Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor

Abstract

Purpose: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors. Experimental Design: Patients (n = 73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of >6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC). Results: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus −−0.01 CEC/μL/d, P = 0.03) and smaller decreases in monocyte levels (47% versus 60%, P = 0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment. Conclusions: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.

Circulating perivascular progenitors: A target of PDGFR inhibition

“…However, the lack of surrogate biomarkers able to define their optimal biological dosage (OBD), and/or to predict the clinical benefit in a given patient, and/or to predict patient's escape from the therapy is hampering their clinical development. 18 We and others [19][20][21][22][23][24][25][26][27][28][29] have recently reported that the measurement of CECs and CEPs in cancer patients receiving antiangiogenic drugs is a surrogate biomarker that has clinical predictive potential for patients' selection and follow-up. Using a flow cytometry approach similar to what we have developed and validated for CEC and CEP count, 13 we report here a protocol for PPC enumeration in the preclinical and clinical settings.…”

Identification of TNF-α and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array

“…Low baseline levels of sVEGFR-3 and VEGF-C have been associated with a longer TTP and an improved response rate (Rini et al, 2008b). Other investigators have reported that patients with gastrointestinal stromal tumours that showed clinical benefit with sunitinib had a reduced number of circulating endothelial cells and monocytes, as compared with patients who did not respond (Norden-Zfoni et al, 2007). Greater variations in VEGF, sVEGFR-2, and s-VEGFR-3 were observed in patients presenting objective tumour responses than in patients with stable disease or progression .…”

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients

“…Circulating endothelial cells are a very rare cell population, normally defined as mature endothelial cells shed from the vasculature and are considered to be a useful biomarker of vascular damage (Willett et al, 2004;Duda et al, 2006;Batchelor et al, 2007;Norden-Zfoni et al, 2007). In addition, the possibility to monitor circulating endothelial progenitor cells (CEPs) has been proposed as an attractive biomarker for anti-angiogenic agents after the seminal identification of circulating progenitors, which could grow out to highly proliferative endothelial outgrowth cells (EOCs) (Ingram et al, 2005;Shaked et al, 2006).…”