Jean-Charles Soria

Publications (204)1398.18 Total impact

• Article: Detection of Circulating Tumor Cells Harboring a Unique ALK Rearrangement in ALK-Positive Non-Small-Cell Lung Cancer.

  Emma Pailler, Julien Adam, Amélie Barthélémy, Marianne Oulhen, Nathalie Auger, Alexander Valent, Isabelle Borget, David Planchard, Melissa Taylor, Fabrice André, Jean Charles Soria, Philippe Vielh, Benjamin Besse, Françoise Farace
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  ABSTRACT: PURPOSEThe diagnostic test for ALK rearrangement in non-small-cell lung cancer (NSCLC) for crizotinib treatment is currently done on tumor biopsies or fine-needle aspirations. We evaluated whether ALK rearrangement diagnosis could be performed by using circulating tumor cells (CTCs). PATIENTS AND METHODS The presence of an ALK rearrangement was examined in CTCs of 18 ALK-positive and 14 ALK-negative patients by using a filtration enrichment technique and filter-adapted fluorescent in situ hybridization (FA-FISH), a FISH method optimized for filters. ALK-rearrangement patterns were determined in CTCs and compared with those present in tumor biopsies. ALK-rearranged CTCs and tumor specimens were characterized for epithelial (cytokeratins, E-cadherin) and mesenchymal (vimentin, N-cadherin) marker expression. ALK-rearranged CTCs were monitored in five patients treated with crizotinib.ResultsAll ALK-positive patients had four or more ALK-rearranged CTCs per 1 mL of blood (median, nine CTCs per 1 mL; range, four to 34 CTCs per 1 mL). No or only one ALK-rearranged CTC (median, one per 1 mL; range, zero to one per 1 mL) was detected in ALK-negative patients. ALK-rearranged CTCs harbored a unique (3'5') split pattern, and heterogeneous patterns (3'5', only 3') of splits were present in tumors. ALK-rearranged CTCs expressed a mesenchymal phenotype contrasting with heterogeneous epithelial and mesenchymal marker expressions in tumors. Variations in ALK-rearranged CTC levels were detected in patients being treated with crizotinib. CONCLUSIONALK rearrangement can be detected in CTCs of patients with ALK-positive NSCLC by using a filtration technique and FA-FISH, enabling both diagnostic testing and monitoring of crizotinib treatment. Our results suggest that CTCs harboring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC.
  Journal of Clinical Oncology 05/2013; · 18.37 Impact Factor
• Article: IGF-1R targeting increases the antitumor effects of DNA damaging agents in SCLC model: an opportunity to increase the efficacy of standard therapy.

  Charles Ferte, Yohann Loriot, Celine Clemenson, Frederic Commo, Andrea Gombos, Jean-Emmanuel Bibault, Ingrid Fumagalli, Saad Hamama, Nathalie Auger, Benoit Lahon, Cyrus Chargari, Julien Calderaro, Jean-Charles Soria, Eric Deutsch
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  ABSTRACT: Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146 and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 demonstrated single agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both Cisplatin and IR in vitro. The triple combination R1507-Cisplatin-IR led to a dramatic delay in tumor growth compared to Cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis and survival. Finally, we identified that the nucleotide excision repair pathway (NER) was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard Cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting.
  Molecular Cancer Therapeutics 05/2013; · 5.23 Impact Factor
• Article: Next-Generation Sequencing Reveals High Concordance of Recurrent Somatic Alterations Between Primary Tumor and Metastases From Patients With Non-Small-Cell Lung Cancer.

