Oncotarget

Clinical Research Papers:

Clinical and kinomic analysis identifies peripheral blood mononuclear cells as a potential pharmacodynamic biomarker in metastatic renal cell carcinoma patients treated with sunitinib

Gaёlle Noé, Audrey Bellesoeur, Audrey Thomas-Schoemann, Savithri Rangarajan, Faris Naji, Alicja Puszkiel, Olivier Huillard, Nathaniel Saidu, Lisa Golmard, Jerome Alexandre, Francois Goldwasser, Benoit Blanchet _ and Michel Vidal

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Oncotarget. 2016; 7:67507-67520. https://doi.org/10.18632/oncotarget.11686

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Abstract

Gaёlle Noé1,2,*, Audrey Bellesoeur1,2,3,*, Audrey Thomas-Schoemann1,2, Savithri Rangarajan4, Faris Naji4 , Alicja Puszkiel1, Olivier Huillard3, Nathaniel Saidu6 , Lisa Golmard5, Jerome Alexandre3,6, Francois Goldwasser3,6, Benoit Blanchet1 and Michel Vidal1,2

1 Assistance Publique Hôpitaux de Paris, Hôpital Cochin, UF Pharmacocinétique et Pharmacochimie, Paris, France

2 UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France

3 Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Service de Cancérologie Médicale, Paris, France

4 PamGene International BV, ‘s-Hertogenbosch, The Netherlands

5 Institut Curie, Département de Biopathologie, Paris, France

6 U1016 INSERM, UMR 8104 CNRS, UMR-S1016, CARPEM, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

* These authors have contributed equally to this work

Correspondence to:

Benoit Blanchet, email:

Keywords: sunitinib, kinome, PBMC, renal carcinoma

Received: April 14, 2016 Accepted: July 10, 2016 Published: August 29, 2016

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.

Conclusion: 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.


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