title: Clinical and kinomic analysis identifies peripheral blood mononuclear cells as a potential pharmacodynamic biomarker in metastatic renal cell carcinoma patients treated with sunitinib.
abstract: BACKGROUND
  Sunitinib is a protein tyrosine kinase (PTK) inhibitor that has immune-modulating properties. In this context, peripheral blood mononuclear cells (PBMC), mainly constituted by lymphocytes, could be a perfect surrogate tissue for identifying and assaying pharmacodynamic biomarkers of sunitinib. In this study, we investigated the changes in lymphocytes count as pharmacodynamic biomarker in metastatic renal cell carcinoma (mRCC) patients under sunitinib therapy. Thereafter, we studied the ex vivo effect of sunitinib and SU12262 (active metabolite) on PBMC from naïve mRCC patients using a high throughput kinomic profiling method.
  
  
  METHODS
  The prognostic value of total lymphocytes count between Day 0 and Day 21 (expressed as a ratio D21/D0) was retrospectively investigated in 88 mRCC patients under sunitinib therapy. PTK PamChip® microarrays were used to explore prospectivelythe ex vivo effect of sunitinib and SU12662 on PTK activity in PBMC from 21 naïve mRCC patients.
  
  
  RESULTS
  In this retrospective study, D21/D0 lymphocytes ratio (Hazard Ratio, 1.83; CI95%, 1.24-2.71; p=0.0023) was independently associated with PFS. Interestingly, kinomic analysis showed that D21/D0 lymphocytes ratio and Heng prognostic model was statistically associated with the ex vivo sunitinib and SU12662 effect in PBMC.
  
  
  CONCLUSIONS
  The present study highlights that D21/D0 total lymphocytes ratio could be a promising pharmacodynamic biomarker in mRCC patients treated with sunitinib. Additionally, it paves the way to investigate the kinomic profile in PBMC as a prognostic factor in a larger cohort of mRCC patients under sunitinib therapy.
authors: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, UF Pharmacocinétique et Pharmacochimie, Paris, France.|UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.
authors: Gaёlle
authors: G
authors: Noé
authors: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, UF Pharmacocinétique et Pharmacochimie, Paris, France.|UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.|Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Service de Cancérologie Médicale, Paris, France.
authors: Audrey
authors: A
authors: Bellesoeur
authors: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, UF Pharmacocinétique et Pharmacochimie, Paris, France.|UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.
authors: Audrey
authors: A
authors: Thomas-Schoemann
authors: PamGene International BV, 's-Hertogenbosch, The Netherlands.
authors: Savithri
authors: S
authors: Rangarajan
authors: PamGene International BV, 's-Hertogenbosch, The Netherlands.
authors: Faris
authors: F
authors: Naji
authors: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, UF Pharmacocinétique et Pharmacochimie, Paris, France.
authors: Alicja
authors: A
authors: Puszkiel
authors: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Service de Cancérologie Médicale, Paris, France.
authors: Olivier
authors: O
authors: Huillard
authors: U1016 INSERM, UMR 8104 CNRS, UMR-S1016, CARPEM, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Nathaniel
authors: N
authors: Saidu
authors: Institut Curie, Département de Biopathologie, Paris, France.
authors: Lisa
authors: L
authors: Golmard
authors: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Service de Cancérologie Médicale, Paris, France.|U1016 INSERM, UMR 8104 CNRS, UMR-S1016, CARPEM, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Jerome
authors: J
authors: Alexandre
authors: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Service de Cancérologie Médicale, Paris, France.|U1016 INSERM, UMR 8104 CNRS, UMR-S1016, CARPEM, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Francois
authors: F
authors: Goldwasser
authors: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, UF Pharmacocinétique et Pharmacochimie, Paris, France.
authors: Benoit
authors: B
authors: Blanchet
authors: Assistance Publique Hôpitaux de Paris, Hôpital Cochin, UF Pharmacocinétique et Pharmacochimie, Paris, France.|UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.
authors: Michel
authors: M
authors: Vidal
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D002292:Carcinoma, Renal Cell / Q000097:blood* / Q000188:drug therapy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000097:blood* / Q000188:drug therapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D011758:Pyrroles / Q000627:therapeutic use*; D012189:Retrospective Studies; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
keywords: PBMC; kinome; renal carcinoma; sunitinib