GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma

  • Sonia BrunEmail author
  • Firas Bassissi
  • Cindy Serdjebi
  • Marie Novello
  • Jennifer Tracz
  • François Autelitano
  • Marie Guillemot
  • Philippe Fabre
  • Jérôme Courcambeck
  • Christelle Ansaldi
  • Eric Raymond
  • Philipe Halfon


Among the acquired modifications in cancer cells, changes in lysosomal phenotype and functions are well described, making lysosomes a potential target for novel therapies. Some weak base lipophilic drugs have a particular affinity towards lysosomes, taking benefits from lysosomal trapping to exert anticancer activity. Here, we have developed a new lysosomotropic small molecule, GNS561, and assessed its activity in multiple in vitro intrahepatic cholangiocarcinoma models (HuCCT1 and RBE cell lines and patient-derived cells) and in a chicken chorioallantoic membrane xenograft model. GNS561 significantly reduced cell viability in two intrahepatic cholangiocarcinoma cell lines (IC50 of 1.5 ± 0.2 μM in HuCCT1 and IC50 of 1.7 ± 0.1 μM in RBE cells) and induced apoptosis as measured by caspases activation. We confirmed that GNS561-mediated cell death was related to its lysosomotropic properties. GNS561 induced lysosomal dysregulation as proven by inhibition of late-stage autophagy and induction of a dose-dependent build-up of enlarged lysosomes. In patient-derived cells, GNS561 was more potent than cisplatin and gemcitabine in 2/5 and 1/5 of the patient-derived cells models, respectively. Moreover, in these models, GNS561 was potent in models with low sensitivity to gemcitabine. GNS561 was also efficient in vivo against a human intrahepatic cholangiocarcinoma cell line in a chicken chorioallantoic membrane xenograft model, with a good tolerance at doses high enough to induce an antitumor effect in this model. In summary, GNS561 is a new lysosomotropic agent, with an anticancer activity against intrahepatic cholangiocarcinoma. Further investigations are currently ongoing to fully elucidate its mechanism of action.


GNS561 Cholangiocarcinoma Anticancer Lysosome Apoptosis 



The authors are very grateful to Dr. Emilien Dosda, Dr. Xavier Rousset and Sylvain Roveda from Inovotion for their work on the CAM study.


This study was supported by private funding.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest and consent to the submission of this manuscript.

Ethical approval

According to the French legislation, no ethical approval is needed for scientific experimentations using oviparous embryos (decree n° 2013–118, February 1, 2013; art. R-214–88).

Informed consent

For this type of study, formal consent is not required. This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

10637_2019_741_MOESM1_ESM.pdf (373 kb)
ESM 1 (PDF 373 kb)


