Menée à l'aide de xénogreffes de tumeurs rhabdoïdes/tératoïdes atypiques, cette étude met en évidence l'intérêt de lymphocytes CAR-T ciblant le point de contrôle immunitaire B7-H3 et administrés par voie intracérébroventriculaire ou intratumorale

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors

Theruvath, Johanna ; Sotillo, Elena ; Mount, Christopher W. ; Graef, Claus Moritz ; Delaidelli, Alberto ; Heitzeneder, Sabine ; Labanieh, Louai ; Dhingra, Shaurya ; Leruste, Amaury ; Majzner, Robbie G. ; Xu, Peng ; Mueller, Sabine ; Yecies, Derek W. ; Finetti, Martina A. ; Williamson, Daniel ; Johann, Pascal D. ; Kool, Marcel ; Pfister, Stefan ; Hasselblatt, Martin ; Frühwald, Michael C. ; Delattre, Olivier ; Surdez, Didier ; Bourdeaut, Franck ; Puget, Stéphanie ; Zaidi, Sakina ; Mitra, Siddhartha S. ; Cheshier, Samuel ; Sorensen, Poul H. ; Monje, Michelle ; Mackall, Crystal L.

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by [...]

Menée à l'aide de plusieurs modèles murins de tumeurs, cette étude met en évidence l'intérêt d'inhiber l'activité de la kinase Vps34 pour augmenter l'infiltration intratumorale des cellules immunitaires et améliorer l'efficacité des immunothérapies anti–PD-1/PD-L1

Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti–PD-1/PD-L1 immunotherapy

Noman, Muhammad Zaeem ; Parpal, Santiago ; Van Moer, Kris ; Xiao, Malina ; Yu, Yasmin ; Viklund, Jenny ; De Milito, Angelo ; Hasmim, Meriem ; Andersson, Martin ; Amaravadi, Ravi K. ; Martinsson, Jessica ; Berchem, Guy ; Janji, Bassam

One of the major challenges limiting the efficacy of anti–PD-1/PD-L1 therapy in nonresponding patients is the failure of T cells to penetrate the tumor microenvironment. We showed that genetic or pharmacological inhibition of Vps34 kinase activity using SB02024 or SAR405 (Vps34i) decreased the tumor growth and improved mice survival in multiple tumor models by inducing an infiltration of NK, CD8+, and CD4+ T effector cells in melanoma and CRC tumors. Such infiltration resulted in the [...]

Menée sur des lignées cellulaires et à l'aide de modèles murins de tumeurs stromales gastro-intestinales, cette étude analyse les caractéristiques pharmacologiques de AZD3229, un inhibiteur potentiel de la kinase KIT et du récepteur PDGFRalpha, puis met en évidence son efficacité antitumorale

Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors

Banks, Erica ; Grondine, Michael ; Bhavsar, Deepa ; Barry, Evan ; Kettle, Jason G. ; Reddy, Venkatesh Pilla ; Brown, Crystal ; Wang, Haiyun ; Mettetal, Jerome T. ; Collins, Teresa ; Adeyemi, Oladipupo ; Overman, Ross ; Lawson, Deborah ; Harmer, Alexander R. ; Reimer, Corinne ; Drew, Lisa ; Packer, Martin J. ; Cosulich, Sabina ; Jones, Rhys D. O. ; Shao, Wenlin ; Wilson, David ; Guichard, Sylvie ; Fawell, Stephen ; Anjum, Rana

Gastrointestinal stromal tumor, or GIST, can be targeted by inhibiting KIT and platelet-derived growth factor α (PDGFRα). Unfortunately, the therapeutic effects do not always last, as the tumors develop resistance mutations that are not susceptible to existing drugs. Banks et al. report the design of AZD3229, a compound that combines selectivity for KIT and PDGFRα with broad activity against a variety of disease-causing mutations. Its selectivity decreases the risk of off-target toxicity, which [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle de la protéine YAP1 dans le développement de métastases péritonéales ayant pour origine un adénocarcinome gastrique et démontre que l'inhibition de YAP1 réduit le processus métastatique

YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition

Ajani, Jaffer A. ; Xu, Yan ; Huo, Longfei ; Wang, Ruiping ; Li, Yuan ; Wang, Ying ; Pizzi, Melissa Pool ; Scott, Ailing ; Harada, Kazuto ; Ma, Lang ; Yao, Xiaodan ; Jin, Jiankang ; Zhao, Wei ; Dong, Xiaochuan ; Badgwell, Brian D. ; Shanbhag, Namita ; Tatlonghari, Ghia ; Estrella, Jeannelyn Santiano ; Roy-Chowdhuri, Sinchita ; Kobayashi, Makoto ; Vykoukal, Jody V. ; Hanash, Samir M. ; Calin, George Adrian ; Peng, Guang ; Lee, Ju-Seog ; Johnson, Randy L. ; Wang, Zhenning ; Wang, Linghua ; Song, Shumei

Objective : Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 (YAP1) oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target. Methods : Patient-derived PC cells, [...]

Menée in vitro et à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence l'intérêt d'une petite molécule réprimant l'activité du récepteur nucléaire orphelin COUP-TFII pour traiter un cancer de la prostate

Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment

Wang, Leiming ; Cheng, Chiang-Min ; Qin, Jun ; Xu, Mafei ; Kao, Chung-Yang ; Shi, Jingjing ; You, Erli ; Gong, Wanchun ; Rosa, Laura Pedro ; Chase, Peter ; Scampavia, Louis ; Madoux, Franck ; Spicer, Timothy ; Hodder, Peter ; Xu, H. Eric ; Tsai, Sophia Y. ; Tsai, Ming-Jer

The orphan nuclear receptor COUP-TFII is expressed at a low level in adult tissues, but its expression is increased and shown to promote progression of multiple diseases, including prostate cancer, heart failure, and muscular dystrophy. Suppression of COUP-TFII slows disease progression, making it an intriguing therapeutic target. Here, we identified a potent and specific COUP-TFII inhibitor through high-throughput screening. The inhibitor specifically suppressed COUP-TFII activity to regulate [...]

Menée à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence l'intérêt de délivrer dans le liquide cérébrospinal des lymphocytes CAR-T, ciblant les récepteurs EPHA2, HER2 ou alpha 2 de l'interleukine IL-13, pour traiter un médulloblastome ou un épendymome

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Donovan, Laura K. ; Delaidelli, Alberto ; Joseph, Sujith K. ; Bielamowicz, Kevin ; Fousek, Kristen ; Holgado, Borja L. ; Manno, Alex ; Srikanthan, Dilakshan ; Gad, Ahmed Z. ; Van Ommeren, Randy ; Przelicki, David ; Richman, Cory ; Ramaswamy, Vijay ; Daniels, Craig ; Pallota, Jonelle G. ; Douglas, Tajana ; Joynt, Alyssa C. M. ; Haapasalo, Joonas ; Nor, Carolina ; Vladoiu, Maria C. ; Kuzan-Fischer, Claudia M. ; Garzia, Livia ; Mack, Stephen C. ; Varadharajan, Srinidhi ; Baker, Matthew L. ; Hendrikse, Liam ; Ly, Michelle ; Kharas, Kaitlin ; Balin, Polina ; Wu, Xiaochong ; Qin, Lei ; Huang, Ning ; Stucklin, Ana Guerreiro ; Morrissy, A. Sorana ; Cavalli, Florence M. G. ; Luu, Betty ; Suarez, Raul ; De Antonellis, Pasqualino ; Michealraj, Antony ; Rastan, Avesta ; Hegde, Meenakshi ; Komosa, Martin ; Sirbu, Olga ; Kumar, Sachin A. ; Abdullaev, Zied ; Faria, Claudia C. ; Yip, Stephen ; Hukin, Juliette ; Tabori, Uri ; Hawkins, Cynthia ; Aldape, Ken ; Daugaard, Mads ; Maris, John M. ; Sorensen, Poul H. ; Ahmed, Nabil ; Taylor, Michael D.

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood–brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on [...]