  Stéphane Vignot, Garrett M Frampton, Jean-Charles Soria, Roman Yelensky, Frédéric Commo, Christian Brambilla, Gary Palmer, Denis Moro-Sibilot, Jeffrey S Ross, Maureen T Cronin, Fabrice André, Philip J Stephens, Vladimir Lazar, Vincent A Miller, Elisabeth Brambilla
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  ABSTRACT: PURPOSECharacterization of the genomic changes that drive an individual patient's disease is critical in management of many cancers. In patients with non-small-cell lung cancer (NSCLC), obtaining tumor samples of sufficient size for genomic profiling on recurrence is often challenging. We undertook this study to compare genomic alterations identified in archived primary tumors from patients with NSCLC with those identified in metachronous or synchronous metastases. PATIENTS AND METHODS Primary and matched metastatic tumor pairs from 15 patients were analyzed by using a targeted next-generation sequencing assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage.ResultsAmong 30 tumors, 311 genomic alterations were identified of which 63 were known recurrent (32 in primary tumor, 31 in metastasis) and 248 were nonrecurrent (likely passenger). TP53 mutations were the most frequently observed recurrent alterations (12 patients). Tumors harbored two or more (maximum four) recurrent alterations in 10 patients. Comparative analysis of recurrent alterations between primary tumor and matched metastasis revealed a concordance rate of 94% compared with 63% for likely passenger alterations. CONCLUSION This high concordance suggests that for the purposes of genomic profiling, use of archived primary tumor can identify the key recurrent somatic alterations present in matched NSCLC metastases and may provide much of the relevant genomic information required to guide treatment on recurrence.
  Journal of Clinical Oncology 04/2013; · 18.37 Impact Factor
• Article: Pooled Analysis of the Prognostic and Predictive Effects of KRAS Mutation Status and KRAS Mutation Subtype in Early-Stage Resected Non-Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy.

  Frances A Shepherd, Caroline Domerg, Pierre Hainaut, Pasi A Jänne, Jean-Pierre Pignon, Stephen Graziano, Jean-Yves Douillard, Elizabeth Brambilla, Thierry Le Chevalier, Lesley Seymour, [......], Gwénaël Le Teuff, Robert Pirker, Martin Filipits, Rafael Rosell, Robert Kratzke, Bizhan Bandarchi, Xiaoli Ma, Marzia Capelletti, Jean-Charles Soria, Ming-Sound Tsao
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  ABSTRACT: PURPOSEWe undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non-small-cell lung cancer (NSCLC). METHODSKRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model. RESULTS: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02). CONCLUSIONKRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.
  Journal of Clinical Oncology 04/2013; · 18.37 Impact Factor
• Article: Personalized radiation therapy and biomarker-driven treatment strategies: a systematic review.

  Jean-Emmanuel Bibault, Ingrid Fumagalli, Charles Ferté, Cyrus Chargari, Jean-Charles Soria, Eric Deutsch
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  ABSTRACT: Radiosensitivity varies to a great extent across tumor types and also between patients bearing the same type of tumor. Radiation oncology pioneered the field of biomarkers with attempts to correlate tumor response to clonogenic survival, tumor potential doubling time (Tpot), and PaO2. Biomarkers predicting the clinical outcome after radiotherapy are already available, but their levels of evidence are heterogeneous. In light of these molecular factors, the issue of personalized radiation therapy in combination or as a standalone modality is addressed. Known molecular prognostic and predictive biomarkers and their present or potential respective therapeutic implications are described for six tumor types where radiotherapy is considered to be part of the mainstay: chemoradiation (e.g., gliomas, head and neck, cervical cancer), radiotherapy with or without androgen deprivation (e.g., prostate), neo-adjuvant chemoradiation (e.g., rectum), or adjuvant radiotherapy (e.g., breast).
  CANCER AND METASTASIS REVIEW 04/2013; · 9.35 Impact Factor
• Article: Cisplatin Resistance Associated with PARP Hyperactivation.

