Publications by authors named "Daphne Morel"

11 Publications

  • Page 1 of 1

Prognostic value of tumor immune biomarkers in biopsies from patients with refractory solid cancers.

Cancer Treat Res Commun 2022 Jul 19;32:100611. Epub 2022 Jul 19.

Département de Biologie et Pathologie Médicales, Service de Pathologie Moléculaire, Gustave Roussy, Villejuif; AMMICa, CNRS UAR3655 INSERM US23; Université Paris Saclay.

PD-L1 and tumor-infiltrating lymphocytes play a key role in the immune escape of cancer, although their prognostic value remains unknown in patients with refractory solid cancer compared to other known prognostic estimation methods. In this ancillary study, we assessed the prognostic value of previously-defined prognostic scores (such as the Royal Marsden Hospital (RMH) score) and of PD-L1, CD3, CD8 and FOXP3 expressions based on immunohistochemistry (IHC) and RNA sequencing (RNAseq) of tumor samples from patients included in the personalized-medicine MOSCATO-02 trial. We collected biopsies with successful IHC analysis from 266 patients treated between April 2016 and September 2017, among whom 170 (63.9%) also had a matched RNAseq. We used a Random Forest model to identify the best prognostic factor, and a Lasso-penalized Cox model to validate the findings. We found that the RMH score was the strongest prognostic factor, with high scores associated with a higher risk of death (Hazard Ratio (HR)=1.29; CI95%[1.19-1.21]). The PD-L1 expression score obtained from IHC analyses was the second-best performing predictor, with the 1+ score (low expression) linked to a lower risk of death (HR=0.564; CI95%[0.539-0.580]). Other tested variables, including primary tumor type and subsequent treatments received following biopsy, were not found significantly linked to prognosis. We found modest correlation between IHC and RNAseq expressions of immune genes, but RNAseq related better to prognosis. Overall, our study supports the use of the RMH score and the assessment of PD-L1 expression in IHC to estimate prognosis in patients with advanced cancer.
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http://dx.doi.org/10.1016/j.ctarc.2022.100611DOI Listing
July 2022

Epigenetic gene alterations in metastatic solid tumours: results from the prospective precision medicine MOSCATO and MATCH-R trials.

Eur J Cancer 2022 Jul 21;173:133-145. Epub 2022 Jul 21.

Drug Development Department (DITEP), Gustave Roussy, Villejuif, France; Inserm Unit U981, ATIP-Avenir Team, Villejuif, France. Electronic address:

Introduction: Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumours is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials.

Materials And Methods: On-purpose tumour biopsies from pts with metastatic solid tumours enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using whole exome sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumour board. Clinical characteristics and outcome were collected.

Results: Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumours. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumour samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1-10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p < 0.001). Outcome was not correlated with the presence of EGA.

Conclusions: Epigenetic alterations occur frequently in metastatic solid tumours. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analysed in molecular profiling studies.
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http://dx.doi.org/10.1016/j.ejca.2022.06.014DOI Listing
July 2022

Practice changing data and emerging concepts from recent radiation therapy randomised clinical trials.

Eur J Cancer 2022 08 29;171:242-258. Epub 2022 Jun 29.

Gustave Roussy, Département de Radiothérapie, F-94805, Villejuif, France; Université Paris-Saclay, Faculté de Médecine, F-94270, Le Kremlin Bicêtre, France; Université Paris-Saclay, Inserm U-1030, Laboratoire de Radiothérapie Moléculaire et d'Innovation Thérapeutique, F-94805, Villejuif, France. Electronic address:

Introduction: Oncology treatments are constantly and rapidly evolving. We aimed at highlighting the latest radiation therapy practice changing trials and emerging concepts, through an overview of recent randomised clinical trials (RCTs).

Materials And Methods: Requests were performed in the Medline database to identify all publications reporting radiation therapy RCTs from 2018 to 2021.

Results: Recent RCTs sustained the role of newer combinatorial strategies through radioimmunotherapy for early stage or metastatic lung cancer, newer pro-apoptotic agents (e.g. debio 1143 in locoregionally advanced head and neck squamous cell carcinoma) or nanoparticles (e.g. NBTXR3 in locally advanced soft-tissue sarcoma). High-tech radiotherapy allows intensifying treatments and gaining ground in some indications through the development of stereotactic body radiotherapy for example. First randomised evidence on personalised radiation therapy through imaging-based (FDG positron emission tomography-computed tomography for lung cancer or early stage unfavourable Hodgkin lymphoma, PMSA positron emission tomography-computed tomography or magnetic resonance imaging for high-risk prostate cancer) or biological biomarkers (PSA for prostate cancer, HPV for head and neck cancer, etc) were conducted to more tailored treatments, with more favourable outcomes. Patients' quality of life and satisfaction appeared to be increasing aims. RCTs have validated (ultra)hypofractionated schemes in many indications as for breast, prostate or rectal cancer, resulting in equivalent outcomes and toxicities, more convenient for patients and favouring shared decision making.

