Cet article présente le principe et les avantages d'une nouvelle technique d'imagerie utilisant la fluorescence dans le proche infrarouge pour le traitement chirurgical des cancers

Image-guided cancer surgery using near-infrared fluorescence

Vahrmeijer, Alexander L. ; Hutteman, Merlijn ; van der Vorst, Joost R. ; van de Velde, Cornelis J. H. ; Frangioni, John V.

Paradigm shifts in surgery arise when surgeons are empowered to perform surgery faster, better and less expensively than current standards. Optical imaging that exploits invisible near-infrared (NIR) fluorescent light (700–900 nm) has the potential to improve cancer surgery outcomes, minimize the time patients are under anaesthesia and lower health-care costs largely by way of its improved contrast and depth of tissue penetration relative to visible light. Accordingly, the past few years have [...]

Menée in vitro, cette étude montre qu'un inhibiteur de la protéine de choc thermique HSP90 (17 allylamino-17-déméthoxygeldanamycine) peut augmenter la sensibilité des cellules tumorales aux rayonnements ionisants en réduisant l'expression de la sérine/thréonine kinase 38 via l'inhibition de l'expression du facteur de transcription sp1

The HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin modulates radiosensitivity by downregulating serine/threonine kinase 38 via Sp1 inhibition

Enomoto, Atsushi ; Fukasawa, Takemichi ; Takamatsu, Nobuhiko ; Ito, Michihiko ; Morita, Akinori ; Hosoi, Yoshio ; Miyagawa, Kiyoshi

The ansamycin-based HSP90 inhibitor 17-AAG (17-allylamino-17-demethoxygeldanamycin) combats tumors and has been shown to modulate cellular sensitivity to radiation, prompting researchers to use 17-AAG as a radiosensitizer. 17-AAG causes the degradation of several oncogenic and signaling proteins. We previously demonstrated that oxidative stress activates serine/threonine kinase 38 (STK38), a member of the protein kinase A (PKA)/PKG/PKC-like family. In the present study, we investigated how [...]

Menée sur 1 566 patientes atteintes d'un cancer du sein traité entre 1975 et 1991, cette étude évalue, en fonction du traitement reçu et sur le long terme, le risque de décès par maladie cardiaque ischémique après une radiothérapie hypofractionnée

Long-term Cardiac Mortality After Hypofractionated Radiation Therapy in Breast Cancer

Tjessem, Kristin Holm ; Johansen, Safora ; Malinen, Eirik ; Reinertsen, Kristin V. ; Danielsen, Turi ; Fosså, Sophie D. ; Fosså, Alexander

Purpose : To explore very-long-term mortality from ischemic heart disease (IHD) after locoregional radiation therapy of breast cancer (BC) in relation to degree of hypofractionation and other treatment variables. Methods and Materials : Two hypofractionated regimens used for locoregional radiation therapy for BC from 1975 to 1991 were considered. Patients received 4.3 Gy × 2/week (10 fractions; target dose 43 Gy; n=1107) or 2.5 Gy × 5/week (20 fractions; target dose 50 Gy; n=459). To estimate [...]

A partir d'une revue systématique de la littérature (28 études), cette méta-analyse compare l'efficacité d'une localisation tumorale filoguidée et d'une échographie intra-opératoire dans le traitement chirurgical de cancers du sein non détectables à la palpation

Intra-operative ultrasound versus wire-guided localization in the surgical management of non-palpable breast cancers: systematic review and meta-analysis

Ahmed, M. ; Douek, M.

Introduction : The current standard of treatment for non-palpable breast cancers is wire-guided localization (WGL). WGL has its drawbacks and alternatives such as radio-guided surgery (RGL) and intra-operative ultrasound (IOUS) have been developed. The clinical effectiveness of all forms of RGL has been assessed against WGL in previous systematic reviews and meta-analyses. We performed the first systematic review and meta-analysis of IOUS in the management of non-palpable breast cancers. [...]

Menée sur des lignées cellulaires de cancer de l'estomac HER+ résistantes au lapatinib, cette étude met en évidence le rôle joué par une molécule de la matrice extracellulaire, Testican-1, dans la transition épithélio-mésenchymateuse et la résistance thérapeutique

Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer

Kim, H. P. ; Han, S. W. ; Song, S. H. ; Jeong, E. G. ; Lee, M. Y. ; Hwang, D. ; Im, S. A. ; Bang, Y. J. ; Kim, T. Y.

