Menée in vitro et à l'aide de modèles murins de cancer du poumon non à petites cellules, cette étude évalue l'intérêt d'une nanoparticule comportant le promédicament "cisplatine-polysilsesquioxane" pour améliorer l'efficacité d'une chimioradiothérapie à base de cisplatine

Polysilsesquioxane Nanoparticles for Triggered Release of Cisplatin and Effective Cancer Chemoradiotherapy

Rocca, Joseph Della ; Werner, Michael E. ; Kramer, Stephanie A. ; Huxford-Phillips, Rachel C. ; Sukumar, Rohit ; Cummings, Natalie D. ; Vivero-Escoto, Juan L. ; Wang, Andrew Z. ; Lin, Wenbin

Chemoradiotherapy is a well-established treatment paradigm in oncology. There has been strong interest in identifying strategies to further improve its therapeutic index. An innovative strategy is to utilize nanoparticle (NP)chemotherapeutics in chemoradiation. Since the most commonly utilized chemotherapeutic with radiotherapy is cisplatin, the development of a NP cisplatin for chemoradiotherapy has the highest potential impact on this treatment. Here, we report the development of a NP [...]

Menée à l'aide de xénogreffes sur des modèles murins, cette étude française met en évidence l'intérêt d'une radiothérapie à très haut débit de dose (durée des impulsions : ≤500 ms ; débit de la dose de rayonnements ionisants : ≥40 Gy/s ) pour réduire la croissance tumorale et les atteintes aux tissus sains

Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice

Favaudon, Vincent ; Caplier, Laura ; Monceau, Virginie ; Pouzoulet, Frédéric ; Sayarath, Mano ; Fouillade, Charles ; Poupon, Marie-France ; Brito, Isabel ; Hupé, Philippe ; Bourhis, Jean ; Hall, Janet ; Fontaine, Jean-Jacques ; Vozenin, Marie-Catherine

In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤500 ms) of radiation delivered at ultrahigh dose rate (≥40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤0.03 Gy/s, CONV) in single doses. The growth of human [...]

A partir d'une revue de la littérature publiée entre 2000 et 2012 (63 études, 11 921 patients), cette méta-analyse compare, du point de vue de la survie sans maladie et de la survie globale à 1, 3 et 5 ans, l'efficacité d'une radiothérapie corporelle stéréotaxique et d'un traitement chirurgical chez les patients atteints d'un cancer du poumon non à petites cellules de stade I

Survival Outcome After Stereotactic Body Radiation Therapy and Surgery for Stage I Non-Small Cell Lung Cancer: A Meta-Analysis

Zheng, Xiangpeng ; Schipper, Matthew ; Kidwell, Kelley ; Lin, Jules ; Reddy, Rishindra ; Ren, Yanping ; Chang, Andrew ; Lv, Fanzhen ; Orringer, Mark ; Spring Kong, Feng-Ming

Purpose : This study compared treatment outcomes of stereotactic body radiation therapy (SBRT) with those of surgery in stage I non-small cell lung cancer (NSCLC). Methods and Materials : Eligible studies of SBRT and surgery were retrieved through extensive searches of the PubMed, Medline, Embase, and Cochrane library databases from 2000 to 2012. Original English publications of stage I NSCLC with adequate sample sizes and adequate SBRT doses were included. A multivariate random effects model [...]

Mené sur 254 patients atteints d'un cancer de la vessie sans envahissement musculaire, cet essai compare, du point de vue de la survie sans récidive à 2 ans, l'efficacité de deux modalités de résection transuréthrale, l'une ulitisant la cytoscopie en imagerie à bande étroite et l'autre la cytoscopie en lumière blanche

Randomized Trial of Narrow-band Versus White-light Cystoscopy for Restaging (Second-look) Transurethral Resection of Bladder Tumors

Herr, Harry W.

