Melissa Taylor

High Levels of Circulating VEGFR2+ Bone Marrow–Derived Progenitor Cells Correlate with Metastatic Disease in Patients with Pediatric Solid Malignancies

Purpose: Pediatric solid malignancies display important angiogenic potential, and blocking tumor angiogenesis represents a new therapeutic approach for these patients. Recent studies have evidenced rare circulating cells with endothelial features contributing to tumor neovascularization and have shown the pivotal role of bone marrow–derived (BMD) progenitor cells in metastatic disease progression. We measured these cells in patients with pediatric solid malignancies as a prerequisite to clinical trials with antiangiogenic therapy. Patients and Methods: Peripheral blood was drawn from 45 patients with localized (n = 23) or metastatic (n = 22) disease, and 20 healthy subjects. Subsets of circulating vascular endothelial growth factor receptor (VEGFR)2+-BMD progenitor cells, defined as CD45−CD34+VEGFR2(KDR)+7AAD− and CD45dimCD34+VEGFR2+7AAD− events, were measured in progenitor-enriched fractions by flow cytometry. Mature circulating endothelial cells (CEC) were measured in whole blood as CD31+CD146+CD45−7AAD− viable events. Data were correlated with VEGF and sVEGFR2 plasma levels. Results: The CD45−CD34+VEGFR2(KDR)+7AAD− subset represented <0.003% of circulating BMD progenitor cells (≤0.05 cells/mL). However, the median level (range) of the CD45dimCD34+VEGFR2+7AAD− subset was higher in patients compared with healthy subjects, 1.5% (0%-10.3%) versus 0.3% (0%-1.6%) of circulating BMD progenitors (P < 0.0001), and differed significantly between patients with localized and metastatic disease, 0.7% (0%-8.6%) versus 2.9% (0.6%-10.3%) of circulating BMD progenitors (P < 0.001). Median CEC value was 7 cells/mL (0-152 cells/mL) and similar in all groups. Unlike VEGFR2+-BMD progenitors, neither CECs, VEGF, or sVEGFR2 plasma levels correlated with disease status. Conclusion: High levels of circulating VEGFR2+-BMD progenitor cells correlated with metastatic disease. Our study provides novel insights for angiogenesis mechanisms in pediatric solid malignancies for which antiangiogenic targeting of VEGFR2+-BMD progenitors could be of interest.

Angiogenesis as a target in neuroblastoma

Several research investigations on neuroblastoma (NB) have shown the important dependency of this embryonic tumour on angiogenesis, especially in the advanced and aggressive stages. However, the first pre-clinical data on anti-angiogenic drugs in NB have not been published until recently and clinical trials with anti-angiogenic agents in NB treatment protocols are still missing. Here, we summarise current knowledge on the important role and mechanisms of angiogenesis in NB, and report available pre-clinical results of anti-angiogenic agents used to treat NB. This review clearly shows that angiogenesis is a target in NB and that clinical trials are urgently needed to bring forward promising anti-angiogenesis treatment strategies into NB therapy.

Clinical Utility of Circulating Tumor Cells in ALK-Positive Non-Small-Cell Lung Cancer

The advent of rationally targeted therapies such as small-molecule tyrosine kinase inhibitors (TKIs) has considerably transformed the therapeutic management of a subset of patients with non-small-cell lung cancer (NSCLC) harboring defined molecular abnormalities. When such genetic molecular alterations are detected the use of specific TKI has demonstrated better results (overall response rate, progression free survival) compared to systemic therapy. However, the detection of such molecular abnormalities is complicated by the difficulty in obtaining sufficient tumor material, in terms of quantity and quality, from a biopsy. Here, we described how circulating tumor cells (CTCs) can have a clinical utility in anaplastic lymphoma kinase (ALK) positive NSCLC patients to diagnose ALK-EML4 gene rearrangement and to guide therapeutic management of these patients. The ability to detect genetic abnormalities such ALK rearrangement in CTCs shows that these cells could offer new perspectives both for the diagnosis and the monitoring of ALK-positive patients eligible for treatment with ALK inhibitors.

The potential diagnostic power of circulating tumor cell analysis for non-small-cell lung cancer.

