Publications by authors named "Marie Morfouace"

14 Publications

  • Page 1 of 1

Molecular Characterization of Ovarian Yolk Sac Tumor (OYST).

Cancers (Basel) 2021 Jan 9;13(2). Epub 2021 Jan 9.

Centre Léon Berard (CLB), 69008 Lyon, France.

Most patients with malignant ovarian germ cell tumors (MOGTCs) have a very good prognosis and chemotherapy provides curative treatment; however, patients with yolk sac tumors (OYSTs) have a significantly worse prognosis. OYSTs are rare tumors and promising results are expected with the use of specific therapeutic strategies after the failure of platinum-based first-line and salvage regimens. We initiated a project in collaboration with EORTC SPECTA, to explore the molecular characteristics of OYSTs. The pilot project used retrospective samples from ten OYST relapsed and disease-free patients. Each patient had a molecular analysis performed with FoundationOne CDx describing the following variables according to the Foundation Medicine Incorporation (FMI): alteration type (SNV, deletion), actionable gene alteration, therapies approved in EU (for patient's tumor type and other tumor types), tumor mutational burden (TMB), and microsatellite instability (MSI) status. A total of 10 patients with OYST diagnosed between 2007 and 2017 had a molecular analysis. A molecular alteration was identified in four patients (40%). A subset of three patients (33.3% of all patients) harbored targetable oncogenic mutations in , , . Two patients at relapse harbored a targetable mutation. This retrospective study identifies clinically relevant molecular alterations for all relapsed patients with molecular analysis. Dedicated studies are needed to demonstrate the efficacy of specific therapeutic strategies after the failure of platinum-based first-line and salvage regimens and to explore the potential relationship of a molecular alteration and patient outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13020220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826864PMC
January 2021

First results of the EORTC-SPECTA/Arcagen study exploring the genomics of rare cancers in collaboration with the European reference network EURACAN.

ESMO Open 2020 12;5(6):e001075

Department of Medical Oncology, Center Léon Bérard, Lyon, France; Université Claude Bernard Lyon 1, Villeurbanne, France.

Purpose: Rare cancers are defined by an incidence of <6 out of 100 000 cases per year. They are under-represented in clinical research including tumour molecular analysis. The aim of Arcagen is to generate a multinational database integrating clinical and molecular information of patients with rare cancers.

Patients And Methods: We present the retrospective feasibility cohort of patients with rare cancers, with previously collected tumour samples available from any stage. Molecular analysis was performed using FoundationOne CDx for all histologies except for sarcoma where FoundationOne Heme was used. Clinical data including demographic data, medical history, malignant history, treatment and survival data were collected.

Results: Eighty-seven patients from three centres were screened; molecular data were obtained for 77 patients (41 sarcomas, 9 yolk sac tumours, 14 rare head and neck cancers, 13 thymomas). The median age at the time of diagnosis was 48 (range 28-85). Most patients had reportable genomic alterations (89%). The most common alterations were linked to cell cycle regulation (TP53, RB1, CDKN2A/B deletions and MDM2 amplification). Multiple activating single-nucleotide variants (SNVs) could be detected in the RAS/RAF family. The tumour mutational burden status was globally low across all samples with a median of 3 Muts/MB (range 0-52). Only 4 cases (ie, 4.7% of tumours) had direct actionable mutations for a treatment approved in Europe within the patient's tumour type.

Conclusion: The Arcagen project aims to bridge the gap and improve knowledge of the molecular landscape of rare cancers by prospectively recruiting up to 1000 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2020-001075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709508PMC
December 2020

Bromodomain-Selective BET Inhibitors Are Potent Antitumor Agents against MYC-Driven Pediatric Cancer.

Cancer Res 2020 09 10;80(17):3507-3518. Epub 2020 Jul 10.

Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.

Inhibition of members of the bromodomain and extraterminal (BET) family of proteins has proven a valid strategy for cancer chemotherapy. All BET identified to date contain two bromodomains (BD; BD1 and BD2) that are necessary for recognition of acetylated lysine residues in the N-terminal regions of histones. Chemical matter that targets BET (BETi) also interact via these domains. Molecular and cellular data indicate that BD1 and BD2 have different biological roles depending upon their cellular context, with BD2 particularly associated with cancer. We have therefore pursued the development of BD2-selective molecules both as chemical probes and as potential leads for drug development. Here we report the structure-based generation of a novel series of tetrahydroquinoline analogs that exhibit >50-fold selectivity for BD2 versus BD1. This selective targeting resulted in engagement with BD-containing proteins in cells, resulting in modulation of MYC proteins and downstream targets. These compounds were potent cytotoxins toward numerous pediatric cancer cell lines and were minimally toxic to nontumorigenic cells. In addition, unlike the pan BETi (+)-JQ1, these BD2-selective inhibitors demonstrated no rebound expression effects. Finally, we report a pharmacokinetic-optimized, metabolically stable derivative that induced growth delay in a neuroblastoma xenograft model with minimal toxicity. We conclude that BD2-selective agents are valid candidates for antitumor drug design for pediatric malignancies driven by the MYC oncogene. SIGNIFICANCE: This study presents bromodomain-selective BET inhibitors that act as antitumor agents and demonstrates that these molecules have activity towards neuroblastoma, with essentially no toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-3934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483993PMC
September 2020

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

Neurooncol Adv 2020 Jan-Dec;2(1):vdz051. Epub 2019 Dec 9.