  Judith Michels, Ilio Vitale, Lorenzo Galluzzi, Julien Adam, Ken André Olaussen, Oliver Kepp, Laura Senovilla, Ibtissam Talhaoui, Justine Guegan, David Pierre Enot, [......], Pauline Garcia, Parviz Behnam-Motlagh, Kimitoshi Kohno, Gen Sheng Wu, Catherine Brenner, Philippe Dessen, Murat Saparbaev, Jean-Charles Soria, Maria Castedo, Guido Kroemer
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  ABSTRACT: Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis. Cancer Res; 73(7); 2271-80. ©2013 AACR.
  Cancer Research 04/2013; 73(7):2271-2280. · 7.86 Impact Factor
• Article: ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.

  Luc Friboulet, Ken André Olaussen, Jean-Pierre Pignon, Frances A Shepherd, Ming-Sound Tsao, Stephen Graziano, Robert Kratzke, Jean-Yves Douillard, Lesley Seymour, Robert Pirker, [......], Julien Adam, Elsa Vanhecke, Patrick Saulnier, Jürgen Thomale, Thierry Le Chevalier, Ariane Dunant, Vanessa Rousseau, Gwénaël Le Teuff, Elisabeth Brambilla, Jean-Charles Soria
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  ABSTRACT: The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).
  New England Journal of Medicine 03/2013; 368(12):1101-10. · 53.30 Impact Factor
• Article: Phase I-IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours.

  Jean-Charles Soria, José Baselga, Nasser Hanna, Scott A Laurie, Rastislav Bahleda, Enriqueta Felip, Emiliano Calvo, Jean-Pierre Armand, Frances A Shepherd, Christopher T Harbison, David Berman, Jong-Soon Park, Steven Zhang, Blisse Vakkalagadda, John F Kurland, Ashutosh K Pathak, Roy S Herbst
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  ABSTRACT: PURPOSE: BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514. PATIENTS AND METHODS: In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD. RESULTS: In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (⩾4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways. CONCLUSION: This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.
  European journal of cancer (Oxford, England: 1990) 03/2013; · 4.12 Impact Factor
• Article: What can be done for patients with NSCLC without druggable targets?

  Benjamin Besse, Fabrice Andre, Jean-Charles Soria
  The lancet oncology 03/2013; 14(3):191-2. · 14.47 Impact Factor
• Article: A dose finding, safety and pharmacokinetic study of AVE1642, an anti-insulin-like growth factor-1 receptor (IGF-1R/CD221) monoclonal antibody, administered as a single agent and in combination with docetaxel in patients with advanced solid tumours.

  Jean Charles Soria, Christophe Massard, Vladimir Lazar, Marie-Laure Ozoux, Dominique Mery-Mignard, Antoine Deslandes, Anthony W Tolcher
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  ABSTRACT: PURPOSE: AVE1642, a humanised mAb, binds the human IGF-1R specifically and with high affinity. This study aimed to select the dose of AVE1642 alone and then combined with docetaxel 75mg/m(2) (D). MATERIAL AND METHODS: AVE1642 was administered alone at cycle (cy) 1 and then combined with D from cy2, q3w. RESULTS: A total of 27 patients received a median number of 5 cy (range, 1-10). The most common tumour types were sarcoma (18.5%), osseous tumours (11.1%) and colon cancer (11.1%). Two DLTs were reported in cy1 at dose level (DL) 18mg/kg and dose escalation was stopped. No major safety issue was observed. No anti-drug antibodies were detected. The Maximal Tolerated Dose of AVE1642 was 12mg/kg. The dose selected for further combinations is 6mg/kg, based on PK/PD data. Three objective responses, (two in sarcoma and one breast cancer) were observed but only one was confirmed. Eleven patients appeared to benefit from treatment with prolonged disease stabilisation ⩾4months. CONCLUSION: AVE1642 is well tolerated as a single agent and combined with D. The selected dose of AVE1642 combined with D is 6mg/kg. Promising activity was seen in sarcoma and breast cancer patients.
  European journal of cancer (Oxford, England: 1990) 02/2013; · 4.12 Impact Factor
• Article: Synergistic interaction between cisplatin and PARP inhibitors in non-small cell lung cancer.