  1. 1.
    World Health Organization (2018) Cancer. Accessed December 18, 2018
  2. 2.
    Kirstein MM, Vogel A (2016) Epidemiology and risk factors of cholangiocarcinoma. Visc Med 32(6):395–400. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J, Investigators ABCT (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362(14):1273–1281. CrossRefPubMedGoogle Scholar
  4. 4.
    El-Serag HB, Engels EA, Landgren O, Chiao E, Henderson L, Amaratunge HC, Giordano TP (2009) Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: a population-based study of U.S. veterans. Hepatology 49(1):116–123. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ariizumi S, Yamamoto M (2015) Intrahepatic cholangiocarcinoma and cholangiolocellular carcinoma in cirrhosis and chronic viral hepatitis. Surg Today 45(6):682–687. CrossRefPubMedGoogle Scholar
  6. 6.
    Razumilava N, Gores GJ (2014) Cholangiocarcinoma. Lancet 383(9935):2168–2179. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, Pawlik TM, Gores GJ (2014) Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 60(6):1268–1289. CrossRefPubMedGoogle Scholar
  8. 8.
    Lamarca A, Hubner RA, David Ryder W, Valle JW (2014) Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol 25(12):2328–2338. CrossRefPubMedGoogle Scholar
  9. 9.
    Walter T, Horgan AM, McNamara M, McKeever L, Min T, Hedley D, Serra S, Krzyzanowska MK, Chen E, Mackay H, Feld R, Moore M, Knox JJ (2013) Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: a large retrospective study. Eur J Cancer 49(2):329–335. CrossRefPubMedGoogle Scholar
  10. 10.
    Mahipal A, Kommalapati A, Tella SH, Lim A, Kim R (2018) Novel targeted treatment options for advanced cholangiocarcinoma. Expert Opin Investig Drugs 27(9):709–720. CrossRefPubMedGoogle Scholar
  11. 11.
    Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, Hama N, Hosoda F, Urushidate T, Ohashi S, Hiraoka N, Ojima H, Shimada K, Okusaka T, Kosuge T, Miyagawa S, Shibata T (2015) Genomic spectra of biliary tract cancer. Nat Genet 47(9):1003–1010. CrossRefPubMedGoogle Scholar
  12. 12.
    Kallunki T, Olsen OD, Jaattela M (2013) Cancer-associated lysosomal changes: friends or foes? Oncogene 32(16):1995–2004. CrossRefPubMedGoogle Scholar
  13. 13.
    Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, Lengrand J, Deshpande V, Selig MK, Ferrone CR, Settleman J, Stephanopoulos G, Dyson NJ, Zoncu R, Ramaswamy S, Haas W, Bardeesy N (2015) Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 524(7565):361–365. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Appelqvist H, Waster P, Kagedal K, Ollinger K (2013) The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol 5(4):214–226. CrossRefPubMedGoogle Scholar
  15. 15.
    De Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F (1955) Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J 60(4):604–617CrossRefGoogle Scholar
  16. 16.
    Xu H, Ren D (2015) Lysosomal physiology. Annu Rev Physiol 77:57–80. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    de Duve C (1983) Lysosomes revisited. Eur J Biochem 137(3):391–397CrossRefGoogle Scholar
  18. 18.
    Boyer MJ, Tannock IF (1993) Lysosomes, lysosomal enzymes,. Adv Cancer Res 60:269–291CrossRefGoogle Scholar
  19. 19.
    Kroemer G, Jaattela M (2005) Lysosomes and autophagy in cell death control. Nat Rev Cancer 5(11):886–897. CrossRefPubMedGoogle Scholar
  20. 20.
    Castino R, Demoz M, Isidoro C (2003) Destination 'lysosome': a target organelle for tumour cell killing? J Mol Recognit 16(5):337–348. CrossRefPubMedGoogle Scholar
  21. 21.
    Hamalisto S, Jaattela M (2016) Lysosomes in cancer-living on the edge (of the cell). Curr Opin Cell Biol 39:69–76. CrossRefPubMedGoogle Scholar
  22. 22.
    Davidson SM, Vander Heiden MG (2017) Critical functions of the lysosome in Cancer biology. Annu Rev Pharmacol Toxicol 57:481–507. CrossRefPubMedGoogle Scholar
  23. 23.