Menée à l'aide de deux lignées cellulaires de carcinome épidermoïde de l'

Isocitrate dehydrogenase 2 contributes to radiation resistance of oesophageal squamous cell carcinoma via regulating mitochondrial function and ROS/pAKT signalling

Chen, Xuan ; Zhuo, Shichao ; Xu, Wenzhe ; Chen, Xue ; Huang, Di ; Sun, Xiaozheng ; Cheng, Yufeng

Background : Antioxidase alleviates the accumulation of radiation-induced reactive oxygen species (ROS) and therefore has strong connections with radioresistance. Isocitrate dehydrogenase 2 (IDH2) facilitates the turnover of antioxidase, but its role in radiotherapeutic efficiency in oesophageal squamous cell carcinoma (ESCC) still remains elusive. Methods : The involvement of IDH2 in radiotherapeutic efficacy in ESCC was investigated in vitro and vivo by IDH2 knockdown. IDH2 expression in [...]

Menée sur des lignées cellulaires de carcinome épidermoïde de la tête et du cou, cette étude met en évidence, à l'aide d'une technique de séquençage de l'ARN à l'échelle d'une seule cellule et de la technique ATAC-seq, une hétérogénéité au niveau des programmes transcriptionnels et des évolutions épigénétiques induits par le cétuximab et démontre que des mécanismes de résistance indépendants apparaissent alors que les cellules tumorales sont encore sensibles au traitement

Integrated single-cell and bulk gene expression and ATAC-seq reveals heterogeneity and early changes in pathways associated with resistance to cetuximab in HNSCC-sensitive cell lines

Kagohara, Luciane T. ; Zamuner, Fernando ; Davis-Marcisak, Emily F. ; Sharma, Gaurav ; Considine, Michael ; Allen, Jawara ; Yegnasubramanian, Srinivasan ; Gaykalova, Daria A. ; Fertig, Elana J.

Background : Identifying potential resistance mechanisms while tumour cells still respond to therapy is critical to delay acquired resistance. Methods : We generated the first comprehensive multi-omics, bulk and single-cell data in sensitive head and neck squamous cell carcinoma (HNSCC) cells to identify immediate responses to cetuximab. Two pathways potentially associated with resistance were focus of the study: regulation of receptor tyrosine kinases by TFAP2A transcription factor, and [...]

Mené sur 300 patients atteints d’un cancer de l’estomac ou d’un carcinome de la jonction œsogastrique de stade avancé (âge médian : 62 ans), cet essai de phase III évalue l’efficacité, du point de vue de la survie globale, et la toxicité de l’ajout de l’évérolimus au paclitaxel, après l’échec d’une thérapie à base de fluoropyrimidine ou de sels de platine

Phase III randomized, double-blind study of paclitaxel with and without Everolimus in patients with advanced gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC)

Sylvie Lorenzen, Jorge Riera Knorrenschild, Claudia Pauligk

The RADPAC trial evaluated paclitaxel with everolimus in patients with advanced gastroesophageal cancer (GEC) who have progressed after therapy with a fluoropyrimidine/platinum?containing regimen. Patients were randomly assigned to receive paclitaxel (80 mg/m2) on day 1, 8 and 15 plus everolimus (10mg daily, arm B) d1?d28 or placebo (arm A), repeated every 28?days. Primary end point was overall survival (OS). Efficacy was assessed in the intention?to?treat population and safety in all patients [...]

Mené sur 50 patients atteints d’un cancer gastrique ou d’un cancer colorectal de stade avancé, cet essai de phase IB évalue la dose maximale tolérée du régorafénib en combinaison avec le nivolumab et évalue l’efficacité, du point de vue du taux de réponse objective, de cette combinaison

Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603)

Shota Fukuoka, Hiroki Hara, Naoki Takahashi (et al.)

PURPOSE : This is a phase Ib trial of regorafenib plus nivolumab for gastric and colorectal cancer. PATIENTS AND METHODS : Enrolled patients received regorafenib plus nivolumab in a dose-finding part to estimate the maximum tolerated dose. Additional patients were enrolled in a dose-expansion part. Regorafenib of 80-160 mg was administered once daily for 21 days on/7 days off with nivolumab 3 mg/kg every 2 weeks. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks to [...]

