Highlights of This Issue

Gamma-secretase inhibitors (GSI) have been proposed as anti-NOTCH-targeted therapy in T-cell acute lymphoblastic leukemia (T-ALL). Samon and colleagues characterized the interaction between the clinically relevant GSI PF-03084014 and glucocorticoids in preclinical models of glucocorticoid-resistant T-ALL. The combination of PF-03084014 and dexamethasone induced a synergistic antileukemic response in human T-ALL cell lines, primary patient samples, and in a xenograft model of T-ALL. Moreover, dexamethasone treatment also reversed the gastrointestinal toxicity associated with systemic inhibition of NOTCH signaling by GSIs. These results substantiate the clinical evaluation of PF-03084014 and dexamethasone in combination for the treatment of glucocorticoid-resistant T-ALL.

Targeted cancer therapies that inhibit the IGF-I signaling pathway are under investigation. Dietary fat reduction may have anticancer effects, in part, through inhibition of the IGF-I axis. Konijeti and colleagues reported that combination therapy (low-fat diet and IGF-1 receptor blockade) did not have additive effects on xenograft growth, whereas there was a reduction in tumor proliferation and serum insulin and TNF-α levels. The approach of combining pharmacological and nutritional interventions offers the potential for improving anticancer therapy and limiting the untoward metabolic effects of targeted therapies.

Stem cell pathways have been implicated in tumorigenesis and survival multiple malignancies. Steg and colleagues examined the effects of hedgehog pathway targeting on chemotherapy response. The smoothened inhibitors cyclopamine and LDE225 both sensitized ovarian cancer cells to paclitaxel, but not carboplatin, as did selective knockdown of individual hedgehog signaling components. Combined LDE225 and paclitaxel also significantly reduced tumor burden compared to vehicle or single agents. The increased taxane sensitivity was due at least in part to decreased P-glycoprotein (MDR1) expression. These findings suggest that anti-hedgehog therapies are attractive in ovarian cancer, especially in combination with taxanes.

This is the first study to quantify signaling output of the PI3K pathway in ovarian cells isolated from ascites and to correlate this with response to subsequent chemotherapy. This study also looked for associations between signaling output and known drivers of the PI3K pathway. A raised p-S6K was negatively associated with response to subsequent chemotherapy and interestingly, there was no clear association between PI3K pathway signaling output and PIK3CA/AKT mutation or amplification, or PTEN loss. This reinforces the need to look wider for drivers of the PI3K pathway in ovarian cancer while designing clinical trials of PI3K pathway inhibitors.