Human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed [...]

Menée à l'aide d'un modèle murin, cette étude évalue l'activité antitumorale et la toxicité d'un traitement combinant un anticorps anti PD-1 et une immunothérapie adoptive à base de lymphocytes T modifiés pour exprimer un récepteur antigénique chimérique

Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells

John, Liza B. ; Devaud, Christel ; Duong, Connie M. ; Yong, Carmen ; Beavis, Paul A. ; Haynes, Nicole M. ; Chow, Melvyn T. ; Smyth, Mark J. ; Kershaw, Michael H. ; Darcy, Phillip K.

Purpose: To determine the antitumor efficacy and toxicity of a novel combination approach involving adoptive T cell immunotherapy utilizing chimeric antigen receptor (CAR) T cells with an immunomodulatory reagent for blocking immunosuppression. Experimental Design: We examined whether administration of a PD-1 blocking antibody could increase the therapeutic activity of CAR T cells against two different Her-2+ tumors. The use of a self-antigen mouse model enabled investigation into the efficacy, [...]

Menée in vitro et in vivo, cette étude compare l'activité antitumorale de l'obinutuzumab, un nouvel anticorps monoclonal anti-CD20 de type II, avec celles du rituximab et de l'ofatumumab, deux anticorps anti-CD20 de type I

Preclinical Activity of the Type II CD20 Antibody GA101 (Obinutuzumab) Compared with Rituximab and Ofatumumab In Vitro and in Xenograft Models

Herter, Sylvia ; Herting, Frank ; Mundigl, Olaf ; Waldhauer, Inja ; Weinzierl, Tina ; Fauti, Tanja ; Muth, Gunther ; Ziegler-Landesberger, Doris ; van Puijenbroek, Erwin ; Lang, Sabine ; Duong, Minh-Ngoc ; Reslan, Lina ; Gerdes, Christian A. ; Friess, Thomas ; Baer, Ute ; Burtscher, Helmut ; Weidner, Michael ; Dumontet, Charles ; Umana, Pablo ; Niederfellner, Gerhard ; Bacac, Marina ; Klein, Christian

We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered Type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved Type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP) [...]

A partir de l'exemple du nab-paclitaxel, cet article passe en revue les perspectives thérapeutiques offertes en oncologie par le recours à des nanoparticules chargées en agents cytotoxiques

Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: A focus on nano-albumin-bound drugs

Fanciullino, Raphaelle ; Ciccolini, Joseph ; Milano, Gérard

Improving the efficacy-toxicity balance of anticancer agents remains an ongoing challenge in oncology. Beside the ever-growing development of innovative drugs addressing newly discovered molecular targets, nanotechnologies provide today a promising and exciting strategy to achieve this goal. The idea of carrying active compounds to their respective targets so as to improve their efficacy while sparing healthy tissue and reducing side-effects is not new. However, this area of research is in [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels un composé appelé GNE-900, un inhibiteur de la kinase ChK1, potentialise l'activité de la gemcitabine

Combination drug scheduling defines a "window of opportunity" for chemopotentiation of gemcitabine by an orally bioavailable, selective CHK1 inhibitor, GNE-900

Blackwood, Elizabeth ; Epler, Jennifer ; Yen, Ivana ; Flagella, Michael ; O'Brien, Tom ; Evangelista, Marie ; Schmidt, Stephen ; Xiao, Yang ; Choi, Jonathan ; Kowanetz, Kaska ; Ramiscal, Judi ; Wong, Kenton ; Jakubiak, Diana ; Yee, Sharon ; Cain, Gary ; Gazzard, Lewis ; Williams, Karen ; Halladay, Jason ; Jackson, Peter K ; Malek, Shiva

Checkpoint kinase 1 (ChK1) is a serine/threonine kinase that functions as a central mediator of the intra-S and G2/M cell cycle checkpoints. Following DNA damage or replication stress, ChK1-mediated phosphorylation of downstream effectors delays cell cycle progression so that the damaged genome can be repaired. As a therapeutic strategy, inhibition of ChK1 should potentiate the anti-tumor effect of chemotherapeutic agents by inactivating the post-replication checkpoint, causing premature entry [...]

