A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Lessons Learned

• The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy.
• Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily.
• The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.

BackgroundThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.MethodsThis was a phase I study with a 3+3 design in patients with treatment‐naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.ResultsA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose‐limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment‐related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression‐free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated‐ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated‐ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.ConclusionTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.     

Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

Pathways in the association between sugar sweetened beverages and child asthma traits in the 2nd year of life: Findings from the BRISA cohort

Studies on the exposure of children to sugar-sweetened beverages (SSBs) at an early age may contribute to better understand the common causes and the temporal order of the relationships between obesity and asthma in early childhood. The objective of this study was to estimate the association between SSB and child asthma traits in the 2nd year of life, modeling direct and indirect pathways mediated by the highest BMI-z of the child and allergic inflammation. Data from the BRISA cohort, São Luís-MA, Brazil (n = 1140), were obtained from the baseline and from the follow-up performed at the 2nd year of life. The main explanatory variable was the calories from added sugars in SSBs as a percentage of the total daily energy intake. The outcome child asthma traits was a latent variable deduced from four indicators: medical diagnosis of asthma, wheezing, emergency visit due to intense wheezing, and medical diagnosis of rhinitis. A high percentage of daily calories from sugars added to SSBs was directly associated with higher values of child asthma traits (standardized coefficient (SC = 0.073; P = .030)). High levels of eosinophils were also directly associated with child asthma traits (SC = 0.118; P = .049). No mediation pathways were observed via greater BMI-z or eosinophil counts. Therefore, early exposure of children to SSB may contribute to increased risk of childhood asthma, preceding the link between sugar consumption and overweight/obesity, not yet evident in children in the first 2 years of life.     

Pseudoathetosis: report of three patients.

We report on 3 patients with pseudoathetosis, which are involuntary, slow, writhing movements due to loss of proprioception.     

Primary hypothyroidism presenting as ovarian tumor and precocious puberty in a prepubertal girl.

We report a case of a prepubertal girl with juvenile primary hypothyroidism presenting as ovarian cysts and precocious puberty. The 7-year-old female was referred to our clinic because of a pelvic/abdominal mass and vaginal bleeding. Besides these findings, on physical examination we noticed the thyroid gland globally increased and the presence of secondary sexual characteristics. Based upon the clinical profile and investigations, the patient was diagnosed with juvenile primary hypothyroidism due to autoimmune thyroiditis. The cysts and precocious puberty resolved spontaneously after the simple replacement of thyroid hormone. It is important to bear in mind hypothyroidism in cases of girls presenting ovarian cysts and precocious puberty in order to avoid unnecessary surgery on the ovaries.