Prospects of focal adhesion kinase inhibitors as a cancer therapy in preclinical and early phase study.

Introduction: FAK, a nonreceptor cytoplasmic tyrosine kinase, plays a crucial role in tumor metastasis, drug resistance, tumor stem cell maintenance, and regulation of the tumor microenvironment. FAK has emerged as a promising target for tumor therapy based on both preclinical and clinical data.

Areas Covered: This paper aims to summarize the molecular mechanisms underlying FAK's involvement in tumorigenesis and progression.

Targeting of focal adhesion kinase enhances the immunogenic cell death of PEGylated liposome doxorubicin to optimize therapeutic responses of immune checkpoint blockade.

Backgrounds: Immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of an immunogenic niche. Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types.

Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung adenocarcinoma via remodeling the tumor microenvironment.

Background: KRAS mutation is one of the most common oncogenic drivers in NSCLC, however, the response to immunotherapy is heterogeneous owing to the distinct co-occurring genomic alterations. KRAS/LKB1 co-mutated lung adenocarcinoma displays poor response to PD-1 blockade whereas the mechanism remains undetermined.

Methods: We explored the specific characteristics of tumor microenvironment (TME) in KL tumors using syngeneic KRASLKB1 (KL) and KRASTP53 (KP) lung cancer mouse models.

Simultaneous inhibition of FAK and ROS1 synergistically repressed triple-negative breast cancer by upregulating p53 signalling.

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking effective targeted therapies, necessitating innovative treatment approaches. While targeting ROS proto-oncogene 1 (ROS1) with crizotinib has shown promise, resistance remains a limitation. Recent evidence links focal adhesion kinase (FAK) to drug resistance, prompting our study to assess the combined impact of FAK inhibitor IN10018 and crizotinib in TNBC and elucidate the underlying mechanisms.

Synergism of FAK and ROS1 inhibitors in the treatment of -deficient cancers mediated by FAK-YAP signaling.

deficiency is common in diffuse gastric cancer and triple negative breast cancer patients, both of which still lack effective therapeutics. ROS1 inhibition results in synthetic lethality in -deficient cancers, but often leads to adaptive resistance. Here, we demonstrate that upregulation of the FAK activity accompanies the emergence of resistance to ROS1 inhibitor therapy in gastric and breast -deficient cancers.

A Low-Current and Multi-Channel Chemiresistor Array Sensor Device.

This paper describes the design of a low-current, multichannel, handheld electronic device integrated with nanostructured chemiresistor sensor arrays. A key design feature of the electronic circuit board is its low excitation current for achieving optimal performance with the arrays. The electronics can rapidly acquire the resistances for different sensors, not only spanning several orders of magnitude, but also as high as several hundreds of megaohms.

Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK-YAP Signaling.

KRAS mutation is one of the most prevalent genetic drivers of cancer development, yet KRAS mutations are until very recently considered undruggable. There are ongoing trials of drugs that target the KRAS G12C mutation, yet acquired drug resistance from the extended use has already become a major concern. Here, it is demonstrated that KRAS G12C inhibition induces sustained activation of focal adhesive kinase (FAK) and show that a combination therapy comprising KRAS G12C inhibition and a FAK inhibitor (IN10018) achieves synergistic anticancer effects.

Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy, due in large part to its resistance to conventional therapies, including radiotherapy (RT). Despite RT exerting a modest antitumor response, it has also been shown to promote an immunosuppressive tumor microenvironment. Previous studies demonstrated that focal adhesion kinase inhibitors (FAKi) in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory (T regs) cells, and subsequently enhance effector T cell infiltration.

Efficacy and safety of elbasvir/grazoprevir in treatment-naive Chinese adults with hepatitis C virus infection: A randomized trial.

Background And Aim: In China, clinical experience with direct-acting antiviral treatments for hepatitis C virus (HCV) infection is still emerging. C-CORAL is a phase 3, multinational, placebo-controlled, double-blind trial of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from the Asia-Pacific region and Russia. Here, we report the data from participants enrolled in China.

Efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus genotype 1, 4, or 6 infection from the Asia-Pacific region and Russia: Final results from the randomized C-CORAL study.

Background And Aim: Although treatment with direct-acting antivirals has dramatically improved morbidity and mortality attributable to chronic hepatitis C virus infection, universal access to these medicines has been slow in the Asia-Pacific region and Russia. This study evaluated efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus infection from Asia-Pacific countries and Russia (C-CORAL).

Methods: C-CORAL was a phase 3, randomized, placebo-controlled study (NCT02251990).

A Phase I, Single- and Multiple-dose Study to Evaluate the Pharmacokinetics of Elbasvir and Grazoprevir in Healthy Chinese Participants.

Purpose: This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals.

Methods: This study was a 2-part, parallel-arm, open-label trial. In part 1, single-dose PK variables of elbasvir 10/50/100 mg and grazoprevir 50/100/200 mg were evaluated in 10 participants per drug.

Evaluation of an fMRI USPIO-based assay in healthy human volunteers.

Purpose: To present the testretest and contrast dose effect results of cerebral blood volume (CBV) functional MRI (fMRI) in healthy human volunteers using ferumoxytol (Feraheme), an ultrasmall-superparamagnetic iron oxide (USPIO) nanoparticle.

Materials And Methods: This was an open-label, two-period, fixed-sequence study in healthy young volunteers. In eight subjects, using a 3 Tesla field strength system, blood oxygen level dependent (BOLD) and CBV fMRI were acquired in response to a visual black-and-white checkboard stimulation paradigm using an escalating ferumoxytol dose design (250, 350, and 510 mg iron).