Mené sur 160 patients atteints d’un lymphome primitif du système nerveux central, cet essai de phase III évalue l’intérêt, du point de vue de la qualité de vie déclarée par les patients, de l’ajout du rituximab à une chimiothérapie standard à base de méthotrexate à hautes doses (durée de suivi : 2 ans)

Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients: results from a randomised phase III study

M.van der Meulen, K.Bakunina, M.Nijland, M.C.Minnema (et al.)

Background : The impact of rituximab on health-related quality of life (HRQoL) in primary central nervous system lymphoma patients is not well-known. We determined the impact of rituximab added to standard high-dose methotrexate-based treatment on HRQoL from patients in a large randomised trial. Patients and methods : Patients from a large phase III trial (HOVON 105/ALLG NHL 24), randomised to standard chemotherapy with or without rituximab and followed by 30Gy whole brain radiotherapy (WBRT) [...]

Mené en Allemagne sur 109 patients atteints d’un lymphome hodgkinien classique de stade précoce défavorable (âge : 18-60 ans), cet essai de phase II évalue l’efficacité, du point de vue du taux de rémission complète, et la toxicité d’un traitement de première ligne à base de nivolumab et d’un traitement de type AVD (doxorubicine, vinblastine et dacarbazine) dispensé de façon concomitante ou séquentielle (durée médiane de suivi : 13 mois)

Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma :The Randomized Phase 2 German Hodgkin Study Group NIVAHL Trial

Paul J. Bröckelmann, Helen Goergen, Ulrich Keller (et al.)

Importance : In early-stage unfavorable classic Hodgkin lymphoma (cHL), conventional therapy induces high cure rates but also relevant acute and long-term toxic effects. Nivolumab is well tolerated and highly effective in relapsed/refractory cHL but has not been adequately studied in first-line treatment of early-stage cHL. The NIVAHL trial evaluated nivolumab in this setting with the aim to develop a highly effective yet tolerable systemic therapy to ultimately mitigate morbidity in patients [...]

Mené sur 71 et 75 patients atteints d’un adénocarcinome du pancréas de stade métastatique, cet essai évalue l’efficacité, du point de vue de la survie sans progression, et la toxicité du nab-paclitaxel dispensé de façon séquentielle ou de façon concomitante (le même jour) avec la gemcitabine en traitement de première ligne

Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma

P. G. Corrie, W. Qian, D. I. Jodrell

Background : Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial. Methods : Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered [...]

Mené sur 33 patients atteints d’un cancer du poumon non à petites cellules de stade avancé, cet essai de phase I analyse les facteurs associés à la survenue de troubles ophtalmiques en lien avec un traitement par crizotinib

Ophthalmological assessment of crizotinib in advanced non-small-cell lung cancer

Benjamin J. Solomona, Elizabeth E. Kimb, Maria Winter (et al.)

Objectives : During crizotinib clinical evaluation, visual disturbances, generally of grade 1 severity, were frequently reported adverse events (AE). Consequently, ophthalmologic assessments were included in a patient subgroup enrolled in PROFILE 1001 (NCT00585195), a phase 1, open-label, single-arm trial of crizotinib in patients with advanced NSCLC and are reported here. Materials and methods : At least 30 patients were required to undergo ophthalmologic assessments, including: best-corrected [...]

Mené sur 68 patients atteints d’un cancer du poumon à petites cellules réfractaire ou récidivant, cet essai de phase II évalue l’efficacité, du point de vue du taux de réponse objective, et la toxicité du nab-paclitaxel après l’échec d’une chimiothérapie de première ligne à base de sels de platine

Phase 2 study of NAB-paclitaxel in SensiTivE and refractory relapsed small cell lung cancer (SCLC) (NABSTER TRIAL)

Francesco Gelsomino, Marcello Tiseo, Fausto Barbieri, Ferdinando Riccardi (et al.)

Background : Despite sensitivity to first-line chemotherapy, most small-cell lung cancer (SCLC) patients relapse. In this setting, topotecan demonstrated modest activity with significant toxicity. Paclitaxel was also active. This study was designed to evaluate activity and safety of nab-paclitaxel in relapsed SCLC. Methods : In this multicentre prospective Phase 2 trial, patients with refractory or sensitive SCLC progressed to first-line platinum-based chemotherapy received nab-paclitaxel [...]

