Gillian M. Tozer

Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel with improved response to treatment with the anti-VEGFA antibody bevacizumab. To uncover the underlying mechanism to these observations, we administered anti-VEGFA therapy to mice bearing luminescent mouse fibrosarcomas expressing single VEGFA isoforms or their wild-type counterparts expressing all isoforms (fs120, fs164, fs188, or fsWT). Expression of the more soluble isoforms conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 vs. fs188/WT); fs120 cells also produced more lung colonies than fs188 cells when injected intravenously. Metastasis from subcutaneous fs120 tumors was more sensitive than fs188 to treatment with the anti-VEGFA antibody B20-4.1.1. Despite elevated plasma levels of VEGFA in fs120 tumor-bearing mice and a dependence on VEGF receptor 1 activity for metastasis to the lung, B20-4.1.1 did not affect survival in the lung on intravenous injection. B20-4.1.1 inhibited subcutaneous tumor growth and decreased vascular density in both fs120 and fs188 tumors. However, migration of fs120, but not fs188 cells, in vitro was inhibited by B20-4.1.1. The greater survival of fs120 cells in the lung was associated with VEGFR1-dependent accumulation of CD11b-positive myeloid cells and higher expression of the VEGFR1 ligand, PlGF2, by the fs120 cells in vitro and in the plasma and lungs of fs120 tumor-bearing mice. We conclude that soluble VEGFA isoform expression increases fibrosarcoma metastasis through multiple mechanisms that vary in their sensitivity to anti-VEGF/VEGFR inhibition, with VEGFA-targeted therapy suppressing metastasis through effects on the primary tumor rather than the metastatic site. Cancer Res; 77(10); 2633–46. ©2017 AACR.

Dissolution dynamic nuclear polarisation (dDNP) of ¹³C‐labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of hyperpolarised ¹³C‐labelled pyruvate (¹³C₁‐pyruvate) and urea (¹³C‐urea), a nonmetabolised marker. A general mathematical model of pyruvate‐lactate exchange, incorporating an arterial input function (AIF), enabled the losses of pyruvate and lactate from tumour to be estimated, in addition to the clearance rate of pyruvate signal from blood into tumour, K_ip, and the forward and reverse fractional rate constants for pyruvate‐lactate signal exchange, k_pl and k_lp. An analogous model was developed for urea, enabling estimation of urea tumour losses and the blood clearance parameter, K_iu. A spectral fitting procedure to blood time‐course data proved superior to assuming a gamma‐variate form for the AIFs. Mean arterial blood pressure marginally correlated with clearance rates. K_iu equalled K_ip, indicating equivalent permeability of the tumour vasculature to urea and pyruvate. Fractional loss rate constants due to effluxes of pyruvate, lactate and urea from tumour tissue into blood (k_po, k_lo and k_uo, respectively) indicated that T₁s and the average flip angle, θ, obtained from arterial blood were poor surrogates for these parameters in tumour tissue. A precursor‐product model, using the tumour pyruvate signal time‐course as the input for the corresponding lactate signal time‐course, was modified to account for the observed delay between them. The corresponding fractional rate constant, k_avail, most likely reflected heterogeneous tumour microcirculation. Loss parameters, estimated from this model with different TRs, provided a lower limit on the estimates of tumour T₁ for lactate and urea. The results do not support use of hyperpolarised urea for providing information on the tumour microcirculation over and above what can be obtained from pyruvate alone. The results also highlight the need for rigorous processes controlling signal quantitation, if absolute estimations of biological parameters are required.

The development of blood vessels by the process of angiogenesis underpins the growth and metastasis of many tumour types. Various angiogenesis inhibitors targeted against vascular endothelial growth factor A (VEGF-A) and its receptors have entered the clinic more than a decade ago. However, despite substantial clinical improvements, their overall efficacy proved to be significantly lower than many of the pre-clinical studies had predicted. Antiangiogenic agents have been combined with chemotherapy, radiotherapy and more recently immunotherapy in many pre-clinical and clinical studies in an effort to improve their efficacy. To date, only their use alongside chemotherapy is approved as part of standard treatment protocols. Most pre-clinical studies have reported improved tumour control from the addition of antiangiogenic therapies to radiotherapy and progress has been made in unravelling the complex mechanisms through which VEGF inhibition potentiates radiotherapy responses. However, the efficacy of this combination is variable, and many questions still remain as to how best to administer the two modalities to achieve optimal response and minimal toxicity. One important limiting factor is that, unlike some other targeted therapies, antiangiogenic agents are not administered to selected patient populations, since biomarkers for identifying responders have not yet been established. Here, we outline VEGF biology and review current approaches that aim to identify biomarkers for stratifying patients for treatment with angiogenesis inhibitors. We also discuss current progress in elucidating mechanisms of interaction between radiotherapy and VEGF inhibitors. Ongoing clinical trials will determine whether these combinations will ultimately improve treatment outcomes for cancer patients.

The protective role of sphingosine-1-phosphate against the action of the vascular disrupting agent combretastatin A-4 3- O -phosphate The protective role of sphingosine-1-phosphate against the Action of the vascular disrupting agent Combretastatin A-4 3-O-phosphate