In non-small-cell lung cancer (NSCLC), genotyping tumor biopsies for targetable somatic alterations has become routine practice. However, serial biopsies have limitations: they may be technically difficult or impossible and could incur serious risks to patients. Circulating tumor cells (CTCs) offer an alternative source for tumor analysis that is easily accessible and presents the potential to identify predictive biomarkers to tailor therapies on a personalized basis. Examined here is our current knowledge of CTC detection and characterization in NSCLC and their potential role in EGFR-mutant, ALK-rearranged and ROS1-rearranged patients. This is followed by discussion of the ongoing issues such as the question of CTC partnership as diagnostic tools in NSCLC.

Quantification of circulating vascular endothelial growth factor receptor-3-positive lymphatic/vascular endothelial progenitor cells.

To the Editor: We read with interest the article by Bogos et al. ([1][1]), which showed that circulating lymphatic/vascular endothelial progenitor cells (LVEPC) are significantly increased in small cell lung cancer (SCLC) patients and correlate with clinical behavior. We wish to comment on several

Neuroblastome : intérêt des traitements anti-angiogéniques

Focus on new drug development over the last few years has yielded new agents that differ from unspecific classical chemotherapeutics and ionizing radiation, while still targeting the cancer cell itself. Antiangiogenesis is a totally distinct approach targeting the tumors blood vessels. This concept has now found its eligibility for the treatment of several adult solid tumors: the human antivascular endothelial growth factor (VEGF) antibody bevacizumab, as well as the VEGF receptor tyrosine kinase inhibitors, sunitinib and sorafinib, have recently been licensed by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of colorectal, renal, and lung cancer. Other antiangiogenic drugs are under preclinical and early clinical evaluation. However, what do we know of the use of these drugs in pediatric solid tumors, such as sarcomas and embryonal and neuronal tumors? For some time now, neuroblastoma has been shown to be dependent on angiogenesis. However, the first preclinical data on antiangiogenic drugs in neuroblastoma have not been published until recently, and clinical trials with antiangiogenic agents in neuroblastoma treatment protocols are scarce. This review adresses current knowledge on the important role and mechanisms of angiogenesis in neuroblastoma and summarizes available preclinical and clinical results of antiangiogenic agents used to treat neuroblastoma. Our review clearly demonstrates that clinical trials are urgently needed to bring forward promising antiangiogenesis concepts in neuroblastoma therapy.

Abstract 372: Circulating endothelial progenitor cell levels predict survival benefit in metastatic renal cell cancer patients treated with antiangiogenic agents

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: There is no validated biomarker to predict the efficacy of antiangiogenic therapy in patients with metastatic renal cell carcinoma (MRCC). We tested the hypothesis that circulating endothelial cells (CEC) and circulating endothelial progenitor cell (CEP) could predict clinical outcome in MRCC patients undergoing treatment with tyrosine kinase inhibitors (TKI). Methods: Fifty five patients (pts) with MRCC were monitored both at baseline and day 14 after anti-angiogenic treatment (46 pts received sunitinib and 9, sorafenib). CECs were measured in 1ml erythocyte lysed whole blood by four color flow cytometry (FCM) and identified by a CD45−CD31+CD1467-amino-actinomycin (7AAD)− phenotype. CEPs were measured in 10ml blood after progenitor cell enrichment and were identified by FCM as extremely rare events with a CD45dimCD34+VEGFR2+7AAD− phenotype. Relation between CEC and CEP levels and both response to TKI determined by RECIST criteria after 2 cycles with the Wilcoxon-Mann Whitney test, and progression free survival (PFS) and overall survival (OS) with the Cox model (Log-rank test). Results: CEC and CEP levels at both baseline and day 14 were not correlated to response to TKI. No correlation was found between baseline or day 14 CEC values and PFS or OS. However, pre-treatment CEP levels were correlated to PFS (p=0.01) and OS (p=0.01). Patients with elevated pre-treatment levels of CEP (> 2% of circulating CD34+ cells) had an increased risk of tumor progression and poor prognosis. Changes in CEP levels between day 1 and day 14 were also correlated with PFS (p=0.03). Conclusion: Our results indicate that pre-treatment CEP levels could accurately predict survival in MRCC patients treated with TKI. If these data are confirmed, measurement of CEP levels before TKI therapy in MRCC patients will allow to identify patients who will benefit most from treatment and those who will need to be rapidly switched to another treatment. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 372.