Therapeutic evaluation of palbociclib and its compatibility with other chemotherapies for primary and recurrent nasopharyngeal carcinoma.

Background: Recent genomic analyses revealed that druggable molecule targets were only detectable in approximately 6% of patients with nasopharyngeal carcinoma (NPC). However, a dependency on dysregulated CDK4/6-cyclinD1 pathway signaling is an essential event in the pathogenesis of NPC. In this study, we aimed to evaluate the therapeutic efficacy of a specific CDK4/6 inhibitor, palbociclib, and its compatibility with other chemotherapeutic drugs for the treatment of NPC by using newly established xenograft models and cell lines derived from primary, recurrent, and metastatic NPC.

MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling.

MAPK pathway mutations affect one-fifth of head and neck squamous cell carcinoma (HNSCC). Unexpectedly, MAPK pathway aberrations are associated with remarkably long patient survival, even among patients with mutations (median ∼14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models.

Erlotinib sensitivity of p.D321N mutation in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) lacks predictive biomarkers for drug responses. By targeted sequencing, we identified two mutations in recurrent HNSCC, p.D321N, and p.

An update on genomic-guided therapies for pediatric solid tumors.

Currently, out of the 82 US FDA-approved targeted therapies for adult cancer treatments, only three are approved for use in children irrespective of their genomic status. Apart from leukemia, only a handful of genomic-based trials involving children with solid tumors are ongoing. Emerging genomic data for pediatric solid tumors may facilitate the development of precision medicine in pediatric patients.

Enteral siRNA delivery technique for therapeutic gene silencing in the liver via the lymphatic route.

An efficient targeting delivery technology is needed for functional oligonucleotides to exert their potential effect on the target gene without an adverse effect in vivo. Development of enteral delivery systems for nucleic acids is a major challenge because of their large molecular size and instability. Here, we describe a new enteral delivery technique that enables small interfering RNA (siRNA) selectively delivered to the liver to silence its target Apolipoprotein B gene expression.

DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing.

Antisense oligonucleotides (ASOs) are recognized therapeutic agents for the modulation of specific genes at the post-transcriptional level. Similar to any medical drugs, there are opportunities to improve their efficacy and safety. Here we develop a short DNA/RNA heteroduplex oligonucleotide (HDO) with a structure different from double-stranded RNA used for short interfering RNA and single-stranded DNA used for ASO.

Synthesis and properties of vitamin E analog-conjugated neomycin for delivery of RNAi drugs to liver cells.

RNA interference (RNAi) is a promising tool to regulate gene expression by external double stranded RNAs (dsRNAs) such as siRNAs. As an efficient method to deliver siRNAs to liver cells, we propose a novel strategy using vitamin E (VE)-conjugated neomycin derivatives. With the aim of delivering RNAi-based drugs to liver cells, several tripod-type and prodrug-type neomycin derivatives were synthesized, all of which were thermodynamically stabilized RNA duplexes.

Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol.

We developed an efficient system for delivering short interfering RNA (siRNA) to the liver by using α-tocopherol conjugation. The α-tocopherol-conjugated siRNA was effective and safe for RNA interference-mediated gene silencing in vivo. In contrast, when the 13-mer LNA (locked nucleic acid)-DNA gapmer antisense oligonucleotide (ASO) was directly conjugated with α-tocopherol it showed markedly reduced silencing activity in mouse liver.

Efficient in vivo delivery of antisense oligonucleotide to choroid plexus.

The choroid plexus (CP) is present on the ventricular walls of the brain, produces cerebrospinal fluid (CSF), contains many blood vessels, and is a major functional component of the blood-CSF barrier. The CP is an important site in the pathophysiology of various neurological diseases, including Alzheimer's disease and meningeal amyloidosis. We performed gene silencing in the CP in vivo by using an antisense oligonucleotide (ASO).

Efficient in vivo delivery of siRNA into brain capillary endothelial cells along with endogenous lipoprotein.

The brain capillary endothelial cell (BCEC) is a major functional component of the blood-brain barrier and is an underlying factor in the pathophysiology of various diseases, including brain ischemia, multiple sclerosis, and neurodegenerative disorders. We examined gene silencing in BCECs by using endogenous lipoprotein to introduce short-interfering RNA (siRNA) in vivo. A cholesterol-conjugated 21/23-mer siRNA targeting organic anion transporter 3 (OAT3) mRNA (Chol-siOAT3) was intravenously injected into mice after its incorporation into extracted endogenous lipoproteins.

Intraperitoneal AAV9-shRNA inhibits target expression in neonatal skeletal and cardiac muscles.

Systemic injections of AAV vectors generally transduce to the liver more effectively than to cardiac and skeletal muscles. The short hairpin RNA (shRNA)-expressing AAV9 (shRNA-AAV9) can also reduce target gene expression in the liver, but not enough in cardiac or skeletal muscles. Higher doses of shRNA-AAV9 required for inhibiting target genes in cardiac and skeletal muscles often results in shRNA-related toxicity including microRNA oversaturation that can induce fetal liver failure.

High-density lipoprotein facilitates in vivo delivery of α-tocopherol-conjugated short-interfering RNA to the brain.

We originally reported the use of vitamin E (α-tocopherol) as an in vivo vector of short-interfering RNA (siRNA) to the liver. Here, we apply our strategy to the brain. By combining high-density lipoprotein (HDL) as a second carrier with α-tocopherol-conjugated siRNA (Toc-siRNA) in the brain, we achieved dramatic improvement of siRNA delivery to neurons.

Depletion of vitamin E increases amyloid beta accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease.

Increased oxidative damage is a prominent and early feature in Alzheimer disease. We previously crossed Alzheimer disease transgenic (APPsw) model mice with alpha-tocopherol transfer protein knock-out (Ttpa(-/-)) mice in which lipid peroxidation in the brain was significantly increased. The resulting double-mutant (Ttpa(-/-)APPsw) mice showed increased amyloid beta (Abeta) deposits in the brain, which was ameliorated with alpha-tocopherol supplementation.