Menée sur des lignées cellulaires de cancer du poumon, cette étude met en évidence le rôle joué par une glycolase du mécanisme de réparation de l'ADN par excision de base, UNG, dans la résistance au pemetrexed

Uracil DNA glycosylase expression determines human lung cancer cell sensitivity to pemetrexed

Weeks, Lachelle D ; Fu, Pingfu ; Gerson, Stanton L

Uracil misincorporation into DNA is a consequence of pemetrexed inhibition of thymidylate synthetase. The base excision repair (BER) enzyme, uracil DNA glycosylase (UNG) is the major glycosylase responsible for removal of misincorporated uracil. We previously illustrated hypersensitivity to pemetrexed in UNG-/- human colon cancer cells. Here, we examined the relationship between UNG expression and pemetrexed sensitivity in human lung cancer. We observed a spectrum of UNG expression in human [...]

Menée initialement sur des échantillons tumoraux prélevés sur 103 patients atteints d'un carcinome du poumon non à petites cellules, puis in vitro et in vivo, cette étude suggère l'intérêt d'une stratégie basée sur le concept de létalité synthétique pour traiter les patients dont les tumeurs présentent une sous-expression du gène du facteur de remodelage de la chromatine BRG1

A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1

Oike, Takahiro ; Ogiwara, Hideaki ; Tominaga, Yuichi ; Ito, Kentaro ; Ando, Osamu ; Tsuta, Koji ; Mizukami, Tatsuji ; Shimada, Yoko ; Isomura, Hisanori ; Komachi, Mayumi ; Furuta, Koh ; Watanabe, Shun-ichi ; Nakano, Takashi ; Yokota, Jun ; Kohno, Takashi

The occurrence of inactivating mutations in SWI/SNF chromatin-remodeling genes in common cancers has attracted a great deal of interest. However, mechanistic strategies to target tumor cells carrying such mutations has yet to be developed. This study proposes a synthetic-lethality therapy for treating cancers deficient in the SWI/SNF catalytic (ATPase) subunit, BRG1/SMARCA4. The strategy relies upon inhibition of BRM/SMARCA2, another catalytic SWI/SNF subunit with a BRG1-related activity. [...]

Menée sur des lignées cellulaires de cancer du poumon non à petites cellules, cette étude met en évidence le rôle joué par la signalisation integrinβ1/Src/Akt dans la résistance à l'erlotinib

Erlotinib resistance in lung cancer cells mediated by integrinβ1/Src/Akt-driven bypass signaling

Kanda, Rina ; Kawahara, Akihiko ; Watari, Kosuke ; Murakami, Yuichi ; Sonoda, Kahori ; Maeda, Masashi ; Fujita, Hideaki ; Kage, Masayoshi ; Uramoto, Hidetaka ; Costa, Carlota ; Kuwano, Michihiko ; Ono, Mayumi

EGFR kinase inhibitors including gefitinib and erlotinib exert potent therapeutic efficacy in non-small cell lung cancers harboring EGFR activating mutations. However, most patients ultimately develop resistance to these drugs. Here we report a novel mechanism of acquired resistance the reversal of which could clinical outcomes. In erlotinib-resistant lung cancer cells harboring activating EGFR mutations that we established, there was increased expression of Src, integrinβ1, α2, and α5 along [...]

Cet article passe en revue les perspectives offertes par les connaissances sur le génome des cancers du sein ER+ pour le développement de nouveaux traitements en combinaison

Luminal breast cancer: from biology to treatment

Ignatiadis, Michail ; Sotiriou, Christos

Oestrogen receptor (ER)-positive—or luminal—tumours represent around two-thirds of all breast cancers. Luminal breast cancer is a highly heterogeneous disease comprising different histologies, gene-expression profiles and mutational patterns, with very varied clinical courses and responses to systemic treatment. Despite adjuvant endocrine therapy and chemotherapy treatment for patients at high risk of relapse, both early and late relapses still occur, a fact that highlights the unmet medical [...]