Mometasone furoate nasal spray in the treatment of nasal polyposis in Chinese patients: a double-blind, randomized, placebo-controlled trial.

Background: Although mometasone furoate nasal spray (MFNS) has demonstrated efficacy in nasal polyposis (NP) in Western populations, data in Asian populations is limited.

Methods: This randomized, double-blind study evaluated MFNS 200 μg twice per day (BID) vs placebo in Chinese adults with bilateral nasal polyps (graded as 1, 2, or 3 by the investigator). A 14-day placebo run-in period was followed by a 16-week treatment period with MFNS 200 μg BID vs placebo (1:1 ratio).

Pharmacokinetics of sugammadex 16 mg/kg in healthy Chinese volunteers.

Objective: Elimination of sugammadex occurs predominantly via the kidneys, with the majority of the drug excreted unchanged in the urine. To date, most studies with sugammadex have been performed in non-Asian populations. The objectives of this open-label study were to determine the pharmacokinetics (PK) and safety of single-dose sugammadex (16 mg/kg) in healthy Chinese adult volunteers.

Pharmacokinetics of vorapaxar and its metabolite following oral administration in healthy Chinese and American subjects.

Aim: Vorapaxar is a proteaseactivated receptor (PAR)-1 antagonist being developed for the prevention and treatment of thrombotic vascular events. To evaluate race/ethnic differences between Caucasians and Chinese in the pharmacokinetics of vorapaxar and its active metabolite SCH 2046273 (M20) or in the metabolite/parent ratio, we conducted a cross-study comparison on pharmacokinetic data of vorapaxar and M20 obtained from two similarly designed studies: one in healthy Chinese subjects and the other in a healthy Western (United States, [U.S.

Multiple-dose pharmacokinetics and safety of desloratadine in subjects with moderate hepatic impairment.

Desloratadine, a nonsedating histamine H(1)-receptor antagonist, is metabolized to 3-hydroxy (3-OH) desloratadine. Impaired hepatic function could result in increased exposure to desloratadine. This study assessed possible differences in the pharmacokinetics and safety of desloratadine and 3-OH desloratadine in subjects (N = 21) with moderate hepatic dysfunction or normal liver function.

Retrospective analysis of electrocardiographic changes after administration of oral or intravenous garenoxacin in five phase I, placebo-controlled studies in healthy volunteers.

Background: Certain fluoroquinolones and macrolide antibiotics have been associated with prolongation of the corrected QT (QTc) interval or QT dispersion, leading to cardiac arrhythmias. Garenoxacin is a des-F(6)-quinolone with broad-spectrum antimicrobial activity and a favorable pharmacokinetic/pharmacodynamic profile. Its effects on electrocardiographic (ECG) parameters in healthy volunteers have not been reported.

Penetration of garenoxacin into lung tissues and bone in subjects undergoing lung biopsy or resection.

Objective: Concentrations of garenoxacin in plasma and samples of lung parenchyma, bronchial mucosa, and bone were determined following single-dose administration.

Research Design And Methods: Open-label, non-randomized study in which subjects undergoing invasive lung biopsy or resection were given a single 600-mg oral dose of garenoxacin. Lung parenchyma, and, if possible, bronchial mucosa and bone (i.

Effect of an aluminum- and magnesium-containing antacid on the bioavailability of garenoxacin in healthy volunteers.

Study Objective: To evaluate the effect of an aluminum- and magnesium-containing antacid (Al-Mg antacid), which contains a high concentration of cations, on the pharmacokinetics of garenoxacin.

Design: Prospective, randomized, open-label, control-balanced, residual-effects-design study.

Setting: Pharmaceutical company-affiliated study clinic.

The effect of omeprazole on the bioavailability and safety of garenoxacin in healthy volunteers.

The effect of coadministration of omeprazole on the bioavailability of oral garenoxacin was evaluated in an open-label study in 14 healthy subjects. Single-dose pharmacokinetics of garenoxacin were determined with and without steady-state omeprazole. Following an oral dose of garenoxacin 600 mg on day 1, serial blood samples were obtained over the next 72 hours.

Garenoxacin pharmacokinetics in subjects with renal impairment.

Objective: This open-label, parallel-group study determined the pharmacokinetics of garenoxacin in subjects with severe renal impairment, including subjects maintained on dialysis.

Research Design And Methods: Subjects were assigned to one of four groups according to their underlying renal function: creatinine clearance (CL(cr)) > 80 mL/min, CL(cr) < 30 mL/min, hemodialysis (HD), and continuous ambulatory peritoneal dialysis (CAPD). Subjects received a single oral 600-mg dose of garenoxacin.

Desloratadine dose selection in children aged 6 months to 2 years: comparison of population pharmacokinetics between children and adults.

Aims: The aim of this study was to identify the dose of desloratadine in children aged > or =6 months- < or =2 years that would yield a single-dose target exposure (AUC) comparable with that in adults taking 5 mg desloratadine as syrup.

Methods: In a phase 1, single-dose, open-label, pharmacokinetic study in 58 children aged > or =6 months- <1 year and > or =1 year- < or =2 years were randomly assigned to desloratadine syrup 0.625 mg (1.

Nasogastric administration of garenoxacin as crushed tablets with and without concomitant enteral feeding in healthy subjects.

Background And Objective: Cation-containing drugs have the potential to affect the absorption of quinolones. The current study was conducted to assess whether the bioavailability of garenoxacin was affected by administration as crushed tablets with and without concomitant enteral nutrition.

Methods: This was a randomised, open-label, three-period, single-dose, crossover study carried out in healthy male volunteers who received study treatments at a clinical facility.