Person: Detappe, Alexandre
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Detappe
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Alexandre
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Detappe, Alexandre
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Publication AGuIX nanoparticles as a promising platform for image-guided radiation therapy(Springer Vienna, 2015) Detappe, Alexandre; Kunjachan, Sijumon; Rottmann, Joerg; Robar, James; Tsiamas, Panagiotis; Korideck, Houari; Tillement, Olivier; Berbeco, RossAGuIX are gadolinium-based nanoparticles developed mainly for imaging due to their MR contrast properties. They also have a potential role in radiation therapy as a radiosensitizer. We used MRI to quantify the uptake of AGuIX in pancreatic cancer cells, and TEM for intracellular localization. We measured the radiosensitization of a pancreatic cancer cell line in a low-energy (220 kVp) beam, a standard 6 MV beam (STD) and a flattening filter free 6 MV beam (FFF). We demonstrated that the presence of nanoparticles significantly decreases cell survival when combined with an X-ray beam with a large proportion of low-energy photons (close to the k-edge of the nanoparticles). The concentration of nanoparticles in the cell achieves its highest level after 15 min and then reaches a plateau. The accumulated nanoparticles are mainly localized in the cytoplasm, inside vesicles. We found that the 6 MV FFF beams offer the best trade-off between penetration depth and proportion of low-energy photons. At 10 cm depth, we measured a DEF20 % of 1.30 ± 0.47 for the 6 MV FFF beam, compared to 1.23 ± 0.26 for the 6 MV STD beam. Additional measurements with un-incubated nanoparticles provide evidence that chemical processes might also be contributing to the dose enhancement effect.Publication Publisher Correction: Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer(Nature Publishing Group UK, 2018) Qi, Ruogu; Wang, Yongheng; Bruno, Peter M.; Xiao, Haihua; Yu, Yingjie; Li, Ting; Lauffer, Sam; Wei, Wei; Chen, Qixian; Kang, Xiang; Song, Haiqin; Yang, Xi; Huang, Xing; Detappe, Alexandre; Matulonis, Ursula; Pepin, David; Hemann, Michael T.; Birrer, Michael J.; Ghoroghchian, P. PeterPublication Gadolinium-Based Nanoparticles and Radiation Therapy for Multiple Brain Melanoma Metastases: Proof of Concept before Phase I Trial(Ivyspring International Publisher, 2016) Kotb, Shady; Detappe, Alexandre; Lux, François; Appaix, Florence; Barbier, Emmanuel L.; Tran, Vu-Long; Plissonneau, Marie; Gehan, Hélène; Lefranc, Florence; Rodriguez-Lafrasse, Claire; Verry, Camille; Berbeco, Ross; Tillement, Olivier; Sancey, LucieNanoparticles containing high-Z elements are known to boost the efficacy of radiation therapy. Gadolinium (Gd) is particularly attractive because this element is also a positive contrast agent for MRI, which allows for the simultaneous use of imaging to guide the irradiation and to delineate the tumor. In this study, we used the Gd-based nanoparticles, AGuIX®. After intravenous injection into animals bearing B16F10 tumors, some nanoparticles remained inside the tumor cells for more than 24 hours, indicating that a single administration of nanoparticles might be sufficient for several irradiations. Combining AGuIX® with radiation therapy increases tumor cell death, and improves the life spans of animals bearing multiple brain melanoma metastases. These results provide preclinical proof-of-concept for a phase I clinical trial.Publication The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma(2017) Mishima, Yuji; Paiva, Bruno; Shi, Jiantao; Park, Jihye; Manier, Salomon; Takagi, Satoshi; Massoud, Mira; Perilla-Glen, Adriana; Aljawai, Yosra; Huynh, Daisy; Roccaro, Aldo M.; Sacco, Antonio; Capelletti, Marzia; Detappe, Alexandre; Alignani, Diego; Anderson, Kenneth; Munshi, Nikhil; Prosper, Felipe; Lohr, Jens; Ha, Gavin; Freeman, Sam; Van Allen, Eliezer; Adalsteinsson, Viktor A.; Michor, Franziska; San Miguel, Jesus F.; Ghobrial, IreneSummary The development of sensitive and non-invasive “liquid biopsies” presents new opportunities for longitudinal monitoring of tumor dissemination and clonal evolution. The number of circulating tumor cells (CTCs) is prognostic in multiple myeloma (MM), but there is little information on their genetic features. Here, we have analyzed the genomic landscape of CTCs from 29 MM patients, including eight cases with matched/paired bone marrow (BM) tumor cells. Our results show that 100% of clonal mutations in patient BM were detected in CTCs and that 99% of clonal mutations in CTCs were present in BM MM. These include typical driver mutations in MM such as in KRAS, NRAS, or BRAF. These data suggest that BM and CTC samples have similar clonal structures, as discordances between the two were restricted to subclonal mutations. Accordingly, our results pave the way for potentially less invasive mutation screening of MM patients through characterization of CTCs.Publication Key clinical beam parameters for nanoparticle-mediated radiation dose amplification(Nature Publishing Group, 2016) Detappe, Alexandre; Kunjachan, Sijumon; Drané, Pascal; Kotb, Shady; Myronakis, Marios; Biancur, Douglas E.; Ireland, Thomas; Wagar, Matthew; Lux, Francois; Tillement, Olivier; Berbeco, RossAs nanoparticle solutions move towards human clinical trials in radiation therapy, the influence of key clinical beam parameters on therapeutic efficacy must be considered. In this study, we have investigated the clinical radiation therapy delivery variables that may significantly affect nanoparticle-mediated radiation dose amplification. We found a benefit for situations which increased the proportion of low energy photons in the incident beam. Most notably, “unflattened” photon beams from a clinical linear accelerator results in improved outcomes relative to conventional “flat” beams. This is measured by significant DNA damage, tumor growth suppression, and overall improvement in survival in a pancreatic tumor model. These results, obtained in a clinical setting, clearly demonstrate the influence and importance of radiation therapy parameters that will impact clinical radiation dose amplification with nanoparticles.Publication Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer(Nature Publishing Group UK, 2017) Qi, Ruogu; Wang, Yongheng; Bruno, Peter M.; Xiao, Haihua; Yingjie, Yu; Li, Ting; Lauffer, Sam; Wei, Wei; Chen, Qixian; Kang, Xiang; Song, Haiqin; Yang, Xi; Huang, Xing; Detappe, Alexandre; Matulonis, Ursula; Pepin, David; Hemann, Michael T.; Birrer, Michael J.; Ghoroghchian, P. PeterAdvanced-stage epithelial ovarian cancers are amongst the most difficult to treat tumors and have proven to be refractory to most cytotoxic, molecularly targeted, or immunotherapeutic approaches. Here, we report that nanoparticle-drug conjugates (NDCs) of monomethyl auristatin E (MMAE) significantly increase loading on a per-vehicle basis as compared to antibody-drug conjugates (ADCs). Their intraperitoneal administration enabled triggered release of the active MMAE toxin to inhibit tumor growth and to extend animal survival to >90 days in a cell-line xenograft model of disseminated ovarian cancer. In a patient-derived xenograft model of advanced-stage and platinum-resistant ovarian cancer, an MMAE-based NDC doubled the duration of tumor growth inhibition as compared to cisplatin. NDCs of highly potent toxins thus introduce a translatable platform that may be exploited to maximize the safety and efficacy of cytotoxic chemotherapies, combining the best features of ADCs with those of nanoparticle-based therapeutics.