Abstract
BackgroundSunitinib 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.MethodsThe 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 prospectively the ex vivo effect of sunitinib and SU12662 on PTK activity in PBMC from 21 naïve mRCC patients.ResultsIn 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.ConclusionThe 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.
Highlights
Renal cell carcinoma (RCC) is the third most common malignancy of the urinary tract and is responsible each year for 338,000 new cases worldwide [1]
We hypothesized that peripheral blood mononuclear cells (PBMC) could be a perfect surrogate tissue for identifying and assaying pharmacodynamic biomarkers of kinase inhibitors, as this tissue is readily accessible for repeat sampling throughout therapy
Lower day 21 of treatment (D21)/D0 lymphocytes ratio was associated with higher phosphorylation inhibition of these peptides for sunitinib (Figure 4) and SU12662 (Supplementary Figure 2). This retrospective clinical study is the first to show that D21/D0 lymphocytes ratio could be used as a pharmacodynamic biomarker in metastatic renal cell carcinoma (mRCC) patients under sunitinib therapy
Summary
Renal cell carcinoma (RCC) is the third most common malignancy of the urinary tract and is responsible each year for 338,000 new cases worldwide [1]. Anderson et al have showed that the kinase profiling of clear cell RCC tumors could provide a functional classification strategy before starting a kinase inhibitor therapy [8] These results are very promising, this strategy to process biopsy tumor before treatment initiation may fail to reflect current tumor dynamics and drug sensitivity, which may change during therapy. Circulating cells could be an ideal biological matrix for biomarker discovery In this context, we hypothesized that peripheral blood mononuclear cells (PBMC) could be a perfect surrogate tissue for identifying and assaying pharmacodynamic biomarkers of kinase inhibitors, as this tissue is readily accessible for repeat sampling throughout therapy. 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. 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
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