Mené sur 22 patients atteints d’un cancer du poumon non à petites cellules de stade avancé et réfractaire, cet essai de phase I évalue la faisabilité et la toxicité du système d'édition génomique CRISPR-Cas9 dans le cadre d’une immunothérapie à base de lymphocytes T

Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

You Lu, Jianxin Xue, Tony Mok

Clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR–Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint [...]

Mené sur 57 patients atteints d’un cancer de la prostate résistant à la castration et de stade métastatique, cet essai de phase IB analyse les caractéristiques pharmacocinétiques, l’activité antitumorale et la toxicité de l’apalutamide en combinaison avec de l’acétate d’abiratérone et de la prednisone

Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer: Phase 1b Study

Edwin M Posadas, Kim N. Chi, Ronald de Wit, Maja J. A. de Jonge (et al.)

Introduction: Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). Materials and Methods: Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 [...]

Mené respectivement sur 245 et 142 patients atteints d’un cancer de la prostate de stade métastatique et résistant à la castration, cet essai de phase III compare l’efficacité, du point de vue de la survie sans progression, et la toxicité de l’olaparib et d’un traitement choisi par le médecin (enzalutamide ou abiratérone)

Olaparib for Metastatic Castration-Resistant Prostate Cancer

Johann de Bono, Joaquin Mateo, Karim Fizazi (et al.)

Background : Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition in patients with prostate and other cancers. Methods : We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal [...]

Menée à partir de données portant sur 2 198 patients ayant reçu une greffe de cellules souches hématopoïétiques, cette étude compare l’efficacité, du point de vue de la survie sans récidive et de la survie globale, de différents types de greffes avec donneur alternatif

Composite GRFS and CRFS Outcomes After Adult Alternative Donor HCT

Rohtesh S. Mehta, Shernan G. Holtan, Tao Wang (et al.)

PURPOSE : There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]–bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor. METHODS : We report composite end points of graft-versus-host disease (GVHD)–free relapse-free survival (GRFS) and chronic GVHD (cGVHD)–free relapse-free survival (CRFS) in 2,198 patients who [...]

Menée en Allemagne à partir de données portant sur 448 hommes atteints d’un cancer du sein traité entre 2009 et 2018 (âge médian au diagnostic : 69 ans), cette étude de cohorte évalue l’efficacité, du point de vue de la survie sans maladie, du tamoxifène (durée médiane de suivi : 39 mois)

Survival benefit of tamoxifen in male breast cancer: prospective cohort analysis

Holm Eggemann, Cosima Brucker, Michael Schrauder (et al.)

Background : Due to the lack of prospective data, current treatment of male breast cancer (MBC) is based on information obtained from retrospective analysis or by extrapolation from studies on female patients. In this prospectively enrolled cohort study, we retrospectively examined the survival effect of tamoxifen in MBC patients. Methods : In this prospectively enrolled cohort study, 448 patients with MBC were treated between May 2009 and June 2018. The primary endpoint was disease-free [...]

Menée à partir de données portant sur 17 197 patientes atteintes d’un cancer du sein de stade précoce HR+ ERBR2- et présentant un score, fourni par un test basé sur l'expression de 21 gènes, supérieur ou égal à 26 (âge médian : 60 ans), cette étude rétrospective évalue l’effet, sur la survie globale, d’une chimiothérapie adjuvante (durée médiane de suivi : 40,7 mois)

Association of Adjuvant Chemotherapy With Overall Survival in Patients With Early-Stage Breast Cancer and 21-Gene Recurrence Scores of 26 or Higher

Sung Jun Ma,Oluwadamilola T. Oladeru, Anurag K. Singh (et al.)

A secondary analysis of the Trial Assigning Individualized Options for Treatment (TAILORx) randomized clinical trial1 demonstrated favorable distant metastasis–free survival among patients who received adjuvant chemoendocrine therapy for hormone receptor–positive, ERBR2-negative, axillary node–negative breast cancer and had 21-gene recurrence scores (RSs) of 26 and higher. However, 43% of patients had RSs between 26 and 30,1 and the chemotherapy benefit in this subgroup remains unclear. The [...]

