Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platform

Cancer screening; Non-small-cell lung cancerCribado de cáncer; Cáncer de pulmón de células no pequeñasCribratge de càncer; Càncer de pulmó no de cèl·lules petitesAccess to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients’ molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency.This publication was supported by Fonds Baillet Latour from Belgium and Walgreens Boots Alliance

Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors.

Chemotherapies active in preclinical studies frequently fail in the clinic due to lack of efficacy, which limits progress for rare cancers since only small numbers of patients are available for clinical trials. Thus, a preclinical drug development pipeline was developed to prioritize potentially active regimens for pediatric brain tumors spanning from in vitro drug screening, through intracranial and intra-tumoral pharmacokinetics to in vivo efficacy studies. Here, as an example of the pipeline, data are presented for the combination of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in three pediatric brain tumor models. The in vitro activity of nine novel therapies was tested against tumor spheres derived from faithful mouse models of Group 3 medulloblastoma, ependymoma, and choroid plexus carcinoma. Agents with the greatest in vitro potency were then subjected to a comprehensive series of in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies culminating in preclinical efficacy trials in mice harboring brain tumors. The nucleoside analog 5-fluoro-2'-deoxycytidine (FdCyd) markedly reduced the proliferation in vitro of all three brain tumor cell types at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in brain tumors necessary to inhibit tumor cell proliferation, but no tumor displayed a significant in vivo therapeutic response. Despite promising in vitro activity and in vivo PK properties, FdCyd is unlikely to be an effective treatment of pediatric brain tumors, and therefore was deprioritized for the clinic. Our comprehensive and integrated preclinical drug development pipeline should reduce the attrition of drugs in clinical trials

EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand

Background: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment.Methods: Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit.Results: We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody-drug conjugate. We also identified tumors harboring mutations sensitive to "classical" EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy.Conclusions: These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.</p

Implication du métabolisme dans l'apoptose et la différenciation des cellules souches cancéreuses de gliome murin

Récemment, la présence de cellules souches cancéreuses (CSC) a été mise en évidence dans les gliomes. Ces cellules, de par leur résistance à l'apoptose, seraient responsables de la résurgence des tumeurs après radio et chimiothérapie. Le but de cette étude a été de rechercher des marqueurs/voies de signalisation ciblant ces cellules souches issues de gliomes chimio-induits chez le rat, via une comparaison avec des cellules souches neurales (NSC) murines. Une analyse protéomique comparative a montré que le métabolisme des CSC était différent de celui des NSC : les CSC ont un métabolisme essentiellement glycolytique. Le dichloroacétate (DCA) est une molécule ciblant ce métabolisme particulier. Nous avons mis en évidence qu'elle était capable de potentialiser l'apoptose induite par l'Etoposide ou les irradiations dans les CSC, mais pas dans les NSC. Cette potentialisation est corrélée avec une surexpression de p53, Foxo3 et de certains de leurs gènes-cibles : Bad, Puma et Noxa, qui sont des protéines pro-apoptotiques à domaine BH3-seul. De plus, le DCA induit la différenciation des CSC mais pas celle des NSC, via la modulation de l'interaction entre PKM2 (enzyme de la glycolyse) et Oct4 (facteur de transcription impliqué dans le maintien de l'état indifférencié). Le DCA pourrait donc être un bon adjuvant aux traitements classiques contre les gliomes.The so-called cancer stem cells are thought to be involved in some of the basic features of tumors, especially brain tumors .These cells are known to be extremely resistant to apoptosis and may be responsible for the resurgence of tumors after chemo and radio-therapy. We aimed to compare brain cancer stem cells (CSC) versus neural stem cells (NSC) to find some markers/pathways specific of these CSC. We used rat neural stem cells (NSCs) and cancer stem cells (CSCs) in a model of ENU-induced rat brain tumors. A proteomic comparison of these cells demonstrated that a major difference between CSCs and NSCs is due to metabolism: contrary to NSC, CSCs have a glycolytic metabolism. DCA is a drug involved in this particular metabolism. DCA treatment of CSCs led to a decrease in their resistance to apoptosis induced by etoposide and radiation. This decrease is correlated with an increase of p53, Foxo3 and some of their targets: the pro-apoptotic agents Puma, Noxa, and Bad. Moreover, DCA forces CSCs to differentiate, probably by modulating M2PK (glycolysis enzyme) and Oct4 (transcription factor involved in stemness) interaction. To conclude, DCA may improve the efficiency of usual treatments on patients with glioma.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

From bench to clinical trials the EORTC experience in biology-based clinical cancer research

For over 50 years the European Organization for Research and Treatment of Cancer (EORTC) has delivered major advances in cancer clinical research and cancer therapeutics. The introduction of molecularly targeted agents has led to significant improvements in outcome for patients with specific tumor types; however conventional chemotherapy remains the mainstay of treatment for the majority of patients. Due to increasing knowledge about the diversity of molecular pathways driving malignant progression, strategies to integrate biology into clinical research and development are continuously evolving. The challenges and the experience of the EORTC regarding how translational research is to be an indispensable component of the clinical research environment, which aims to deliver more sophisticated treatment approaches will be discussed in this perspective article

Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platform

Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients\u27 molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency

97TiP Identification of therapeutic targets in patients with squamous cell carcinoma of the head and neck who progress on or after anti-PD-(L)1 therapy: An IMMUcan sub-project

Background: Nivolumab and pembrolizumab are approved for the treatment of recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN). However, a significant number of patients are not responding to PD-(L)1 inhibitors and, ultimately, the majority of the patients will finally progress. No standard of care exists for patients who progress after platinum-based chemotherapy or PD-1 inhibitors. Median overall survival of these patients is dismal (5-6 months). Tumor molecular mechanisms and the role of the immune micro-environment implicated in disease progression on or after anti-PD1 therapy need to be better characterized to identify new therapeutic targets. This will guide the rational development of therapeutic combinations. Trial design: IMMUcan is a European translational research study aiming at generating broad molecular and cellular profiling data of the tumor and its microenvironment from up to 3000 patients derived from 5 different cancer types: head and neck, colorectal, lung, renal and breast cancers. Collaborations with clinical trials are also possible, such as EORTC-HNCG-1559 study (UPSTREAM trial). This biomarker-driven umbrella trial enrolls patients with recurrent/metastatic SCCHN, progressing after platinum-based chemotherapy. The majority of the enrolled patients were pre-treated with PD-(L)1 inhibitors (anti-PD-(L)1 exposed patients), while a control population is also available (anti-PD-(L)1 naïve patients). Biological materials of these two distinct populations will be analyzed in IMMUcan: Whole Exome Sequencing, RNA sequencing, multiplex immunofluorescence and Imaging Mass Cytometry. The biological characteristics together with the clinical data will be analyzed to characterize the immune molecular profile of SCCHN that progress on or after anti-PD-(L)1 therapy with the final aim to identify therapeutic targets and to guide the development of rational therapeutic combinations. Those results will be completed with patients prospectively enrolled in the Head and Neck cohort of IMMUcan, via the EORTC-SPECTA infrastructure. For more information on IMMUcan, please visit https://immucan.eu/

EORTC SPECTA-AYA: A unique molecular profiling platform for adolescents and young adults with cancer in Europe

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