  Judith Michels, Ilio Vitale, Laura Senovilla, David P Enot, Pauline Garcia, Delphine Lissa, Ken A Olaussen, Catherine Brenner, Jean-Charles Soria, Maria Castedo, Guido Kroemer
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  ABSTRACT: The antineoplastic agent cis-diammineplatinum(II) dichloride (cisplatin, CDDP) is part of the poorly effective standard treatment of non-small cell lung carcinoma (NSCLC). Here, we report a novel strategy to improve the efficacy of CDDP. In conditions in which CDDP alone or either of two PARP inhibitors, PJ34 hydrochloride hydrate or CEP 8983, used as standalone treatments were inefficient in killing NSCLC cells, the combination of CDDP plus PJ34 or that of CDDP plus CEP 8983 were found to kill a substantial fraction of the cells. This cytotoxic synergy could be recapitulated by combining CDDP and the siRNA-mediated depletion of the principal PARP isoform, PARP1, indicating that it is mediated by on-target effects of PJ34 or CEP 8983. CDDP and PARP inhibitors synergized in inducing DNA damage foci, mitochondrial membrane permeabilization leading to cytochrome c release, and dissipation of the inner transmembrane potential, caspase activation, plasma membrane rupture and loss of clonogenic potential in NSCLC cells. Collectively, our results indicate that CDDP can be advantageously combined with PARP inhibitors to kill several NSCLC cell lines, independently from their p53 status. Combined treatment with CDDP and PARP inhibitors elicits the intrinsic pathway of apoptosis.
  Cell cycle (Georgetown, Tex.) 02/2013; 12(6). · 5.36 Impact Factor
• Article: Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives.

  Maria Vittoria Dieci, Monica Arnedos, Fabrice Andre, Jean Charles Soria
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  ABSTRACT: The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifications, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, class-specific toxicity profiles and correctly designing clinical trials to address these different issues.
  Cancer discovery. 02/2013;
• Article: ERCC1 and RRM1: Ready for Prime Time?

  Benjamin Besse, Ken A Olaussen, Jean-Charles Soria
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  ABSTRACT: The quest for markers of sensitivity to cytotoxic agents has been ongoing for decades. In non-small-cell lung cancer, platinum compounds represent the cornerstone of systemic therapy. They target DNA and induce damage that cancer cells struggle to overcome. Somatic excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), and ribonucleotide reductase M1 (RRM1) expression levels have been extensively explored as markers of DNA repair capacity in tumor cells. Although low ERCC1 and/or RRM1 expression is generally associated with sensitivity to platinum, the results published in retrospective and prospective studies are not always consistent. Against this background, we will examine in this review the function of these two biomarkers as well as the tools available for their assessment and the associated technical issues. Their prognostic and predictive values will be summarized and considered in terms of customizing systemic therapy according to biomarker (ERCC1 and RRM1) expression levels. We will also discuss why the use of both markers should at this point be restricted to clinical research and underline that functional readouts of DNA repair will help boost future strategies for biomarker discovery in the field.
  Journal of Clinical Oncology 02/2013; · 18.37 Impact Factor
• Article: PARP1 impact on DNA repair of platinum adducts: Preclinical and clinical read-outs.