Mené aux Etats-Unis sur 17 patients pédiatriques atteints d’un neuroblastome réfractaire ou récidivant puis sur 36 patients non randomisés, cet essai évalue l’efficacité, du point de vue du taux de réponse objective, et la toxicité d’un traitement combinant irinotécan, témozolomide, dinutuximab et facteur GM-CSF

Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children’s Oncology Group

Rajen Mody, Alice L. Yu, Arlene Naranjo (et al.)

PURPOSE : The combination of irinotecan, temozolomide, dintuximab, and granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) demonstrated activity in patients with relapsed/refractory neuroblastoma in the randomized Children’s Oncology Group ANBL1221 trial. To more accurately assess response rate and toxicity, an expanded cohort was nonrandomly assigned to I/T/DIN/GM-CSF. PATIENTS AND METHODS : Patients were eligible at first relapse or first designation of refractory disease. Oral [...]

Mené sur 42 patients atteints d’un carcinome anaplasique de la thyroïde de stade avancé et/ou métastatique, cet essai de phase II évalue l’efficacité, du point de vue du taux de réponse globale, et la toxicité du spartalizumab, un anti-PD-1

PD-1 Blockade in Anaplastic Thyroid Carcinoma

Jaume Capdevila, Lori J. Wirth, Thomas Ernst (et al.)

PURPOSE : Anaplastic thyroid carcinoma is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options for patients with BRAF-wild type disease. As part of a phase I/II study in patients with advanced/metastatic solid tumors, patients with anaplastic thyroid carcinoma were treated with spartalizumab, a humanized monoclonal antibody against the programmed death-1 (PD-1) receptor. METHODS : We enrolled patients with locally advanced and/or metastatic [...]

Mené sur 54 patients atteints d’un cancer des voies biliaires de stade avancé et réfractaire (âge médian : 65 ans), cet essai de phase II évalue l’efficacité, du point de vue du taux de réponse objective, et la toxicité du nivolumab (durée médiane de suivi : 12,4 mois)

A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer

Richard D. Kim, Vincent Chung, Olatunji B. Alese (et al.)

Importance : Currently, there is no established second-line systemic treatment for biliary tract cancer (BTC). Preclinical data have demonstrated that the presence of tumor-infiltrating CD8 T cells and programmed cell death 1 ligand 1–expressing tumor cells in the tumor microenvironment of BTC supports the rationale of using programmed cell death 1 protein blockade immunotherapy in BTC. Objective : To evaluate anticancer activity of nivolumab in patients with advanced refractory BTC. Design, [...]

Mené sur 80 patients atteints d’un cancer de la tête et du cou de stade métastatique, récidivant et réfractaire, cet essai de phase II évalue l’efficacité, du point de vue de la survie sans progression, et la toxicité de l’ajout du cétuximab au temsirolimus, après l’échec d’un traitement par cétuximab en monothérapie

A randomized phase 2 study of temsirolimus and cetuximab versus temsirolimus alone in recurrent/metastatic, cetuximab-resistant head and neck cancer: The MAESTRO study

Tanguy Y. Seiwert, Sara Kochanny, Kevin Wood (et al.)

Background : Patients with cetuximab?resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) have poor outcomes. This study hypothesized that dual blockade of mammalian target of rapamycin and epidermal growth factor receptor (EGFR) would overcome cetuximab resistance on the basis of the role of phosphoinositide 3?kinase signaling in preclinical models of EGFR resistance. Methods : In this multicenter, randomized clinical study, patients with recurrent/metastatic HNSCC [...]