    Morgan MJ, Fitzwalter BE, Owens CR, Powers RK, Sottnik JL, Gamez G, Costello JC, Theodorescu D, Thorburn A (2018) Metastatic cells are preferentially vulnerable to lysosomal inhibition. Proc Natl Acad Sci U S A 115(36):E8479–E8488. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Martinez-Carreres L, Nasrallah A, Fajas L (2017) Cancer: linking powerhouses to suicidal bags. Front Oncol 7:204. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Saftig P, Sandhoff K (2013) Cancer: killing from the inside. Nature 502(7471):312–313. CrossRefPubMedGoogle Scholar
  26. 26.
    Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27(50):6434–6451. CrossRefPubMedGoogle Scholar
  27. 27.
    Glunde K, Guggino SE, Solaiyappan M, Pathak AP, Ichikawa Y, Bhujwalla ZM (2003) Extracellular acidification alters lysosomal trafficking in human breast cancer cells. Neoplasia 5(6):533–545CrossRefGoogle Scholar
  28. 28.
    Zhitomirsky B, Assaraf YG (2016) Lysosomes as mediators of drug resistance in cancer. Drug Resist Updat 24:23–33. CrossRefPubMedGoogle Scholar
  29. 29.
    Fehrenbacher N, Gyrd-Hansen M, Poulsen B, Felbor U, Kallunki T, Boes M, Weber E, Leist M, Jaattela M (2004) Sensitization to the lysosomal cell death pathway upon immortalization and transformation. Cancer Res 64(15):5301–5310. CrossRefPubMedGoogle Scholar
  30. 30.
    Domagala A, Fidyt K, Bobrowicz M, Stachura J, Szczygiel K, Firczuk M (2018) Typical and atypical inducers of lysosomal cell death: a promising anticancer strategy. Int J Mol Sci 19(8).
  31. 31.
    Fennelly C, Amaravadi RK (2017) Lysosomal biology in cancer. Methods Mol Biol 1594:293–308. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kirkegaard T, Jaattela M (2009) Lysosomal involvement in cell death and cancer. Biochim Biophys Acta 1793(4):746–754. CrossRefPubMedGoogle Scholar
  33. 33.
    Ono K, Kim SO, Han J (2003) Susceptibility of lysosomes to rupture is a determinant for plasma membrane disruption in tumor necrosis factor alpha-induced cell death. Mol Cell Biol 23(2):665–676CrossRefGoogle Scholar
  34. 34.
    Petersen NH, Olsen OD, Groth-Pedersen L, Ellegaard AM, Bilgin M, Redmer S, Ostenfeld MS, Ulanet D, Dovmark TH, Lonborg A, Vindelov SD, Hanahan D, Arenz C, Ejsing CS, Kirkegaard T, Rohde M, Nylandsted J, Jaattela M (2013) Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase. Cancer Cell 24(3):379–393. CrossRefPubMedGoogle Scholar
  35. 35.
    Piao S, Amaravadi RK (2016) Targeting the lysosome in cancer. Ann N Y Acad Sci 1371(1):45–54. CrossRefPubMedGoogle Scholar
  36. 36.
    Serrano-Puebla A, Boya P (2018) Lysosomal membrane permeabilization as a cell death mechanism in cancer cells. Biochem Soc Trans 46(2):207–215. CrossRefPubMedGoogle Scholar
  37. 37.
    Wang F, Gomez-Sintes R, Boya P (2018) Lysosomal membrane permeabilization and cell death. Traffic 19(12):918–931. CrossRefPubMedGoogle Scholar
  38. 38.
    Halaby R (2015) Role of lysosomes in cancer therapy. Res Rep Biol 6:147–155. CrossRefGoogle Scholar
  39. 39.
    Hou YJ, Dong LW, Tan YX, Yang GZ, Pan YF, Li Z, Tang L, Wang M, Wang Q, Wang HY (2011) Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma. Lab Investig 91(8):1146–1157. CrossRefPubMedGoogle Scholar
  40. 40.
    Nitta T, Sato Y, Ren XS, Harada K, Sasaki M, Hirano S, Nakanuma Y (2014) Autophagy may promote carcinoma cell invasion and correlate with poor prognosis in cholangiocarcinoma. Int J Clin Exp Pathol 7(8):4913–4921PubMedPubMedCentralGoogle Scholar
  41. 41.
    Thongchot S, Yongvanit P, Loilome W, Seubwai W, Phunicom K, Tassaneeyakul W, Pairojkul C, Promkotra W, Techasen A, Namwat N (2014) High expression of HIF-1alpha, BNIP3 and PI3KC3: hypoxia-induced autophagy predicts cholangiocarcinoma survival and metastasis. Asian Pac J Cancer Prev 15(14):5873–5878CrossRefGoogle Scholar
  42. 42.
    Sasaki M, Nitta T, Sato Y, Nakanuma Y (2015) Autophagy may occur at an early stage of cholangiocarcinogenesis via biliary intraepithelial neoplasia. Hum Pathol 46(2):202–209. CrossRefPubMedGoogle Scholar
  43. 43.
    Boya P, Gonzalez-Polo RA, Poncet D, Andreau K, Vieira HL, Roumier T, Perfettini JL, Kroemer G (2003) Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 22(25):3927–3936. CrossRefPubMedGoogle Scholar
  44. 44.