  Ken A Olaussen, Julien Adam, Elsa Vanhecke, Philippe Vielh, Robert Pirker, Luc Friboulet, Helmut Popper, Angélique Robin, Fréderic Commo, Jürgen Thomale, Louis Kayitalire, Martin Filipits, Thierry Le Chevalier, Fabrice André, Elisabeth Brambilla, Jean-Charles Soria
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  ABSTRACT: Evaluation of DNA repair proteins might provide meaningful information in relation to prognosis and chemotherapy efficacy in Non-Small Cell Lung Cancer (NSCLC) patients. The role of Poly(ADP-Ribose) Polymerase (PARP) in DNA repair of platinum adducts has not been firmly established. We used a DNA repair functional test based on antibody recognition of cisplatin intrastrand platinum adducts on DNA. We evaluated the effect of PARP inhibition on DNA repair functionality in a panel of cisplatin cell lines treated by the clinical-grade pharmacological inhibitor CEP8983 (a 4-methoxy-carbazole derivate) and the commercially available inhibitor PJ34 (phenanthridinone). We determined PARP1 protein expression in whole tumor sections from the International Adjuvant Lung cancer Trial (IALT)-bio study and tested a 3-marker PARP1/MSH2/ERCC1 algorithm combining PARP1 tumor status with previously published data. Chemosensitivity of cisplatin in NSCLC cell lines was correlated with the accumulation of cisplatin DNA adducts (P=0.0004). Further, the pharmacological inhibition of PARP induced a 1.7 to 2.3-fold increase in platinum adduct accumulation (24h) in A549 cell line suggesting a slow-down of platinum DNA-adduct repair capacity. In parallel, PARP1 inhibition increased the sensitivity to cisplatin treatment. In patient samples, PARP1 expression levels did not influence patient survival or the effect of platinum-based post-operative chemotherapy in the global IALT-bio population (interaction P=0.79). Among cases with high expression of all three markers (triple positive), untreated patients had prolonged survival with a median DFS of 7.8 years, (HR=0.34, 95%CI [0.19-0.61], adjusted P=0.0003) compared to triple negative patients (1.4 years). Remarkably, triple positive patients suffered from a detrimental effect (4.9-year reduction of median DFS) by post-operative cisplatin-based chemotherapy (HR=1.79, 95%CI [1.01-3.17], adjusted P=0.04, chemotherapy vs. control). Combinatorial sub-group analysis of the 3 markers further suggested that PARP1 tumor positivity might constitute a molecular context with high theranostic interest of ERCC1 and MSH2 in NSCLC. In conclusion, our data confirm that platinum DNA adduct accumulation is linked to chemosensitivity, which increase by pharmacological PARP inhibitors points to a role of PARP-dependent DNA repair in the process. We further suggest DNA repair biomarkers should be analyzed in a larger context of multiple DNA repair pathway regulation.
  Lung cancer (Amsterdam, Netherlands) 02/2013; · 3.14 Impact Factor
• Article: Phase I clinical trial combining imatinib mesylate and IL-2 in refractory cancer patients: IL-2 interferes with the pharmacokinetics of imatinib mesylate.

  Patricia Pautier, Clara Locher, Caroline Robert, Alain Deroussent, Caroline Flament, Axel Le Cesne, Annie Rey, Ratislav Bahleda, Vincent Ribrag, Jean-Charles Soria, Gilles Vassal, Alexander Eggermont, Laurence Zitvogel, Nathalie Chaput, Angelo Paci
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  ABSTRACT: Imatinib mesylate (IM) is a small molecule inhibitor of protein tyrosine kinases. In addition to its direct effect on malignant cells, it has been suggested IM may activate of natural killer (NK) cells, hence exerting immunomodulatory functions. In preclinical settings, improved antitumor responses have been observed when IM and interleukin-2 (IL-2), a cytokine that enhances NK cells functions, were combined. The goals of this study were to determine the maximum tolerated dose (MTD) of IL-2 combined with IM at a constant dose of 400 mg, the pharmacokinetics of IM and IL-2, as well as toxicity and clinical efficacy of this immunotherapeutic regimen in patients affected by advanced tumors. The treatment consisted in 50 mg/day cyclophosphamide from 21 d before the initiation of IM throughout the first IM cycle (from D-21 to D14), 400 mg/day IM for 14 d (D1 to D14) combined with escalating doses of IL-2 (3, 6, 9 and 12 MIU/day) from days 10 to 14. This treatment was administered at three week intervals to 17 patients. Common side effects of the combination were mild to moderate, including fever, chills, fatigue, nausea and hepatic enzyme elevation. IL-2 dose level II, 6 MIU/day, was determined as the MTD with the following dose-limiting toxicities: systemic capillary leak syndrome, fatigue and anorexia. Pharmacokinetic studies revealed that the area under the curve and the maximum concentration of IM and its main metabolite CGP74588 increased significantly when IM was concomitantly administered with IL-2. In contrast, IM did not modulate IL-2 pharmacokinetics. No objective responses were observed. The best response obtained was stable disease in 8/17 (median duration: 12 weeks). Finally, IL-2 augmented the impregnation of IM and its metabolite. The combination of IM (400 mg/day) and IL-2 (6 MIU/day) in tumors that express IM targets warrants further investigation.
  Oncoimmunology. 02/2013; 2(2):e23079.
• Article: Phase I clinical trial combining imatinib mesylate and IL-2: HLA-DR(+) NK cell levels correlate with disease outcome.

