Abstract #LB-284: Sunitinib (SU) affects specific peripheral blood mononuclear cell subpopulations (PBMC) and circulating endothelial cells (CEC) in patients (pts) with neuroendocrine tumors (NET): correlation with plasma proteins and pharmacokinetics
Authors: Amado Zurita, Hua-Kang Wu, E Lin, Matthew Kulke, Lesley Tye, Carlo Bello, Samuel DePrimo, Kathryn McKee, John Heymach
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Background: Blood-based biomarkers of drug activity hold potential to improve the clinical application of targeted agents. SU, an oral tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, RET, and FLT3, demonstrated antitumor efficacy in a phase II trial in pts with advanced unresectable carcinoid and pancreatic NET (Kulke et al., JCO 2008). We previously reported that CEC, monocytes and other PBMC populations were consistently modulated by SU, and that these changes correlated with clinical benefit in GIST pts (Norden-Zfoni et al. CCR 2007). Here, we investigated changes in specific PBMC subsets expressing targets relevant to SU inhibition and CEC in pts treated in the NET trial. Methods: Pts received SU 50 mg/day for 4 consecutive weeks followed by 2 weeks off therapy in 6-week cycles. PBMC fractions were assessed before and 2, 4, and 6 weeks during the first cycle. Monocyte subpopulations (nucleated cells expressing CD14) and CEC were serially evaluated by 8-color FACS in 17 pts. Target receptor tyrosine kinases (RTK), including VEGFR-1, PDGFR-\#914;, and KIT, and other biologically relevant PB populations expressing CXCR4, CD34, and Tie-2 were analyzed. CEC were defined as CD45-CD31+CD146+ (progenitors [CEP] were additionally CD133+). VEGF, soluble (s)VEGFR-2, sVEGFR-3, IL-8 and SDF-1\#945; concentrations were determined by ELISA. Day 28 on-treatment levels of single and multiple cell and plasma markers were compared to baseline values and correlated with SU trough concentrations. Results: Overall, WBCs and monocytes decreased significantly (P=0.002 and P=0.0012, respectively), whereas lymphocytes by comparison did not. CD14-neg cells remained unaffected on treatment, indicating that SU may preferentially target CD14+ monocytes in PB. Among specific CD14+, RTK-expressing cells, CD14+VEGFR-1+ decreased significantly, but CD14+PDGFR-B+, CD14+Kit+, or the triple pos VEGFR-1/PDGFR-\#914;/Kit did not, suggesting that VEGFR-1 is a preferential RTK target for SU in monocytes. Levels of CXCR4+, CD34+, and Tie-2+ PBMCs, as well as Tie2+ monocytes or VEGFR-1+CXCR4+ cells, did not demonstrate changes. CEC, sVEGFR-2 and -3 decreased, while VEGF, IL-8 and SDF-1\#945; significantly increased on SU. Interestingly, CEP and CXCR4+ monocyte drops correlated with IL-8, whereas CEC correlated with sVEGFR-2 and -3. VEGF, sVEGFR-3 and CEP changes showed a moderate correlation with SU concentrations. Conclusions: In this study in NET pts, SU treatment affected specific (CD14+) PBMC subpopulations, particularly those bearing VEGFR-1, a known target for the drug. VEGF, sVEGFR-3 and CEP may be useful as indicators of SU exposure. Simultaneous profiling of RTK-expressing PBMCs, CEC and plasma angiogenic factors is feasible and may lead to the identification of potential biomarkers for SU activity.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-284.