Narrow-band imaging (NBI) cystoscopy detects more bladder tumors than standard white-light imaging (WLI) cystoscopy, but it is unclear whether NBI improves transurethral resection (TUR) of bladder tumors. This study compares 2-yr recurrence-free survival (RFS) of patients with non–muscle-invasive bladder tumors following restaging TUR using NBI or WLI cystoscopy. Patients were randomized 1:1 to undergo NBI-assisted TUR (NBI-TUR) or WLI-assisted TUR (WLI-TUR). The main outcome was number of [...]

Cet article passe en revue les perspectives offertes par le ciblage d'éléments de la signalisation adénosinergique pour le développement de traitements anticancéreux

Targeting Cancer-Derived Adenosine: New Therapeutic Approaches

Young, Arabella ; Mittal, Deepak ; Stagg, John ; Smyth, Mark J.

CD73 generation of immunosuppressive adenosine within the hypoxic tumor microenvironment causes dysregulation of immune cell infiltrates, resulting in tumor progression, metastases, and poor disease outcomes. Therapies targeted toward the adenosinergic pathway, such as antibodies targeting CD73 and CD39, have proven efficacy in mouse tumor models; however, humanized versions are only in preliminary development. In contrast, A2A adenosine receptor antagonists have progressed to late-stage [...]

Menée sur des lignées cellulaires de neuroblastome et un modèle murin de médulloblastome, cette étude met en évidence l'intérêt de lymphocytes NKT, manipulés pour exprimer un récepteur d'antigène chimérique contre le ganglioside GD2, pour réduire la toxicité associée à cette forme d'immunothérapie

Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy

Heczey, Andras ; Liu, Daofeng ; Tian, Gengwen ; Courtney, Amy N. ; Wei, Jie ; Marinova, Ekaterina ; Gao, Xiuhua ; Guo, Linjie ; Yvon, Eric ; Hicks, John ; Liu, Hao ; Dotti, Gianpietro ; Metelitsa, Leonid S.

Advances in the design of chimeric antigen receptors (CARs) have improved the antitumor efficacy of redirected T cells. However, functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. We proposed that CAR expression in Vα24-invariant NKT cells (NKTs) can build upon the natural antitumor properties of these cells while their restriction by monomorphic CD1d limits toxicity. Primary human NKTs were engineered to express a CAR against the GD2 [...]

Cet article passe en revue les perspectives offertes par le ciblage d'éléments de la voie de signalisation de la transition épithélio-mésenchymateuse pour le développement de traitements des cancers

Targeting EMT in cancer: opportunities for pharmacological intervention

Davis, Felicity M. ; Stewart, Teneale A. ; Thompson, Erik W. ; Monteith, Gregory R.

The spread of cancer cells to distant organs represents a major clinical challenge in the treatment of cancer. Epithelial–mesenchymal transition (EMT) has emerged as a key regulator of metastasis in some cancers by conferring an invasive phenotype. As well as facilitating metastasis, EMT is thought to generate cancer stem cells and contribute to therapy resistance. Therefore, the EMT pathway is of great therapeutic interest in the treatment of cancer and could be targeted either to prevent [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes suggérant que l'inhibition combinée des signalisations PI3K et Notch1 favorise l'apparition d'une résistance thérapeutique dans les leucémies aiguës lymphoblastiques T

Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia

Dail, Monique ; Wong, Jason ; Lawrence, Jessica ; O/'Connor, Daniel ; Nakitandwe, Joy ; Chen, Shann-Ching ; Xu, Jin ; Lee, Leslie B. ; Akagi, Keiko ; Li, Qing ; Aster, Jon C. ; Pear, Warren S. ; Downing, James R. ; Sampath, Deepak ; Shannon, Kevin

Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and KrasG12D mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels un anticorps monoclonal bloquant la signalisation ERBB3 augmente l'efficacité d'un inhibiteur de RAF dans le traitement d'un mélanome présentant un gène BRAF muté

Function-Blocking ERBB3 Antibody Inhibits the Adaptive Response to RAF Inhibitor

Kugel, Curtis H. ; Hartsough, Edward J. ; Davies, Michael A. ; Setiady, Yulius Y. ; Aplin, Andrew E.

