Graillon et al. Page 552

Therapeutic alternatives are limited for aggressive and recurrent meningiomas. Hyperactivation of the mTOR pathway and robust SSTR2A receptor expression has been demonstrated in meningiomas. Based on the authors' preclinical studies that assessed the additive antiproliferative effect of the combination of everolimus and octreotide on meningiomas, Graillon and colleagues initiated a clinical trial using the combination of everolimus and octreotide in aggressive meningiomas not amenable to any form of surgery/radiotherapy. The combination therap. was well-tolerated and resulted in a decline in tumor growth rate, suggesting that the combination of everolimus and octreotide could be considered an option for meningiomas.

McCloskey et al. Page 632

Ovulation is the primary nonhereditary risk factor for ovarian cancer, yet the median age of diagnosis is 63 years old. To explore this timing disparity, McCloskey and colleagues investigated the effects of aging on both mouse and human ovaries and find that fibrosis develops with age in both species. Ovarian fibrosis correlated with the presence of cell types known to facilitate cancer growth. Importantly, postmenopausal women using the antidiabetic drug metformin had no evidence of ovarian fibrosis. This study positions ovarian fibrosis as a potential new target for ovarian cancer prevention and provides support for metformin use in ovarian cancer prophylaxis.

Yang et al. Page 643

TGF-β pathway antagonists are in early phase oncology trials based on encouraging preclinical data; however, most preclinical drug intervention studies use only a small number of models in any disease histology, which may distort the apparent outcome. Using a panel of 12 immunocompetent metastatic breast cancer models to capture more of the diversity of the human disease, Yang and colleagues show heterogeneous responses to TGF-β antagonists, with evidence for undesirable disease hyperprogression in 25% of the models. Biomarker discovery approaches using this panel provide guidance as to which patient subpopulations might benefit most from anti-TGF-β therap. and which should probably be excluded.

Hicks et al. Page 704

Multimodal therapies may improve responses to immunotherapy in patients with solid carcinomas. Hicks and colleagues demonstrated that entinostat, a class I HDAC inhibitor, synergized with an IL-15 superagonist and vaccine to promote significant tumor control in murine models. Although vaccine/IL-15 activated CD8+ T cells, these remained largely excluded from the tumor. Addition of entinostat maximized their infiltration and cytolytic function in the tumor, while reducing immune suppression. These data identify novel cooperative immune-mediated mechanisms by which a multimodal therapy promotes an inflamed tumor microenvironment, resulting in enhanced antitumor activity. These findings form the rationale for clinical translation for patients with solid tumors.