  Nathalie Chaput, Caroline Flament, Clara Locher, Mélanie Desbois, Annie Rey, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Patricia Pautier, Axel Le Cesne, Jean-Charles Soria, Angelo Paci, Michelle Rosenzwajg, David Klatzmann, Alexander Eggermont, Caroline Robert, Laurence Zitvogel
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  ABSTRACT: We performed a Phase I clinical trial from October 2007 to October 2009, enrolling patients affected by refractory solid tumors, to determine the maximum tolerated dose (MTD) of interleukin (IL)-2 combined with low dose cyclophosphamide (CTX) and imatinib mesylate (IM). In a companion paper published in this issue of OncoImmunology, we show that the MTD of IL-2 is 6 MIU/day for 5 consecutive days, and that IL-2 increases the impregnation of both IM and of its main metabolite, CGP74588. Among the secondary objectives, we wanted to determine immunological markers that might be associated with progression-free survival (PFS) and/or overall survival (OS). The combination therapy markedly reduced the absolute counts of B, CD4(+) T and CD8(+) T cells in a manner that was proportional to IL-2 dose. There was a slight (less than 2-fold) increase in the proportion of regulatory T cells (Tregs) among CD4(+) T cells in response to IM plus IL-2. The natural killer (NK)-cell compartment was activated, exhibiting a significant upregulation of HLA-DR, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD56. The abundance of HLA-DR(+) NK cells after one course of combination therapy positively correlated with both PFS and OS. The IL-2-induced rise of the CD4(+):CD8(+) T-cell ratio calculated after the first cycle of treatment was also positively associated with OS. Overall, the combination of IM and IL-2 promoted the rapid expansion of HLA-DR(+) NK cells and increased the CD4(+):CD8(+) T-cell ratio, both being associated with clinical benefits. This combinatorial regimen warrants further investigation in Phase II clinical trials, possibly in patients affected by gastrointestinal stromal tumors, a setting in which T and NK cells may play an important therapeutic role.
  Oncoimmunology. 02/2013; 2(2):e23080.
• Source

  Available from: Lorenzo Galluzzi

  Article: Prognostic value of LIPC in non-small cell lung carcinoma.

