Circulating tumor and endothelial cells as pharmacodynamic biomarkers in a phase I clinical trial of intravenous bevacizumab....

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Author(s): D. W. Davis,
W. Liu, R. Kurzrock, A. Naing, J. Wheler, L. W. Ricks, S. Ivy, D. Hong;
ApoCell, Inc., Houston, TX; University of Texas M. D. Anderson Cancer
Center, Houston, TX; Department of Investigational Cancer Therapeutics;
Rare circulating tumor cells (CTCs) and endothelial cells (CECs) offer
a feasible approach for studying the pharmacodynamic effects of
investigational agents. We investigated the effects of bevacizumab (B)
and cediranib (C) on inhibition of the VEGFR pathway and correlated
these changes with dose and clinical response.
Methods: Peripheral
blood was obtained at baseline, 24hrs and at C2D26-30 post-treatment
from patients (n=14) undergoing dose escalation of intravenous B and
oral C. CTCs and CECs (CD31+ or CD105+) were isolated and
immunofluorescently stained. Laser scanning cytometry (LSC) was used to
quantify phosphorylated and total-VEGFR2 (pVEGFR2/VEGFR2), pERK/ERK,
and apoptosis in each phenotype. Changes in each biomarker were
correlated with partial response (PR) or stable disease and progression
> 2 months, evaluated using RECIST.
Results: Overall,
immature CECs (CD105+) enumerated by CellSearch™ revealed a
dose-dependent significant decrease (p=0.0001). A 3-fold induction in
apoptosis was observed at 24 hrs compared to baseline in the CD105+
CECs. Mature CD31+ cells assessed for VEGFR2 activity revealed an 83%
and 1.9% significant (p=0.019) inhibition in pVEGFR2 expression at low
(B;3mg/kg) and high (B;5mg/kg) doses, respectively. In the
non-responders, mature CECs revealed a dose-dependent significant
increase (-6.8% to 63%;p=0.031) in pERK/ERK expression levels. No
significant changes were observed in CTC enumeration by CellSearch™.
LSC-mediated CTC enumeration revealed a 4.77 % and 2.33% increase in
CTCs following treatment in the non- responders and responder
(p=0.809), respectively. Analysis of pVEGFR2 in CTCs revealed a 58%
inhibition in the responder versus a 163% increase in expression in the
non-responders (p=0.63).
Conclusions: Inhibition of pVEGFR2 and
induction of apoptosis in CECs confirmed the target therapy. An
increase in CD105+ CECs is consistent with the hypothesis that
anti-angiogenic efficacy induces endothelial cell shedding. Assessment
of CECs indicates that B and C are more biologically active at lower
doses, and resistance may be attributed to ERK activity. Support: UO1
CA062461 (RK)