    Zhang Y, Liao Z, Zhang LJ, Xiao HT (2015) The utility of chloroquine in cancer therapy. Curr Med Res Opin 31(5):1009–1013. CrossRefPubMedGoogle Scholar
  45. 45.
    Fu W, Li X, Lu X, Zhang L, Li R, Zhang N, Liu S, Yang X, Wang Y, Zhao Y, Meng X, Zhu WG (2017) A novel acridine derivative, LS-1-10 inhibits autophagic degradation and triggers apoptosis in colon cancer cells. Cell Death Dis 8(10):e3086. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Xu R, Ji Z, Xu C, Zhu J (2018) The clinical value of using chloroquine or hydroxychloroquine as autophagy inhibitors in the treatment of cancers: a systematic review and meta-analysis. Medicine (Baltimore) 97(46):e12912. CrossRefGoogle Scholar
  47. 47.
    Rebecca VW, Amaravadi RK (2016) Emerging strategies to effectively target autophagy in cancer. Oncogene 35(1):1–11. CrossRefPubMedGoogle Scholar
  48. 48.
    Manic G, Obrist F, Kroemer G, Vitale I, Galluzzi L (2014) Chloroquine and hydroxychloroquine for cancer therapy. Mol Cell Oncol 1(1):e29911. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Verbaanderd C, Maes H, Schaaf MB, Sukhatme VP, Pantziarka P, Sukhatme V, Agostinis P, Bouche G (2017) Repurposing drugs in oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience 11:781. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Plantone D, Koudriavtseva T (2018) Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: a mini-review. Clin Drug Investig 38(8):653–671. CrossRefPubMedGoogle Scholar
  51. 51.
    Pascolo S (2016) Time to use a dose of chloroquine as an adjuvant to anti-cancer chemotherapies. Eur J Pharmacol 771:139–144. CrossRefGoogle Scholar
  52. 52.
    Bernstein HN (1991) Ocular safety of hydroxychloroquine. Ann Ophthalmol 23(8):292–296PubMedGoogle Scholar
  53. 53.
    Prudent R, Vassal-Stermann E, Nguyen CH, Mollaret M, Viallet J, Desroches-Castan A, Martinez A, Barette C, Pillet C, Valdameri G, Soleilhac E, Di Pietro A, Feige JJ, Billaud M, Florent JC, Lafanechere L (2013) Azaindole derivatives are inhibitors of microtubule dynamics, with anti-cancer and anti-angiogenic activities. Br J Pharmacol 168(3):673–685. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Al Dhaheri Y, Attoub S, Arafat K, Abuqamar S, Viallet J, Saleh A, Al Agha H, Eid A, Iratni R (2013) Anti-metastatic and anti-tumor growth effects of Origanum majorana on highly metastatic human breast cancer cells: inhibition of NFkappaB signaling and reduction of nitric oxide production. PLoS One 8(7):e68808. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    El Hasasna H, Saleh A, Al Samri H, Athamneh K, Attoub S, Arafat K, Benhalilou N, Alyan S, Viallet J, Al Dhaheri Y, Eid A, Iratni R (2016) Rhus coriaria suppresses angiogenesis, metastasis and tumor growth of breast cancer through inhibition of STAT3, NFkappaB and nitric oxide pathways. Sci Rep 6:21144. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Gilson P, Josa-Prado F, Beauvineau C, Naud-Martin D, Vanwonterghem L, Mahuteau-Betzer F, Moreno A, Falson P, Lafanechere L, Frachet V, Coll JL, Fernando Diaz J, Hurbin A, Busser B (2017) Identification of pyrrolopyrimidine derivative PP-13 as a novel microtubule-destabilizing agent with promising anticancer properties. Sci Rep 7(1):10209. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    de Duve C, de Barsy T, Poole B, Trouet A, Tulkens P, Van Hoof F (1974) Commentary. Lysosomotropic agents. Biochem Pharmacol 23(18):2495–2531CrossRefGoogle Scholar
  58. 58.
    Nadanaciva S, Lu S, Gebhard DF, Jessen BA, Pennie WD, Will Y (2011) A high content screening assay for identifying lysosomotropic compounds. Toxicol in Vitro 25(3):715–723. CrossRefPubMedGoogle Scholar
  59. 59.
    Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y (1991) Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J Biol Chem 266(26):17707–17712PubMedGoogle Scholar
  60. 60.
    Klionsky DJ, Abdelmohsen K, Abe A et al (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12 (1):1–222.
  61. 61.
    Logan R, Kong AC, Axcell E, Krise JP (2014) Amine-containing molecules and the induction of an expanded lysosomal volume phenotype: a structure-activity relationship study. J Pharm Sci 103(5):1572–1580. CrossRefPubMedGoogle Scholar