Menée à l'aide de modèles murins de glioblastome, cette étude met en évidence l'intérêt de la trifluopérazine, un antagoniste du récepteur de la dopamine, pour prévenir la conversion phénotypique radio-induite des cellules cancéreuses et améliorer la survie

The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma

Bhat, Kruttika ; Saki, Mohammad ; Vlashi, Erina ; Cheng, Fei ; Duhachek-Muggy, Sara ; Alli, Claudia ; Yu, Garrett ; Medina, Paul ; He, Ling ; Damoiseaux, Robert ; Pellegrini, Matteo ; Zemke, Nathan R. ; Nghiemphu, Phioanh Leia ; Cloughesy, Timothy F. ; Liau, Linda M. ; Kornblum, Harley I. ; Pajonk, Frank

GBM is the most deadly adult brain cancer. The current standard-of-care is surgery followed by RT and temozolomide, which results in a median survival time of only 15 mo. The efficacy of chemotherapies and targeted therapies in GBM is very limited because most of these drugs do not pass the blood−brain barrier (BBB). Ultimately, all patients succumb to the disease. Our study describes radiation-induced cellular plasticity as a resistance mechanism in GBM. We identified a dopamine receptor [...]

Menée à partir de l'examen approfondi de 476 patients atteints d'un cancer puis de l'analyse d'échantillons tumoraux et d'échantillons tissulaires normaux, cette étude évalue la possibilité d'identifier rétrospectivement des patients dont la réponse thérapeutique est exceptionnelle ainsi que des mutations constitutionnelles actionnables

The Exceptional Responders Initiative: Feasibility of A National Cancer Institute Pilot Study

Conley, Barbara A. ; Staudt, Lou ; Takebe, Naoko ; Wheeler, David A. ; Wang, Linghua ; Cardenas, Maria F. ; Korchina, Viktoriya ; Zenklusen, Jean Claude ; McShane, Lisa M. ; Tricoli, James V. ; Williams, Paul M. ; Lubensky, Irina ; O’Sullivan-Coyne, Geraldine ; Kohn, Elise ; Little, Richard F. ; White, Jeffrey ; Malik, Shakun ; Harris, Lyndsay N. ; Mann, Bhupinder ; Weil, Carol ; Tarnuzzer, Roy ; Karlovich, Chris ; Rodgers, Brian ; Shankar, Lalitha ; Jacobs, Paula M. ; Nolan, Tracy ; Berryman, Sean M. ; Gastier-Foster, Julie ; Bowen, Jay ; Leraas, Kristen ; Shen, Hui ; Laird, Peter W. ; Esteller, Manel ; Miller, Vincent ; Johnson, Adrienne ; Edmondson, Elijah F. ; Giordano, Thomas J. ; Kim, Benjamin ; Ivy, S. Percy

Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.Exceptional response was defined as partial [...]

Cet article passe en revue les progrès réalisés dans la prise en charge clinique d'un cancer d'origine primitive inconnue

Progress in refining the clinical management of cancer of unknown primary in the molecular era

Rassy, Elie ; Pavlidis, Nicholas

Cancer of unknown primary (CUP) is an enigmatic disease entity encompassing heterogeneous malignancies without a detectable primary tumour, despite a thorough diagnostic workup. A minority of patients with CUP (15–20%) can be assigned a putative primary tissue of origin according to clinical and histopathological findings and typically have a more favourable prognosis with the use of corresponding tumour type-specific therapies. Thus, the majority of patients with CUP have disease that cannot [...]

Cet article présente les principaux points d'une conférence organisée aux Etats-Unis les 12 et 13 décembre 2019 et concernant la recherche sur les cancers du rein

Summary from the First Kidney Cancer Research Summit, September 12-13, 2019: A Focus on Translational Research

Choueiri, Toni K. ; Atkins, Michael B. ; Bakouny, Ziad ; Carlo, Maria I. ; Drake, Charles G. ; Jonasch, Eric ; Kapur, Payal ; Lewis, Bryan ; Linehan, W. Marston ; Mitchell, Michael J. ; Pal, Sumanta K. ; Pels, Kevin ; Poteat, Susan ; Rathmell, W. Kimryn ; Rini, Brian I. ; Signoretti, Sabina ; Tannir, Nizar ; Uzzo, Robert ; Wood, Christopher G. ; Hammers, Hans J.

Kidney cancer is one of the ten most common cancers both in the United States and worldwide. Until this year, there had not previously been a conference focused on translational studies in the broad and heterogeneous group of kidney cancers. Therefore, a group of researchers, clinicians, and patient advocates dedicated to renal cell carcinoma (RCC) launched the Kidney Cancer Research Summit (KCRS) to spur collaboration and further therapeutic advances in these tumors. This commentary aims to [...]