Chronic DLL4 blockade induces vascular neoplasms.

Delta-like 4 (DLL4)-mediated Notch signalling has emerged as an attractive target for cancer therapy. However, the potential side effects of blocking this pathway remain uncertain. Here we show that chronic DLL4 blockade causes pathological activation of endothelial cells, disrupts normal organ homeostasis and induces vascular tumours, raising important safety concerns.

A comparison of least squares and conditional maximum likelihood estimators under volume endpoint censoring in tumor growth experiments.

Measurements in tumor growth experiments are stopped once the tumor volume exceeds a preset threshold: a mechanism we term volume endpoint censoring. We argue that this type of censoring is informative. Further, least squares (LS) parameter estimates are shown to suffer a bias in a general parametric model for tumor growth with an independent and identically distributed measurement error, both theoretically and in simulation experiments. In a linear growth model, the magnitude of bias in the LS growth rate estimate increases with the growth rate and the standard deviation of measurement error. We propose a conditional maximum likelihood estimation procedure, which is shown both theoretically and in simulation experiments to yield approximately unbiased parameter estimates in linear and quadratic growth models. Both LS and maximum likelihood estimators have similar variance characteristics. In simulation studies, these properties appear to extend to the case of moderately dependent measurement error. The methodology is illustrated by application to a tumor growth study for an ovarian cancer cell line.

Analysis of multi-arm tumor growth trials in xenograft animals using phase change adaptive piecewise quadratic models.

Xenograft trials allow tumor growth in human cell lines to be monitored over time in a mouse model. We consider the problem of inferring the effect of treatment combinations on tumor growth. A piecewise quadratic model with flexible phase change locations is proposed to model the effect of change in therapy over time. Each piece represents a growth phase, with phase changes in response to change in treatment. Piecewise slopes represent phase-specific (log) linear growth rates and curvature parameters represent departure from linear growth. Trial data are analyzed in two stages: (i) subject-specific curve fitting (ii) analysis of slope and curvature estimates across subjects. A least-squares approach with penalty for phase change point location is proposed for curve fitting. In simulation studies, the method is shown to give consistent estimates of slope and curvature parameters under independent and AR (1) measurement error. The piecewise quadratic model is shown to give excellent fit (median R(2)=0.98) to growth data from a six armed xenograft trial on a lung carcinoma cell line.

Delta-like 4/Notch signaling and its therapeutic implications.

Intense research efforts have been focused toward the identification of regulators of angiogenesis and the development of antiangiogenesis-based cancer therapies. The approval of anti-vascular endothelial growth factor (VEGF) monoclonal antibody (bevacizumab) for use in colorectal and lung cancer provides clinical validation for targeting angiogenesis for the treatment of cancer. Delta-like 4 (Dll4)-mediated Notch signaling represents another key pathway essential for vascular development. Recent studies yield substantial insights into the role of Dll4 in angiogenesis. Dll4 is downstream of VEGF signaling and its activation triggers a negative feedback that restrains the effects of VEGF. Attenuation of Dll4/Notch signaling results in chaotic vascular network with excessive branching and sprouting. In preclinical studies, blocking of Dll4/Notch signaling is associated with a paradoxical increase in tumor vessel density, yet causes marked growth inhibition due to functionally defective vasculature. Dll4 blockade holds promise as an additional strategy for angiogenesis-based cancer therapy, especially when resistance to and/or escape from existing therapies evolve.

Use of anti-VEGF adjuvant therapy in cancer: challenges and rationale.

Several ongoing clinical studies are designed to test the efficacy of antiangiogenic therapies in the adjuvant setting, where the goal is to increase the cure rate in patients who have just undergone surgical resection of all visible disease. Tumors depend on angiogenesis to support their growth and progression and blockade of this process has proven to be a valid strategy for treating multiple types of advanced metastatic cancer. However, results from the first of these clinical adjuvant studies were disappointing, stimulating extensive debate as to the potential of this approach. It will require additional clinical studies before we realize whether the effects of angiogenic blockade are durable, and if they are able to cure a subset of patients with early stage cancer.

Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy.

PURPOSE: Inhibition of the vascular endothelial growth factor (VEGF) axis is the basis of all currently approved antiangiogenic therapies. In preclinical models, anti-VEGF blocking antibodies have shown broad efficacy that is dependent on both tumor context and treatment duration. We aimed to characterize this activity and to evaluate the effects of discontinuation of treatment on the dynamics of tumor regrowth. EXPERIMENTAL DESIGN: We evaluated the effects of anti-VEGF treatment on tumor growth and survival in 30 xenograft models and in genetic mouse models of cancer. Histologic analysis was used to evaluate the effects of treatment on tumor vasculature. We used a variety of treatment regimens to allow analysis of the effects of treatment duration and cessation on growth rate, survival, and vascular density. RESULTS: Preclinical tumor models were characterized for their varied dependence on VEGF, thereby defining models for testing other agents that may complement or augment anti-VEGF therapy. We also found that longer exposure to anti-VEGF monoclonal antibodies delayed tumor growth and extended survival in established tumors from both cell transplants and genetic tumor models and prevented regrowth of a subset of residual tumors following cytoablative therapy. Discontinuation of anti-VEGF in established tumors resulted in regrowth at a rate slower than that in control-treated animals, with no evidence of accelerated tumor growth or rebound. However, more rapid regrowth was observed following discontinuation of certain chemotherapies. Concurrent administration of anti-VEGF seemed to normalize these accelerated growth rates. CONCLUSIONS: In diverse preclinical models, continuous VEGF suppression provides maximal benefit as a single agent, combined with chemotherapy, or as maintenance therapy once chemotherapy has been stopped.