The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer.

PURPOSE: This study evaluated the clinical relevance of the dual-targeting strategy involving PI3K/AKT/mTOR and RAF/MEK/ERK pathways. EXPERIMENTAL DESIGN: We investigated safety, efficacy, and correlations between tumor genetic alterations and clinical benefit in 236 patients with advanced cancers treated with phase I study drugs targeting phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways in our Phase I Clinical Trials Program. RESULTS: Seventy-six (32.2%) patients received a PI3K pathway inhibitor in combination with a MAPK pathway inhibitor (D), whereas 124 (52.5%) and 36 (15.3%), respectively, received an inhibitor of either the PI3K or MAPK pathways (S). The rates of drug-related grade >III adverse events were 18.1% for (S) and 53.9% for (D; P < 0.001); the rates of dose-limiting toxicities were 9.4% for (S) and 18.4% for (D; P = 0.06). The most frequent grade >III adverse events were transaminase elevations, skin rash, and mucositis. In our comprehensive tumor genomic analysis, of 9 patients who harbored coactivation of both pathways (colorectal cancer, n = 7; melanoma, n = 2), all 5 patients treated with (D) had tumor regression ranging from 2% to 64%. CONCLUSIONS: These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth.

Effects of chronic dietary and waterborne cadmium exposures on the contamination level and reproduction of Daphnia magna.

Regulatory assessments of metal toxicity on freshwater organisms assume that toxic effects are caused by dissolved metals. In aquatic systems, organisms are exposed to both dissolved and particulate-bound metals. In this study, the chronic toxicity of dietary cadmium (Cd) on the reproduction and Cd body burden of Daphnia magna was investigated. Daphnids (<24 h) were successively exposed to dissolved Cd (8 h) and then to uncontaminated or contaminated algae (16 h) for 21 d. The results show a higher Cd burden in daphnids because of the addition of contaminated food and reveal that Cd uptake by D. magna from water and food was additive for the lowest Cd concentrations tested. Similar Cd distributions (cytosolic and insoluble fractions) were observed in the two groups of organisms, showing similar potential toxicity of Cd accumulated from the two exposure routes. Dietary Cd induces deleterious effects on D. magna reproduction. On the basis of Cd body burden of daphnids, the results support the claim that waterborne and dietary Cd exposures were additive in causing toxicity for Cd concentrations lower than 25 microg/L. At the highest Cd concentrations, the importance of dietary Cd on the daphnid contamination level decreases and confounding factors such as feeding rate reduction seem to appear, which induce an effect on neonate reproduction. In this study, we illustrate the need to take the dietary pathway into account in regulatory assessments and to establish effective concentrations with particulate-bound metals.