  62. 62.
    Logan R, Kong AC, Krise JP (2014) Time-dependent effects of hydrophobic amine-containing drugs on lysosome structure and biogenesis in cultured human fibroblasts. J Pharm Sci 103(10):3287–3296. CrossRefPubMedGoogle Scholar
  63. 63.
    Lu S, Sung T, Lin N, Abraham RT, Jessen BA (2017) Lysosomal adaptation: how cells respond to lysosomotropic compounds. PLoS One 12(3):e0173771. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Ventola CL (2017) Cancer immunotherapy, part 3: challenges and future trends. P T 42(8):514–521PubMedPubMedCentralGoogle Scholar
  65. 65.
    DeBord LC, Pathak RR, Villaneuva M, Liu HC, Harrington DA, Yu W, Lewis MT, Sikora AG (2018) The chick chorioallantoic membrane (CAM) as a versatile patient-derived xenograft (PDX) platform for precision medicine and preclinical research. Am J Cancer Res 8(8):1642–1660PubMedPubMedCentralGoogle Scholar
  66. 66.
    Repnik U, Borg Distefano M, Speth MT, Ng MYW, Progida C, Hoflack B, Gruenberg J, Griffiths G (2017) L-leucyl-L-leucine methyl ester does not release cysteine cathepsins to the cytosol but inactivates them in transiently permeabilized lysosomes. J Cell Sci 130(18):3124–3140. CrossRefPubMedGoogle Scholar
  67. 67.
    Ashoor R, Yafawi R, Jessen B, Lu S (2013) The contribution of lysosomotropism to autophagy perturbation. PLoS One 8(11):e82481. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Hsu SPC, Kuo JS, Chiang HC, Wang HE, Wang YS, Huang CC, Huang YC, Chi MS, Mehta MP, Chi KH (2018) Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells. Oncotarget 9(6):6883–6896. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Chwieralski CE, Welte T, Buhling F (2006) Cathepsin-regulated apoptosis. Apoptosis 11(2):143–149. CrossRefPubMedGoogle Scholar
  70. 70.
    Repnik U, Hafner Cesen M, Turk B (2014) Lysosomal membrane permeabilization in cell death: concepts and challenges. Mitochondrion 19 Pt A:49–57. CrossRefPubMedGoogle Scholar
  71. 71.
    Aits S, Jaattela M (2013) Lysosomal cell death at a glance. J Cell Sci 126(Pt9):1905–1912. CrossRefPubMedGoogle Scholar
  72. 72.
    Uchimoto T, Nohara H, Kamehara R, Iwamura M, Watanabe N, Kobayashi Y (1999) Mechanism of apoptosis induced by a lysosomotropic agent, L-Leucyl-L-Leucine methyl ester. Apoptosis 4(5):357–362CrossRefGoogle Scholar
  73. 73.
    Thiele DL, Lipsky PE (1990) Mechanism of L-leucyl-L-leucine methyl ester-mediated killing of cytotoxic lymphocytes: dependence on a lysosomal thiol protease, dipeptidyl peptidase I, that is enriched in these cells. Proc Natl Acad Sci U S A 87(1):83–87CrossRefGoogle Scholar
  74. 74.
    Kornhuber J, Tripal P, Reichel M, Terfloth L, Bleich S, Wiltfang J, Gulbins E (2008) Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model. J Med Chem 51(2):219–237. CrossRefPubMedGoogle Scholar
  75. 75.
    Villamil Giraldo AM, Appelqvist H, Ederth T, Ollinger K (2014) Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death. Biochem Soc Trans 42(5):1460–1464. CrossRefPubMedGoogle Scholar
  76. 76.
    Fehrenbacher N, Bastholm L, Kirkegaard-Sorensen T, Rafn B, Bottzauw T, Nielsen C, Weber E, Shirasawa S, Kallunki T, Jaattela M (2008) Sensitization to the lysosomal cell death pathway by oncogene-induced down-regulation of lysosome-associated membrane proteins 1 and 2. Cancer Res 68(16):6623–6633. CrossRefPubMedGoogle Scholar
  77. 77. (2018) Study of GNS561 in Patients with liver cancer - full text view - Accessed December 18, 2018

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Sonia Brun
    • 1
    Email author
  • Firas Bassissi
    • 1
  • Cindy Serdjebi
    • 1
  • Marie Novello
    • 1
  • Jennifer Tracz
    • 1
  • François Autelitano
    • 2
  • Marie Guillemot
    • 2
  • Philippe Fabre
    • 2
  • Jérôme Courcambeck
    • 1
  • Christelle Ansaldi
    • 1
  • Eric Raymond
    • 1
    • 3
  • Philipe Halfon
    • 1
  1. 1.Genoscience PharmaMarseilleFrance
  2. 2.Biomarker Discovery DepartmentEvotec SASToulouseFrance
  3. 3.Department of OncologyHôpital Paris Saint JosephParisFrance

Personalised recommendations