Increases in the number of circulating endothelial cells (CECs) and progenitors (CEPs) have been reported in various pathological conditions including cancer. Preclinical studies have shown that CEC and CEP kinetics correlate well with several standard laboratory angiogenesis assays, which cannot be used in humans. At the clinical level, evidence is emerging that CEC kinetics and viability might correlate with clinical outcomes in cancer patients who undergo anti-angiogenic treatment. Therefore, CEC and CEP measurement has potential as a surrogate marker for monitoring anti-angiogenic treatment and drug activity, and could help to determine the optimal biological dose of anti-angiogenic drugs, which are being used with increasing frequency in medical oncology.

SUMMARY Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g. paclitaxel, can rapidly induce pro-angiogenic bone marrow derived circulating endothelial cell (CEP) mobilization, and subsequent tumor homing, whereas others, e.g. gemcitabine, did not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1α and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or by paclitaxel treatment in CEP-deficient Id-mutant mice, both of which resulted in enhanced anti-tumor effects mediated by paclitaxel, but not gemcitabine.

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Vaccination of metastatic melanoma patients with autologous HSPPC-96 is feasible and devoid of significant toxicity. This vaccine induced clinical and tumor-specific T-cell responses in a significant minority of patients.

Development of antiangiogenic therapies would be significantly facilitated by quantitative surrogate pharmacodynamic markers. Circulating peripheral blood endothelial cells (CECs) and/or their putative progenitor subset (CEPs) have been proposed but not yet fully validated for this purpose. Herein, we provide such validation by showing a striking correlation between highly genetically heterogeneous bFGF- or VEGF-induced angiogenesis and intrinsic CEC or CEP levels measured by flow cytometry, among eight different inbred mouse strains. Moreover, studies using genetically altered mice showed that levels of these cells are affected by regulators of angiogenesis, including VEGF, Tie-2, and thrombospondin-1. Finally, treatment with a targeted VEGFR-2 antibody caused a dose-dependent reduction in viable CEPs that precisely paralleled its previously and empirically determined antitumor activity.

SummaryIt is now well established that solid tumour growth depends on angiogenesis. However, less is known about the generation of new vessels in haematological malignancies and, in particular, in preleukaemic-myelodysplastic syndromes (MDS). In this study, bone marrow microvessel density (MVD) was assessed by immunohistochemistry and compared in trephine biopsies from 14 controls, five infectious disease (ID), 82 MDS, 15 acute myeloid leukaemia (AML) and 14 myeloproliferative disorder (MPD) patients. Statistical analysis (P < 0.001) demonstrated that MDS MVD was higher than in controls and ID (21 ± 9 vs 6 ± 2 and 10 ± 8 respectively) but lower than AML (30 ± 12) and MPD (40 ± 12). Among MDS-FAB subtypes, MVD was significantly higher in RAEB-t, CMML and fibrosis subsets compared to RA, RARS and RAEB subsets (P = 0.008). To further investigate angiogenesis machinery, the expression of vascular endothelial growth factor (VEGF) was evaluated by means of immunohistochemistry in control, MDS, AML and MPD biopsies. Even though VEGF mRNA expression was reported in the past in AML cell cultures and cell lines, in our samples VEGF expression was found to be particularly strong in most of the megakaryocytes but significantly less prominent in other cell populations including blasts. Since our findings suggest a correlation between angiogenesis and progression to leukaemia, additional work is now warranted to determine what regulates the generation of new vessels in MDS and leukaemia.

In most countries, healthcare service budgets are not likely to support the current explosion in the cost of new oncology drugs. Repurposing the large arsenal of approved, non-anticancer drugs is an attractive strategy to offer more-effective options to patients with cancer, and has the substantial advantages of cheaper, faster and safer preclinical and clinical validation protocols. The potential benefits are so relevant that funding of academically and/or independently driven preclinical and clinical research programmes should be considered at both national and international levels. To date, successes in oncology drug repurposing have been limited, despite strong evidence supporting the use of many different drugs. A lack of financial incentives for drug developers and limited drug development experience within the non-profit sector are key reasons for this lack of success. We discuss these issues and offer solutions to finally seize this opportunity in the interest of patients and societies, globally.

Low-dose metronomic chemotherapy is a promising therapeutic cancer treatment strategy thought to have an antiangiogenic basis. However, the advantages of reduced toxicity, increased efficacy in some cases, and ability to combine chemotherapy administered long term in this way with targeted therapies can be compromised by the empiricism associated with determining the optimum biologic dose (OBD). Using 4 distinct metronomic chemotherapy regimens in 4 different preclinical tumor models, including a hematologic malignancy, we established the OBD by determining the maximum efficacy associated with minimum or no toxicity. We then found each OBD to be strikingly correlated with the maximum reduction in viable peripheral blood circulating vascular endothelial growth factor receptor 2-positive (VEGFR-2 ؉ ) endothelial precursors (CEPs). These results suggest that CEPs may serve as a pharmacodynamic biomarker to determine the OBD of metronomic chemotherapy regimens. IntroductionThe tumor vasculature has emerged as a clinically validated therapeutic target. 1 In addition to rationally designed, molecularly targeted antiangiogenic drugs such as anti-vascular endothelial growth factor (anti-VEGF) antibodies, 1 many conventional and new therapeutic agents may have antiangiogenic effects that can contribute to their treatment efficacy. 2,3 These agents include chemotherapy drugs, the antiangiogenic efficacy of which appear to be optimized by "metronomic" dosing or the administration of relatively low, nontoxic doses at regular close intervals with no prolonged interruptions. 3-5 Some metronomic regimens can have surprisingly potent antitumor effects in preclinical models compared with respective maximum tolerated dose regimens, despite being less toxic. 4,6,7 This makes it possible to consider combining simultaneously such long-term "maintenance" chemotherapy with targeted antiangiogenic drugs 8,9 or other agents, such as tumor vaccines. 10 Some promising preliminary results have also begun to emerge in small clinical studies using mostly orally administered metronomic chemotherapy-based regimens, 3,11,12 including those in the adjuvant setting for early-stage cancer. 13 However, a significant disadvantage is the empiricism in establishing the optimal biologic dose (OBD) and in monitoring therapeutic activity early during the course of treatment. 3 Using (1) previous observations showing significant and sustained declines in circulating VEGF receptor 2-positive (VEGFR-2 ϩ ) endothelial progenitor cells (CEPs) induced by prolonged daily low-dose metronomic chemotherapy 6 ; (2) preclinical validation of measuring levels of such cells as a surrogate blood-based marker of angiogenesis and targeted antiangiogenic drug activity, including optimal biologic dosing 14 ; and (3) CEP potentially as a marker in the clinic of targeted antiangiogenic drug activity, 15 we assessed whether determining OBD ranges of various chemotherapy drugs is possible using this cellular pharmacodynamic biomarker approach. Specifically, we addressed the q...