ERBB3/HER3 expression and signaling are upregulated in mutant BRAF melanoma as an adaptive, prosurvival response to FDA-approved RAF inhibitors. Because compensatory ERBB3 signaling counteracts the effects of RAF inhibitors, cotargeting ERBB3 may increase the efficacy of RAF inhibitors in mutant BRAF models of melanoma. Here, we corroborate this concept by showing that the ERBB3 function-blocking monoclonal antibody huHER3-8 can inhibit neuregulin-1 activation of ERBB3 and downstream signaling [...]

A partir d'un modèle numérique, puis menée in vitro et in vivo, cette étude suggère l'intérêt du citalopram, un anti-dépresseur, pour le traitement d'un cancer colorectal

Novel drug candidates for the treatment of metastatic colorectal cancer through global inverse gene expression profiling

van Noort, Vera v ; Schölch, Sebastian ; Iskar, Murat ; Zeller, Georg ; Ostertag, Kristina ; Schweitzer, Christine ; Werner, Kristin ; Weitz, Juergen ; Koch, Moritz ; Bork, Peer

Drug-induced gene expression profiles that invert disease profiles have recently been illustrated to be a starting point for drug-repositioning. In this study, we validate this approach and focus on prediction of novel drugs for colorectal cancer (CRC), for which there is a pressing need to find novel anti-metastatic compounds. We computationally predicted three novel and still unknown compounds against CRC; citalopram (an anti-depressant), troglitazone (an anti-diabetic) and enilconazole (a [...]

Menée sur des lignées cellulaires de cancer du sein et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé CFI-400945, un inhibiteur de PLK4, notamment pour les tumeurs présentant un déficit d'expression du gène PTEN

Functional Characterization of CFI-400945, a Polo-like Kinase 4 Inhibitor, as a Potential Anticancer Agent

Mason, Jacqueline M ; Lin, Dan Chi-Chia ; Wei, Xin ; Che, Yi ; Yao, Yi ; Kiarash, Reza ; Cescon, David W ; Fletcher, Graham C ; Awrey, Donald E ; Bray, Mark R ; Pan, Guohua ; Mak, Tak W

PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing [...]

Cet article passe en revue les travaux récents permettant de définir une stratégie intégrant des inhibiteurs de la signalisation BCR, tel que l'ibrutinib, dans le traitement des patients atteints d'une leucémie lymphocytaire chronique

Entering the Era of Targeted Therapy for Chronic Lymphocytic Leukemia: Impact on the Practicing Clinician

Byrd, John C. ; Jones, Jeffrey J. ; Woyach, Jennifer A. ; Johnson, Amy J. ; Flynn, Joseph M.

Purpose : Chemoimmunotherapy has been the standard of care for chronic lymphocytic leukemia (CLL). However, the introduction of B-cell receptor (BCR) kinase inhibitors such as ibrutinib has the potential to eliminate the role of chemotherapy in the treatment of CLL. How to best incorporate old and new therapies for CLL in this landscape is increasingly complex. Methods : This article reviews current data available to clinicians and integrates these data to provide a strategy that can be used to [...]

Mené sur 471 patients atteints d'un carcinome métastatique à cellules rénales, cet essai multicentrique de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'évérolimus en traitement de première ligne suivi par du sunitinib à l'observation de la progression de la maladie, par comparaison avec la séquence de référence sunitinib-évérolimus

Phase II Randomized Trial Comparing Sequential First-Line Everolimus and Second-Line Sunitinib Versus First-Line Sunitinib and Second-Line Everolimus in Patients With Metastatic Renal Cell Carcinoma

Motzer, Robert J. ; Barrios, Carlos H. ; Kim, Tae Min ; Falcon, Silvia ; Cosgriff, Thomas ; Harker, W. Graydon ; Srimuninnimit, Vichien ; Pittman, Ken ; Sabbatini, Roberto ; Rha, Sun Young ; Flaig, Thomas W. ; Page, Ray ; Bavbek, Sevil ; Beck, J. Thaddeus ; Patel, Poulam ; Cheung, Foon-yiu ; Yadav, Sunil ; Schiff, Edward M. ; Wang, Xufang ; Niolat, Julie ; Sellami, Dalila ; Anak, Oezlem ; Knox, Jennifer J.

