Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients

Yamamoto

Clinical Cancer Research

et al. 2011

144

Purpose: E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors. Experimental Design: In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis. Results: Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, Cmax and area under the plasma concentration–time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(−) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect. Conclusion: E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors. Clin Cancer Res; 17(8); 2528–37. ©2011 AACR.

Section: Discussionmentioning

confidence: 99%

Phase I Dose-Escalation Study and Biomarker Analysis of E7080 in Patients with Advanced Solid Tumors

Yamamoto

Clinical Cancer Research

et al. 2011

144

“…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.…”

Section: Discussionmentioning

confidence: 99%

Circulating perivascular progenitors: A target of PDGFR inhibition

Mancuso

Martín‐Padura

Calleri

et al. 2011

Intl Journal of Cancer

Cancer blood vessels consist of two interacting types of cells: inner lining endothelial cells (ECs) and surrounding perivascular cells (pericytes, vascular smooth muscle cells or mural cells). PDGFRbeta(CD140b)+ progenitor perivascular cells (PPC) can differentiate into pericytes and regulate vessel stability and vascular survival in tumors. Similarly to what we have done with circulating ECs and progenitors, we developed a flow cytometry procedure for the enumeration of circulating PPCs and the study of their viability in murine models of cancer and in cancer patients. DNA+CD45−CD31−CD140b+ cells were enumerated by six‐colour flow cytometry, their morphology was studied by electron microscopy, PPC specificity confirmed by reverse trascription‐PCR (RT‐PCR) expression of CD140b mRNA, and viability assessed by Syto16 and 7AAD. In preclinical marrow transplantation studies, 9 ± 4% of circulating PPCs were derived from the marrow donor. PPCs were increased in cancer‐bearing mice and in patients affected by some types of cancer. At variance with the kinetic of circulating endothelial progenitors, high‐dose cyclophosphamide reduced the number of viable PPCs. The administration of sunitinib, a drug known to inhibit PDGFR, was associated in murine models and in cancer patients with an increase of apoptotic/necrotic circulating PPC, suggesting a direct targeting of these cells. PPC enumeration might be studied as a tool for the definition of the optimal biologic dose of anti‐PDGFR drugs and investigated clinically as a possible predictive/prognostic tool in patients receiving anti‐PDGFR drugs.

Molecular and Clinical Oncology

“…Since CECs are rare events, their precise quantification in peripheral blood (PB) samples requires a technically rigorous analytical approach, which should take many factors into consideration (8). Several pre-analytical and analytical steps significantly affect not only the quantification of CECs, but can also result in a change in the definition of these cells, leading to problems in the interpretation of the results (Table I) and in their potential association with clinical endpoints (Table II) (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34).…”

Section: Flow Cytometric Analysis Of Circulating Endothelial Cells Inmentioning

confidence: 99%

Flow cytometric analysis of circulating endothelial cells and endothelial progenitors for clinical purposes in oncology: A critical evaluation

Danova

Comolli

Manzoni

et al. 2016

Abstract. Malignant tumors are characterized by uncontrolled cell growth and metastatic spread, with a pivotal importance of the phenomenon of angiogenesis. For this reason, research has focused on the development of agents targeting the vascular component of the tumor microenvironment and regulating the angiogenic switch. As a result, the therapeutic inhibition of angiogenesis has become an important component of anticancer treatment, however, its utility is partly limited by the lack of an established methodology to assess its efficacy in vivo. Circulating endothelial cells (CECs), which are rare in healthy subjects and significantly increased in different tumor types, represent a promising tool for monitoring the tumor clinical outcome and the treatment response. A cell population circulating into the blood also able to form endothelial colonies in vitro and to promote vasculogenesis is represented by endothelial progenitor cells (EPCs). The number of both of these cell types is extremely low and they cannot be identified using a single marker, therefore, in absence of a definite consensus on their phenotype, require discrimination using combinations of antigens. Multiparameter flow cytometry (FCM) is ideal for rapid processing of high numbers of cells per second and is commonly utilized to quantify CECs and EPCs, however, remains technically challenging since there is as yet no standardized protocol for the identification and enumeration of these rare events. Methodology in studies on CECs and/or EPCs as clinical biomarkers in oncology is heterogeneous and data have been obtained from different studies leading to conflicting conclusions. The present review presented a critical review of the issues that limit the comparability of results of the most significant studies employing FCM for CEC and/or EPC detection in patients with cancer.