Departments of Neurology, Erasmus MC, Rotterdam, The Netherlands.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/noajnl/vdz051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212878PMC
December 2019

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

Int J Cancer 2020 08 14;147(4):1180-1184. Epub 2019 Sep 14.

Division of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.

For most adolescent and young adult (AYA) cancers, age-specific molecular features are poorly understood. EORTC-SPECTA, an academic translational research infrastructure for biomaterial collection, will explicitly recruit AYA patients and will therefore collect empirical data to bridge the molecular gap between pediatric and adult oncology. The initial pilot study, activated in February 2019 across Europe, will recruit 100 AYA patients (aged 12-29 years) with newly diagnosed or relapsed high-grade gliomas and high-grade bone and soft tissue sarcomas. The primary objective of the pilot is to determine feasibility and recruitment rates. Formalin-fixed tumor tissue and whole blood from study participants will be prospectively collected with clinical data and stored centrally at the Integrated BioBank of Luxembourg. Whole exome sequencing of matched tumor and blood, and tumor RNA sequencing and DNA methylation profiling will be performed at the German Cancer Research Center, Heidelberg, Germany. Virtual central pathology review of scanned diagnostic slides will be undertaken by an international expert panel, and diagnostic material returned to the participating centers. A multidisciplinary molecular tumor board will release a clinically validated report to referring clinicians within 4-6 weeks after biopsy. SPECTA-AYA constitutes a major opportunity to gain knowledge about the tumor biology of this unique age group. It incorporates notable innovative aspects: AYA specificity, pan-European academic collaboration, centralized biobanking, comprehensive molecular profiling and virtual central pathology review, among others. SPECTA-AYA will help untangle the tumor particularities of AYAs with cancer and aims to improve their access to novel drugs and personalized medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383917PMC
August 2020

Defining EGFR amplification status for clinical trial inclusion.

Neuro Oncol 2019 10;21(10):1263-1272

Department of Neurology, Erasmus Medical Center Cancer Institute, Rotterdam, Netherlands.

Background: Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma patients require selection for EGFR-amplified tumors. However, there is currently no gold standard in determining the amplification status of EGFR or variant III (EGFRvIII) expression. Here, we aimed to determine which technique and which cutoffs are suitable to determine EGFR amplification status.

Methods: We compared fluorescence in-situ hybridization (FISH) and real-time quantitative (RT-q)PCR data from patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation sequencing (NGS) platform (both DNA and RNA).

Results: By using data from >1000 samples, we show that at least 50% of EGFR amplified nuclei should be present to define EGFR gene amplification by FISH. Gene amplification (as determined by FISH) correlates with EGFR expression levels (as determined by RT-qPCR) with receiver operating characteristics analysis showing an area under the curve of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate marker for EGFR amplification. Our NGS data show that EGFR copy numbers can strongly vary between tumors, with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define EGFR-amplification by NGS; below this level, FISH detects very few (if any) EGFR amplified nuclei and none of the samples express EGFRvIII.

Conclusion: Our data from central laboratories and diagnostic sequencing facilities, using material from patients eligible for clinical trial inclusion, help define the optimal cutoff for various techniques to determine EGFR amplification for diagnostic purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noz096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784284PMC
October 2019

CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss.

J Exp Med 2018 04 7;215(4):1187-1203. Epub 2018 Mar 7.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN

Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration-approved drugs to prevent or treat it. We screened 4,385 small molecules in a cochlear cell line and identified 10 compounds that protected against cisplatin toxicity in mouse cochlear explants. Among them, kenpaullone, an inhibitor of multiple kinases, including cyclin-dependent kinase 2 (CDK2), protected zebrafish lateral-line neuromasts from cisplatin toxicity and, when delivered locally, protected adult mice and rats against cisplatin- and noise-induced hearing loss. CDK2-deficient mice displayed enhanced resistance to cisplatin toxicity in cochlear explants and to cisplatin- and noise-induced hearing loss in vivo. Mechanistically, we showed that kenpaullone directly inhibits CDK2 kinase activity and reduces cisplatin-induced mitochondrial production of reactive oxygen species, thereby enhancing cell survival. Our experiments have revealed the proapoptotic function of CDK2 in postmitotic cochlear cells and have identified promising therapeutics for preventing hearing loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20172246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881471PMC
April 2018

Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors.