Conclusion: Radiation therapy is a dynamic field of research, and many RCTs have greatly impacted therapeutic standards over the last years. Investments in radiotherapy research should facilitate the transfer of innovation to clinic.
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http://dx.doi.org/10.1016/j.ejca.2022.04.038DOI Listing
August 2022

PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer.

Cancer Res 2021 06;81(11):2888-2902

ATIP-Avenir group, Inserm Unit U981, Gustave Roussy, Villejuif, France.

Inactivation of (), a specific subunit of the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% of clear cell renal cell carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used a series of orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with deficiency. The PBRM1/PARP inhibitor synthetic lethality was recapitulated using several clinical PARP inhibitors in a series of model systems and in a xenograft model of ccRCC. In the absence of exogenous DNA damage, PBRM1-defective cells exhibited elevated levels of replication stress, micronuclei, and R-loops. PARP inhibitor exposure exacerbated these phenotypes. Quantitative mass spectrometry revealed that multiple R-loop processing factors were downregulated in PBRM1-defective tumor cells. Exogenous expression of the R-loop resolution enzyme RNase H1 reversed the sensitivity of PBRM1-deficient cells to PARP inhibitors, suggesting that excessive levels of R-loops could be a cause of this synthetic lethality. PARP and ATR inhibitors also induced cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) innate immune signaling in PBRM1-defective tumor cells. Overall, these findings provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers. SIGNIFICANCE: This study demonstrates that PARP and ATR inhibitors are synthetic lethal with the loss of PBRM1, a PBAF-specific subunit, thus providing the rationale for assessing these inhibitors in patients with PBRM1-defective cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/2888/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0628DOI Listing
June 2021

Applications of single-cell and bulk RNA sequencing in onco-immunology.

Eur J Cancer 2021 05 15;149:193-210. Epub 2021 Apr 15.

Département d'Innovations Thérapeutiques et Essais Précoces (DITEP), Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, 94800, Villejuif, France; INSERM UMR1030, Molecular Radiotherapy and Therapeutic Innovations, Gustave Roussy, 114 rue Edouard Vaillant, 94800, Villejuif, France; Institut Curie, PSL Research University, F-75005, Paris, France; Université Paris-Saclay, France. Electronic address:

The rising interest for precise characterization of the tumour immune contexture has recently brought forward the high potential of RNA sequencing (RNA-seq) in identifying molecular mechanisms engaged in the response to immunotherapy. In this review, we provide an overview of the major principles of single-cell and conventional (bulk) RNA-seq applied to onco-immunology. We describe standard preprocessing and statistical analyses of data obtained from such techniques and highlight some computational challenges relative to the sequencing of individual cells. We notably provide examples of gene expression analyses such as differential expression analysis, dimensionality reduction, clustering and enrichment analysis. Additionally, we used public data sets to exemplify how deconvolution algorithms can identify and quantify multiple immune subpopulations from either bulk or single-cell RNA-seq. We give examples of machine and deep learning models used to predict patient outcomes and treatment effect from high-dimensional data. Finally, we balance the strengths and weaknesses of single-cell and bulk RNA-seq regarding their applications in the clinic.
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http://dx.doi.org/10.1016/j.ejca.2021.03.005DOI Listing
May 2021

Combining epigenetic drugs with other therapies for solid tumours - past lessons and future promise.

Nat Rev Clin Oncol 2020 02 30;17(2):91-107. Epub 2019 Sep 30.

ATIP-Avenir Group, UMR981, INSERM (French National Institute of Health and Medical Research), Gustave Roussy Cancer Campus, Villejuif, France.

