout de sorafenib à la gemcitabine ou la capécitabine

Sorafenib With Gemcitabine or Capecitabine in Patients With HER-2 Negative Advanced Breast Cancer That Progressed During or After Bevacizumab

Schwartzberg, Lee S. ; Tauer, Kurt W. ; Hermann, Robert C. ; Makari-Judson, Grace ; Isaacs, Claudine ; Beck, J. Thaddeus ; Kaklamani, Virginia ; Stepanski, Edward J. ; Rugo, Hope ; Wang, Wei ; Bell-McGuinn, Katherine ; Kirshner, Jeffrey ; Eisenberg, Peter D. ; Emanuelson, Richard ; Keaton, Mark R. ; Levine, Ellis ; Medgyesy, Diana C. ; Qamar, Rubina ; Starr, Alexander ; Kwon Ro, Sunhee ; Lokker, Nathalie A. ; Hudis, Clifford A.

Purpose:We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab. Experimental Design:This double-blind, randomized, placebo-controlled phase 2b study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic HER2-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily [...]

Cet article présente un système liposomal combinant un monoacide dérivé de la benzoporphyrine A et un anticorps monoclonal anti-récepteur EGFR, le cetuximab, pour traiter un cancer de l'ovaire par immunophotothérapie

A new nanoconstruct for epidermal growth factor receptor-targeted photo-immunotherapy of ovarian cancer

Mir, Youssef ; Elrington, Stefan A. ; Hasan, Tayyaba

Targeted photodynamic therapy (TPDT) involves the administration of a photosensitizer (PS) conjugated with a targeting moiety followed by light activation. The systemic toxicity associated with conventional therapy may thus be significantly reduced in TPDT due to the dual selectivity provided by the spatial localization of the illumination as well as the target-localizing ability of the conjugate. Herein, a Photo-Immuno-Conjugate-Associating-Liposome (PICAL) for TPDT has been developed in which [...]

Menée sur des lignées cellulaires de cancer du poumon non à petites cellules, cette étude montre que le crizotinib, un inhibiteur de la tyrosine kinase de la protéine ALK, augmente la sensibilité aux rayonnements ionisants des cellules tumorales présentant une fusion des gènes EML4 et ALK

ALK inhibitor PF02341066 (crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK

Sun, Yunguang ; Nowak, Kamila A ; Zaorsky, Nicholas G ; Winchester, Chia-Lin C ; Dalal, Kunal ; Giacalone, Nicholas J ; Liu, Ningbo ; Werner-Wasik, Maria ; Wasik, Mariusz A ; Dicker, Adam P. ; Lu, Bo

Crizotinib (PF02341066) is a tyrosine kinase inhibitor of ALK that has been shown to selectively inhibit growth of cancer cells that harbor the EML4-ALK fusion, found in a subset of patients with non-small cell lung cancer (NSCLC). While in clinical trials PF02341066 has shown a significant therapeutic benefit as a single agent, the effectiveness of combining it with other therapeutic modalities including ionizing radiation remains unknown. To further elucidate the role of PF02341066 in tumor [...]

Menée sur un modèle murin de gliome intracrânien, cette étude montre qu'un traitement combinant une radiothérapie stéréotaxique et une immunothérapie à base d'un anticorps anti récepteur PD-1 peut améliorer la survie à long terme

Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas

Zeng, Jing ; See, Alfred P. ; Phallen, Jillian ; Jackson, Christopher M. ; Belcaid, Zineb ; Ruzevick, Jacob ; Durham, Nicholas ; Meyer, Christian ; Harris, Timothy J. ; Albesiano, Emilia ; Pradilla, Gustavo ; Ford, Eric ; Wong, John ; Hammers, Hans-Joerg ; Mathios, Dimitris ; Tyler, Betty ; Brem, Henry ; Tran, Phuoc T. ; Pardoll, Drew ; Drake, Charles G. ; Lim, Michael

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which [...]

A partir d'une revue systématique de la littérature publiée entre 2005 et 2012 (16 essais cliniques de phase III), cette étude évalue la toxicité et l'efficacité de diverses modalités thérapeutiques pour traiter un glioblastome (résection chirurgicale, radiothérapie, chimiothérapie, combinaison de traitements et thérapie ciblée), puis analyse les controverses associées

The treatment of glioblastomas: A systematic update on clinical Phase III trials

Yin, An-an ; Cheng, Jin-xiang ; Zhang, Xiang ; Liu, Bo-lin

Glioblastomas (GBMs) are invariably associated with unavoidable tumor recurrence and overall poor prognosis. The present study is to summarize the results of clinical Phase III studies on GBMs over the past seven years. A systematic literature search was performed using major electronic databases and by screening meeting abstracts. Totally, 16 studies of patients with newly diagnosed GBMs, recurrent GBMs, and elderly patients with GBMs were selected for this review. Although the outcomes of the [...]

Menée sur 173 patients atteints d'un glioblastome traité par résection puis chimioradiothérapie, cette étude évalue, du point de vue de la survie sans progression et de la survie globale, l'intérêt d'une forte dose de rayonnements ciblant les cellules souches cancéreuses de la zone sous-ventriculaire homolatérale du cerveau

Evaluation of High Ipsilateral Subventricular Zone Radiation Therapy Dose in Glioblastoma: A Pooled Analysis

Lee, Percy ; Eppinga, Wietse ; Lagerwaard, Frank ; Cloughesy, Timothy ; Slotman, Benjamin ; Nghiemphu, Phioanh L. ; Wang, Pin-Chieh ; Kupelian, Patrick ; Agazaryan, Nzhde ; Demarco, John ; Selch, Michael T. ; Steinberg, Michael ; Kang, Jung Julie

Cancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma. 173 patients with glioblastoma pooled from 2 academic centers were treated with resection followed by chemoradiation [...]