Bioorg Med Chem 2018 01 4;26(1):25-36. Epub 2017 Nov 4.

Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC values comparable to BET inhibitor (BETi) clinical candidates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2017.10.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733700PMC
January 2018

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

J Egypt Natl Canc Inst 2017 Dec 6;29(4):171-176. Epub 2017 Nov 6.

European Organization for Research and Treatment of Cancer (EORTC), Av. Mounier 83/11, 1200 Brussels, Belgium.

For over 50years 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jnci.2017.09.001DOI Listing
December 2017

Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention.

Cell Rep 2017 05;19(8):1640-1653

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Influenza is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry, we found metabolic changes occurring after influenza infection in primary human respiratory cells and validated infection-associated increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1 and p85 phosphorylation, and reversed infection-induced changes in metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on the early stages of viral replication. BEZ235 significantly increased survival in mice, while reducing viral titer. We show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2017.04.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599215PMC
May 2017

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

J Neurooncol 2016 Jan 30;126(2):225-34. Epub 2015 Oct 30.

Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-015-1965-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718940PMC
January 2016

ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy.

Cancer Res 2015 Sep 21;75(18):3879-89. Epub 2015 Jul 21.

Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.

While a small number of plasma membrane ABC transporters can export chemotherapeutic drugs and confer drug resistance, it is unknown whether these transporters are expressed or functional in less therapeutically tractable cancers such as Group 3 (G3) medulloblastoma. Herein we show that among this class of drug transporters, only ABCG2 was expressed at highly increased levels in human G3 medulloblastoma and a mouse model of this disease. In the mouse model, Abcg2 protein was expressed at the plasma membrane where it functioned as expected on the basis of export of prototypical substrates. By screening ABC substrates against mouse G3 medulloblastoma tumorspheres in vitro, we found that Abcg2 inhibition could potentiate responses to the clinically used drug topotecan, producing a more than 9-fold suppression of cell proliferation. Extended studies in vivo in this model confirmed that Abcg2 inhibition was sufficient to enhance antiproliferative responses to topotecan, producing a significant survival advantage compared with subjects treated with topotecan alone. Our findings offer a preclinical proof of concept for blockade of ABCG2 transporter activity as a strategy to empower chemotherapeutic responses in G3 medulloblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-15-0030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573843PMC
September 2015

Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma.

Cancer Cell 2014 Apr 27;25(4):516-29. Epub 2014 Mar 27.

Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

We devised a high-throughput, cell-based assay to identify compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs neurospheres were screened against a library of approximately 7,000 compounds including US Food and Drug Administration-approved drugs. We found that pemetrexed and gemcitabine preferentially inhibited G3 MB proliferation in vitro compared to control neurospheres and substantially inhibited G3 MB proliferation in vivo. When combined, these two drugs significantly increased survival of mice bearing cortical implants of mouse and human G3 MBs that overexpress MYC compared to each agent alone, while having little effect on mouse MBs of the sonic hedgehog subgroup. Our findings strongly suggest that combination therapy with pemetrexed and gemcitabine is a promising treatment for G3 MBs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccr.2014.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994669PMC
April 2014

Comparison of spheroids formed by rat glioma stem cells and neural stem cells reveals differences in glucose metabolism and promising therapeutic applications.

J Biol Chem 2012 Sep 10;287(40):33664-74. Epub 2012 Jul 10.

UMR INSERM 892-CNRS 6299, Centre de Recherche en Cancérologie Nantes-Angers, Nantes, France.

Cancer stem cells (CSCs) are thought to be partially responsible for cancer resistance to current therapies and tumor recurrence. Dichloroacetate (DCA), a compound capable of shifting metabolism from glycolysis to glucose oxidation, via an inhibition of pyruvate dehydrogenase kinase was used. We show that DCA is able to shift the pyruvate metabolism in rat glioma CSCs but has no effect in rat neural stem cells. DCA forces CSCs into oxidative phosphorylation but does not trigger the production of reactive oxygen species and consecutive anti-cancer apoptosis. However, DCA, associated with etoposide or irradiation, induced a Bax-dependent apoptosis in CSCs in vitro and decreased their proliferation in vivo. The former phenomenon is related to DCA-induced Foxo3 and p53 expression, resulting in the overexpression of BH3-only proteins (Bad, Noxa, and Puma), which in turn facilitates Bax-dependent apoptosis. Our results demonstrate that a small drug available for clinical studies potentiates the induction of apoptosis in glioma CSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M111.320028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460464PMC
September 2012
-->