Epigenetic dysregulation has long been recognized as a key factor contributing to tumorigenesis and tumour maintenance that can influence all of the recognized hallmarks of cancer. Despite regulatory approvals for the treatment of certain haematological malignancies, the efficacy of the first generation of epigenetic drugs (epi-drugs) in patients with solid tumours has been disappointing; however, successes have now been achieved in selected solid tumour subtypes, thanks to the development of novel compounds and a better understanding of cancer biology that have enabled precision medicine approaches. Several lines of evidence support that, beyond their potential as monotherapies, epigenetic drugs could have important roles in synergy with other anticancer therapies or in reversing acquired therapy resistance. Herein, we review the mechanisms by which epi-drugs can modulate the sensitivity of cancer cells to other forms of anticancer therapy, including chemotherapy, radiation therapy, hormone therapy, molecularly targeted therapy and immunotherapy. We provide a critical appraisal of the preclinical rationale, completed clinical studies and ongoing clinical trials relating to combination therapies incorporating epi-drugs. Finally, we propose and discuss rational clinical trial designs and drug development strategies, considering key factors including patient selection, tumour biomarker evaluation, drug scheduling and response assessment and study end points, with the aim of optimizing the development of such combinations.
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http://dx.doi.org/10.1038/s41571-019-0267-4DOI Listing
February 2020

Exploiting epigenetic vulnerabilities in solid tumors: Novel therapeutic opportunities in the treatment of SWI/SNF-defective cancers.

Semin Cancer Biol 2020 04 27;61:180-198. Epub 2019 Sep 27.

Université Paris Saclay, Université Paris-Sud, Faculté de médicine, Le Kremlin Bicêtre, France; ATIP-Avenir Group, Inserm Unit U981, Gustave Roussy, Villejuif, France; DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif, France. Electronic address:

Mammalian switch/sucrose non-fermentable (mSWI/SNF) family complexes are pivotal elements of the chromatin remodeling machinery, which contribute to the regulation of several major cellular functions. Large-scale exome-wide sequencing studies have identified mutations in genes encoding mSWI/SNF subunits in 20% of all human cancers, establishing mSWI/SNF deficiency as a recurrent oncogenic alteration. Accumulating evidence now supports that several mSWI/SNF defects represent targetable vulnerabilities in cancer; notably, recent research advances have unveiled unexpected synthetic lethal opportunities that foster the development of novel biomarker-driven and mechanism-based therapeutic approaches for the treatment of mSWI/SNF-deficient tumors. Here, we review the latest breakthroughs and discoveries that inform our understanding of the mSWI/SNF complexes biology in carcinogenesis, and discuss the most promising therapeutic strategies to target mSWI/SNF defects in human solid malignancies.
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http://dx.doi.org/10.1016/j.semcancer.2019.09.018DOI Listing
April 2020

PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.

J Clin Invest 2019 03 11;129(3):1211-1228. Epub 2019 Feb 11.

Université Paris Saclay, Université Paris-Sud, Faculté de médicine, Le Kremlin Bicêtre, Paris, France.

The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations.
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http://dx.doi.org/10.1172/JCI123319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391116PMC
March 2019

DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade.

J Clin Invest 2018 04 19;128(4):1671-1687. Epub 2018 Mar 19.

Inserm U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro - ERCC1-deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells - and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD+ acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.
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http://dx.doi.org/10.1172/JCI90277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873862PMC
April 2018

Otorhinolaryngological Toxicities of New Drugs in Oncology.

Adv Ther 2017 04 17;34(4):866-894. Epub 2017 Mar 17.

Department of Drug Development (DITEP), Gustave Roussy Cancer Center and School of Medicine, Paris Sud University, Paris, France.

Many new or relatively new cancer drugs-personalized anticancer agents-have been approved for use in various clinical settings in oncology or are still under evaluation in clinical trials. Targeted therapies as well as new immune checkpoint blockers have toxicity profiles that differ from conventional cytotoxic chemotherapy, and many can cause adverse effects that affect the mouth and pharynx, the nasal cavities, and the larynx. This review aims to provide an overview of current knowledge concerning these side effects and contemporary management. Adverse effects of the mouth/pharynx, nasal cavities, larynx, and cochlear-vestibular system are generally low grade (according to the Common Terminology Criteria for Adverse Events) and generally present non-life-threatening symptoms. However, the impact on patients' quality of life could be important. The incidence and severity vary according to the drug, its target(s), and dose, but there are currently no known predictive factors, and each patient has an individual toxicity profile. Management guidelines are based on expert opinion. These ear, nose, and throat adverse effects are not frequently mentioned in the literature because of the often non-specific nature of the symptoms and their mildness, but also the absence of specific treatment. These symptoms can contribute to decreased quality of life and lead to drug compliance issues if not diagnosed and managed appropriately.
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http://dx.doi.org/10.1007/s12325-017-0512-0DOI Listing
April 2017
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