  Lorenzo Galluzzi, Aicha Goubar, Ken André Olaussen, Ilio Vitale, Laura Senovilla, Judith Michels, Angélique Robin, Nicolas Dorvault, Benjamin Besse, Pierre Validire, Pierre Fouret, Carmen Behrens, Ignacio Ivan Wistuba, Jean-Charles Soria, Guido Kroemer
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  ABSTRACT: Non-small cell lung carcinoma (NSCLC) is the most common form of lung cancer and is associated with a high mortality rate worldwide. The majority of individuals bearing NSCLC are treated with surgery plus adjuvant cisplatin, an initially effective therapeutic regimen that, however, is unable to prevent relapse within 5 y after tumor resection in an elevated proportion of patients. The factors that predict the clinical course of NSCLC and its sensitivity to therapy remain largely obscure. One notable exception is provided by pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. PDXK has recently been shown to be required for optimal cisplatin responses in vitro and in vivo and to constitute a bona fide prognostic marker in the NSCLC setting. Together with PDXK, 84 additional factors were identified that influence the response of NSCLC cells to cisplatin in vitro including the hepatic lipase LIPC. Here, we report that the intratumoral levels of LIPC, as assessed by immunohistochemistry in two independent cohorts of NSCLC patients, positively correlate with disease outcome. In one out of two cohorts studied, the overall survival of NSCLC patients bearing LIPC (high) lesions was unaffected, if not slightly worsened, by cisplatin-based adjuvant therapy. Conversely, the overall survival of patients with LIPC (low) lesions was prolonged by post-operative cisplatin. Pending validation in appropriate clinical series, these results suggest that LIPC (low) NSCLC patients would be those who mainly benefit from adjuvant cisplatin therapy. Thus, the expression levels of LIPC appear to have an independent prognostic value (and perhaps a predictive potential) in the setting of NSCLC. If these findings were confirmed by additional studies, LIPC expression levels might allow not only for NSCLC patient stratification, but also for the implementation of personalized therapeutic approaches.
  Cell cycle (Georgetown, Tex.) 01/2013; 12(4). · 5.36 Impact Factor
• Article: Inclusion of Patients With Advanced Cancer in Phase I Trials: Is This a Tool for Improving Optimism and Emotional Well-Being?

  Mathieu Rouanne, Elodie Jacquelet, Antoine Hollebecque, Thierry Lebret, Jean-Charles Soria, Christophe Massard
  Journal of Clinical Oncology 01/2013; · 18.37 Impact Factor
• Article: First case report of intrathecal panitumumab for treatment of meningeal carcinomatousis in an EGFR mutant lung adenocarcinoma patient.

  Antoine Hollebecque, Antonin Levy, Sophie Broutin, François Lemare, Anas Gazzah, Romain Desmaris, Catherine Chenailler, Matthieu Elbaum, Benjamin Besse, Angelo Paci, Jean-Charles Soria
  Lung cancer (Amsterdam, Netherlands) 01/2013; · 3.14 Impact Factor
• Article: Modifying phase I methodology to facilitate enrolment of molecularly selected patients.

  Antoine Hollebecque, Sophie Postel-Vinay, Jaap Verweij, George D Demetri, Keith Flaherty, Philippe Bedard, Jean-Charles Soria
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  ABSTRACT: Over the last decade, the focus of anticancer drug development has shifted from empirical cytotoxic chemotherapy to mechanism-defined molecularly targeted agents, for which appropriate patient selection at the earliest possible point in drug development is rational and critical to success. With the recently legislated "breakthrough product" definition in the U.S., it may be possible to plan a single trial for registration purposes to confirm a major clinical effect observed in phase I. However, most phase I trial designs remain excessively conservative and are driven by criteria developed for cytotoxic agents with the goal of identifying a "maximum tolerable dose" with acceptable risks to patients. This focus on empiric "most dose with acceptable risk" may be misguided for mechanism-targeting new agents, and this could lead to unnecessary delays, increased costs and even higher risk of missing important signals of activity and benefit. There is a compelling need to modify phase I trial designs to facilitate enrichment in molecularly selected patients who are the most likely to harbour disease driven by the targeted pathway and to avoid unjustified exclusions based on obsolete criteria so that the right subset of patients can participate. After discussion of the main inconsistencies of current phase I designs, we propose a new strategy to facilitate the inclusion of molecularly selected patients, in order to accelerate and mitigate risks in drug development as well as to increase the chance of benefit among trial participants.
  European journal of cancer (Oxford, England: 1990) 01/2013; · 4.12 Impact Factor