Purpose : A multicenter, randomized phase II trial, RECORD-3, was conducted to compare first-line everolimus followed by sunitinib at progression with the standard sequence of first-line sunitinib followed by everolimus in patients with metastatic renal cell carcinoma. Patients and Methods : RECORD-3 used a crossover treatment design. The primary objective was to assess progression-free survival (PFS) noninferiority of first-line everolimus compared with first-line sunitinib. Secondary end [...]

Menée à partir de données du registre américain des cancers portant sur 287 patients atteints d'un carcinome à petites cellules de la prostate de stade localisé diagnostiqué entre 1998 et 2011, cette étude identifie les modalités de traitement et évalue leurs effets sur la survie globale

Population-based analysis of treatment modalities and survival for clinically localized small-cell carcinoma of the prostate

Weiner, A. B. ; Patel, S. G. ; Richards, K. A. ; Szmulewitz, R. Z. ; Eggener, S. E.

Background : Small-cell carcinoma of the prostate is an aggressive cancer whose rarity has prevented the development of a consensus management approach. The objective of the current study was to determine the treatment patterns and evaluate factors affecting overall survival for patients with localized small-cell carcinoma of the prostate. Methods : After querying the National Cancer Database, we identified all patients diagnosed with localized small-cell carcinoma of the prostate between 1998 [...]

A partir de l'analyse de 239 essais de phase I ayant évalué un vaccin thérapeutique chez des patients atteints de cancer, cette étude suggère que le schéma traditionnel avec escalade de dose est mal adapté à l'évaluation de ces vaccins, puis propose un schéma mieux adapté

Is the "3+3" dose escalation phase 1 clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design

Rahma, Osama E ; Gammoh, Emily ; Simon, Richard ; Khleif, Samir N

Purpose: Phase 1 clinical trials are generally conducted to identify the maximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose escalation design. This design may not be applied to cancer vaccines, given their unique mechanism of action. The FDA recently published "Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines." However, many questions about the design of cancer vaccine studies remain unanswered. Experimental Design: We [...]

Signé par quatre auteurs français, cet article passe en revue les enjeux organisationnels et économiques associés à la mise en place de traitements personnalisés des patients atteints de cancer

Personalized Treatments of Cancer Patients A Reality in Daily Practice, A Costly Dream or a Shared Vision of the Future From the Oncology Community?

Arnedos, Monica ; Soria, Jean-Charles ; Andre, Fabrice ; Tursz, Thomas

Therapies targeting activated oncogenes have been associated with several successes in the last decades that are described in this review, together with their limits and related unsolved questions. Most of the tumours will eventually develop drug resistance potentially due to intratumor heterogeneity and selection of additional molecular events. Moreover, studies in the field of molecular characterisation of cancers have shown that most tumors include large number of rare genomic events. [...]

Cet article passe en revue les travaux récents sur la caractérisation moléculaire et la prise en charge clinique d'un cancer du sein de type luminal B, ainsi que les perspectives en matière de développement de thérapies ciblées

Luminal B Breast Cancer: Molecular Characterization, Clinical Management, and Future Perspectives

Ades, Felipe ; Zardavas, Dimitrios ; Bozovic-Spasojevic, Ivana ; Pugliano, Lina ; Fumagalli, Debora ; de Azambuja, Evandro ; Viale, Giuseppe ; Sotiriou, Christos ; Piccart, Martine

Gene expression profiling has reshaped our understanding of breast cancer by defining and characterizing four main intrinsic molecular subtypes: human epidermal growth factor receptor 2–enriched, basal-like, luminal A, and luminal B subtypes. Luminal B breast cancer has been reported to have lower expression of hormone receptors, higher expression of proliferation markers, and higher histologic grade than luminal A. It also exhibits worse prognosis and has a distinct profile of response to [...]