BackgroundAnti-angiogenesis is a validated strategy to treat cancer, with efficacy in controlling both primary tumor growth and metastasis. The role of the Notch family of proteins in tumor angiogenesis is still emerging, but recent data suggest that Notch signaling may function in the physiologic response to loss of VEGF signaling, and thus participate in tumor adaptation to VEGF inhibitors.MethodsWe asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct, which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle.ResultsCombining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability.ConclusionsOur results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone.

Janus kinase-2 (JAK2) supports breast cancer growth and clinical trials testing JAK2 inhibitors are underway. In addition to the tumor epithelium, JAK2 is also expressed in other tissues including immune cells; whether the JAK2 mRNA levels in breast tumors correlate with outcomes has not been evaluated. Using a case-control design, JAK2 mRNA was measured in 223 archived breast tumors and associations with distant recurrence were evaluated by logistic regression. The frequency of correct pairwise comparisons of patient rankings based on JAK2 levels versus survival outcomes, the concordance index (CI), was evaluated using data from 2,460 patients in 3 cohorts. In the case-control study, increased JAK2 was associated with a decreasing risk of recurrence (multivariate p=0.003, n=223). Similarly, JAK2 was associated with a protective CI (<0.5) in the public cohorts: NETHERLANDS CI=0.376, n=295; METABRIC CI=0.462, n=1,981; OSLOVAL CI=0.452, n=184. Furthermore, JAK2 strongly correlated with the favorable prognosis LYM metagene signature for infiltrating T cells (r=0.5, p<2×10−16, n=1,981) and with severe lymphocyte infiltration (p=0.00003, n=156). Moreover, the JAK1/2 inhibitor ruxolitinib potently inhibited the anti-CD3-dependent production of interferon-γ, a marker of the differentiation of T-helper cells along the tumor-inhibitory Th1 pathway. The potential for JAK2 inhibitors to interfere with the antitumor capacities of T cells should be evaluated.