Menée in vitro et in vivo, cette étude évalue l'intérêt de cibler la kinase Ret pour le traitement d'un cancer métastatique du sein ER+

Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells

Gattelli, Albana ; Nalvarte, Ivan ; Boulay, Anne ; Roloff, Tim C. ; Schreiber, Martin ; Carragher, Neil ; Macleod, Kenneth K. ; Schlederer, Michaela ; Lienhard, Susanne ; Kenner, Lukas ; Torres-Arzayus, Maria I. ; Hynes, Nancy E.

We show that elevated levels of Ret receptor are found in different sub-types of human breast cancers and that high Ret correlates with decreased metastasis-free survival. The role of Ret in ER+ breast cancer models was explored combining in vitro and in vivo approaches. Our analyses revealed that ligand-induced Ret activation: (i) stimulates migration of breast cancer cells; (ii) rescues cells from anti-proliferative effects of endocrine treatment and (iii) stimulates expression of cytokines [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes de cancer épidermoïde de la tête et du cou, cette étude évalue l'activité antitumorale du rigosertib, un inhibiteur de PI3K et PLK1

The dual pathway inhibitor rigosertib is effective in direct-patient tumor xenografts of head and neck squamous cell carcinomas

Anderson, Ryan T. ; Keysar, Stephen B ; Bowles, Daniel W ; Glogowska, Magdalena J. ; Astling, David P ; Morton, J Jason ; Le, Phuong ; Umpierrez, Adrian ; Eagles-Soukup, Justin ; Gan, Gregory N. ; Vogler, Brian W. ; Sehrt, Daniel ; Takimoto, Sarah M. ; Aisner, Dara L ; Wilhem, Francois ; Frederick, Barbara A ; Varella-Garcia, Marileila ; Tan, Aik Choon ; Jimeno, Antonio

The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in head and neck squamous cell cancer (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor [...]

Mené sur 20 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la toxicité et l'efficacité antitumorale d'un traitement combinant un inhibiteur de gamma-secrétase et un inhibiteur du récepteur VEGF, le cediranib

A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503)

Sahebjam, S. ; Bedard, P. L. ; Castonguay, V. ; Chen, Z. ; Reedijk, M. ; Liu, G. ; Cohen, B. ; Zhang, W. J. ; Clarke, B. ; Zhang, T. ; Kamel-Reid, S. ; Chen, H. ; Ivy, S. P. ; Razak, A. R. A. ; Oza, A. M. ; Chen, E. X. ; Hirte, H. W. ; McGarrity, A. ; Wang, L. ; Siu, L. L. ; Hotte, S. J.

Background : The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a

Mené sur 41 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale d'un composé appelé BIIB028, un promédicament conçu pour inhiber l'activité de la protéine de choc thermique Hsp90

Phase I Study of BIIB028, a selective heat shock protein 90 inhibitor, in patients with refractory metastatic or locally advanced solid tumors

Hong, David S. ; Said, Rabih ; Falchook, Gerald S. ; Naing, Aung ; Moulder, Stacy L. ; Tsimberidou, Apostolia M. ; Galluppi, Gerald ; Dakappagari, Naveen ; Storgard, Chris ; Kurzrock, Razelle ; Rosen, Lee S.

Purpose:Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone involved in protein folding, activation, and assembly, including key mediators of signal transduction, cell cycle control, and transcriptional regulation. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of BIIB028, a prodrug designed to inhibit Hsp90 activity. Experimental Design: Patients with advanced solid tumors were enrolled and received escalating doses of BIIB028 intravenously twice a [...]

Cet article passe en revue les travaux récents en matière de traitement personnalisé d'une leucémie lymphocytaire chronique

Personalized medicine in CLL: Current status and future perspectives

Rozovski, Uri ; Hazan-Halevy, Inbal ; Keating, Michael J. ; Estrov, Zeev

Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in the Western Hemisphere. Despite advances in research and the development of effective treatment regimens, CLL is still largely an incurable disease. Although several prognostic factors have been identified in recent years, most of the new prognostic factors are not utilized, and treatment decisions are still based on clinical staging and limited use of cytogenetic analysis. Patients with advanced disease are treated [...]