Benoit Lahon

Institut de Cancérologie Gustave Roussy, Île-de-France, France

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Publications (7)19.03 Total impact

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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; · 5.60 Impact Factor
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    ABSTRACT: The central role of p53 after exposure to ionizing radiation has been widely demonstrated. Mdm2, the main cellular regulator of p53, is a promising target for radiosensitizing purposes. In this article, we review the most recent data on the pharmacological targeting of Mdm2, with focus on strategies of radiosensitization. Antitumor activity of Mdm2 inhibitors has been related with activation of p53-dependant apoptosis, action on DNA repair systems, and antiangiogenic activity. Preliminary data suggested a synergic interaction between Mdm2 inhibitors and ionizing radiations. However, no clinical data has been published yet on the pharmacological targeting of Mdm2. Given their new mechanisms of action, these new molecules should be subject to careful clinical assessment. Although promising, these strategies expose to unexpected toxicities.
    Cancer/Radiothérapie 06/2011; 15(4):316-22. · 1.48 Impact Factor
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    ABSTRACT: Despite recent advances in prevention, screening, molecular characterization, and treatment, cancer evolution is still associated with late local, regional, or metastastic recurrence, even in early stages. Residual tumor cells can persist locally as cancer stem cells, in the blood flow as circulating tumor cells, and in distant organs as disseminated tumor cells or micrometastasis, defining three faces of minimal residual disease. Definition, preclinical models and clinical implications of these patterns will be detailed, with emphasis on overlaps and therapeutic implications, to determine whether minimal residual disease is only an old concept currently revisited, or a major shift in cancer paradigm.
    Cancer Treatment Reviews 05/2011; 38(2):101-10. · 6.02 Impact Factor
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    ABSTRACT: This study aimed to describe and to analyze early severe digestive complications (ESDC) after lung transplantation (LT) in our center. A retrospective study included 351 patients, who underwent LT without cardiopulmonary bypass (CPB) at our center between March 1988 and December 2009. There were 86 double LTs and 265 single LTs. ESDCs were defined as complications (1) occurring during the first 30 days after transplantation or during initial hospitalization if longer; (2) involving the gastrointestinal tract; and (3) jeopardizing survival or requiring invasive therapeutic procedure. Patients' characteristics, associated risk factors, and influence of ESDC on early outcome have been analyzed. During the first 30 days after LT or initial hospitalization if longer, 26 ESDCs occurred in 26 patients (rate 7.4%, sex ratio M/F 66%, mean age 56 ± 6 years). This included 10 acute cholecystitis (38%), four angiocholitis (15%), three perforated gastroduodenal ulcers (11%), three digestive perforations (11%), two intestinal occlusions (8%), two mesenteric ischemia (8%), and two acute pancreatitis (8%). ESDC occurred after a mean postoperative follow-up of 14 days (5-46), required emergency surgical treatment in 20 cases (77%), significantly prolonged the mean duration of hospitalization (96 days with ESDC vs 55 days without ESDC, p < 0.0001), and was responsible for death in five cases (19%). Surgical treatment included cholecystectomy (n = 11), bowel resection (n = 3), ulcer surgery (n = 2), subtotal colectomy (n = 2), Hartmann procedure (n = 1), and open coelioscopy (n = 1). Age and bilateral LT were found to be significant risk factors for ESDC in both uni- and multivariate analyses. ESDC occurred in 7.4% of patients after LT without CPB, and was responsible for longer in-hospital stay. Relevant risk factors included older age and bilateral LT, interfering with current debate regarding recipients' selection and procedure's choice.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 04/2011; 40(6):1419-24. · 2.40 Impact Factor
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    ABSTRACT: The central role of p53 after exposure to ionizing radiation has been widely demonstrated. Mdm2, the main cellular regulator of p53, is a promising target for radiosensitizing purposes. In this article, we review the most recent data on the pharmacological targeting of Mdm2, with focus on strategies of radiosensitization. Antitumor activity of Mdm2 inhibitors has been related with activation of p53-dependant apoptosis, action on DNA repair systems, and antiangiogenic activity. Preliminary data suggested a synergic interaction between Mdm2 inhibitors and ionizing radiations. However, no clinical data has been published yet on the pharmacological targeting of Mdm2. Given their new mechanisms of action, these new molecules should be subject to careful clinical assessment. Although promising, these strategies expose to unexpected toxicities.
    Cancer Radiotherapie - CANCER RADIOTHER. 01/2011; 15(4):316-322.
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    ABSTRACT: Preclinical models of non-small cell lung cancer (NSCLC) require better clinical relevance to study disease mechanisms and innovative therapeutics. We sought to compare and refine bioluminescent orthotopic mouse models of human localized NSCLC. Athymic nude mice underwent subcutaneous injection (group 1-SC, n = 15, control), percutaneous orthotopic injection (group 2-POI, n = 30), surgical orthotopic implantation of subcutaneously grown tumours (group 3-SOI, n = 25), or transpleural orthotopic injection (group 4-TOI, n = 30) of A549-luciferase cells. Bioluminescent in vivo imaging was then performed weekly. Circulating tumour cells (CTCs) were searched using Cellsearch® system in SC and TOI models. Group 2-POI was associated with unexpected direct pleural spreading of the cellular solution in 53% of the cases, forbidding further evaluation of any localized lung tumour. Group 3-SOI was characterized by high perioperative mortality, initially localized lung tumours, and local evolution. Group 4-TOI was associated with low perioperative mortality, initially localized lung tumours, loco regional extension, and distant metastasis. CTCs were detected in 83% of nude mice bearing subcutaneous or orthotopic NSCLC tumours. Transpleural orthotopic injection of A549-luc cells in nude mouse lung induces localized tumour, followed by lymphatic extension and specific mortality, and allowed the first time identification of CTCs in a NSCLC mice model.
    PLoS ONE 01/2011; 6(10):e26073. · 3.53 Impact Factor
  • Ejc Supplements - EJC SUPPL. 01/2010; 8(7):91-92.