STNM01, the RNA oligonucleotide targeting carbohydrate sulfotransferase 15, as second-line therapy for chemotherapy-refractory patients with unresectable pancreatic cancer: An open label, phase I/IIa trial.

Background: The impact of stroma-targeting therapy on tumor immune suppression is largely unexplored. An RNA oligonucleotide, STNM01, has been shown to repress carbohydrate sulfotransferase 15 (CHST15) responsible for tumor proteoglycan synthesis and matrix remodeling. This phase I/IIa study aimed to evaluate the safety and efficacy of STNM01 in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). Methods: This was an open-label, dose-escalation study of STNM01 as second-line therapy in gemcitabine plus nab-paclitaxel-refractory PDAC. A cycle comprised three 2-weekly endoscopic ultrasound-guided locoregional injections of STNM01 at doses of 250, 1,000, 2,500, or 10,000 nM in combination with S-1 (80-120 mg twice a day for 14 days every 3 weeks). The primary outcome was the incidence of dose-liming toxicity (DLT). The secondary outcomes included overall survival (OS), tumor response, changes in tumor microenvironment on immunohistopathology, and safety (jRCT2031190055). Findings: A total of 22 patients were enrolled, and 3 cycles were repeated at maximum; no DLT was observed. The median OS was 7.8 months. The disease control rate was 77.3%; 1 patient showed complete disappearance of visible lesions in the pancreas and tumor-draining lymph nodes. Higher tumoral CHST15 expression was associated with poor CD3+ and CD8+ T cell infiltration at baseline. STNM01 led to a significant reduction in CHST15, and increased tumor-infiltrating CD3+ and CD8+ T cells in combination with S-1 at the end of cycle 1. Higher fold increase in CD3+ T cells correlated with longer OS. There were 8 grade 3 adverse events. Interpretation: Locoregional injection of STNM01 was well tolerated in patients with unresectable PDAC as combined second-line therapy. It prolonged survival by enhancing T cell infiltration in tumor microenvironment. Funding: The present study was supported by the Japan Agency for Medical Research and Development (AMED).

Label-Free Antifouling Photoelectrochemical Sensing Strategy for Detecting Breast Tumor Cells Based on Ligand-Receptor Interactions.

Biomarker expression both on the cell surface and in serum is directly related to the pathological process of tumor. Based on the interaction between the ligand and the protein receptor, a label-free photoelectrochemical (PEC) biosensing interface with good antifouling ability was proposed for tumor cell detection. TiO2 nanotube (NT) arrays were used as the substrate to enhance the ability of the biosensor to capture the target. Mercapto-terminated 8-arm poly(ethylene glycol) was introduced onto the electrode surface by the deposition of Au nanoparticles on TiO2 NTs, creating an antifouling molecular layer. The recognition ligand hyaluronic acid (HA) was functionalized by dopamine and introduced onto the sensing surface based on the unique chelating interaction between the catechol group and the titanium atom. Benefitting from the specific recognition of HA with CD44 and the 3D porous structures of NTs, the constructed PEC biosensor showed excellent abilities toward the detection of MDA-MB-231 breast tumor cells and the soluble form of CD44. The ligand-receptor PEC sensing strategy has promising potential for the detection of tumor cells and protein biomarkers.

Correlation of Soluble CD44 Expression in Saliva and CD44 Protein in Oral Leukoplakia Tissues.

The aim of this study was to determine whether and how pan-CD44 protein expression in leukoplakia tissues correlates with positive SolCD44 test presence and their role in oral leukoplakia. SolCD44 and total protein expression in saliva were determined using an OncAlert® Oral Cancer Rapid test. Comparison of paired associations of total protein, SolCD44, mean number of CD44 expressed epithelial layers in leukoplakia tissue, and macrophages below the basement membrane between control group and patients with leukoplakia showed statistically significant results (p < 0.0001). It is shown that the total protein indicates low or elevated risk of possible malignant transformation processes in leukoplakia. Statistically significant differences between higher total protein level and clinical forms of oral leukoplakia (p < 0.0001), as well as CD44-labeled epithelial cell layer decrease (p < 0.0001), were found. This possibly points to the onset of the stemness loss in leukoplakia tissue. CD9 antigen expression in the exosomes of the oral epithelium explained the intercellular flow of SolCD44 and other fluids in the leukoplakia area. We conclude that the OncAlert® Oral Cancer Rapid test is a valuable screening method in daily clinical practice, in terms of complementing clinical diagnostics methods and to assess the potential for early malignancy.

Photoelectrochemical Biosensor for Sensitive Detection of Soluble CD44 Based on the Facile Construction of a Poly(ethylene glycol)/Hyaluronic Acid Hybrid Antifouling Interface.

The serum level of soluble CD44 is directly associated with several clinicopathological parameters of malignant diseases. There is a great need for the development of an easy and cost-effective detection method for soluble CD44 for both the diagnosis and the treatment of cancers. In this work, a simple photoelectrochemical (PEC) method for the sensitive detection of serum-soluble CD44 is proposed based on the construction of a hybrid antifouling coating on the TiO2 substrate. Hyaluronic acid (HA) and poly(ethylene glycol) (PEG) are co-immobilized using a biomimetic one-step surface functionalization approach. The immobilized HA shows strong recognition abilities toward soluble CD44, and the synergistic antifouling effect achieved by the combination of PEG and HA improves the sensing specificity. Based on the inhibitory effect of CD44 recognition on the PEC signal of the TiO2 substrate, a PEC biosensor is developed with a wide response range and a low detection limit. The development of antibody-free biosensors may promote the application of soluble CD44 as a biomarker for the diagnosis and treatment of malignant diseases.

Evaluation of the CD44 isoform v-6 (sCD44var, v6) in the saliva of patients with laryngeal carcinoma and its prognostic role.

BACKGROUND: The soluble fraction of the CD44 protein (solCD44) may constitute a valuable biological marker of Cancer Stem Cells (CSCs), useful for screening/early detection of laryngeal cancer, and for the prognosis. In previous papers, in fact, we have studied the expression of salivary solCD44 in patients with laryngeal tumors, supporting its use for early diagnosis of laryngeal carcinoma with high sensitivity and specificity, also with prognostic role, useful for clinical outcome. OBJECTIVE: The purpose of present study was to verify the levels of solCD44 isoform v6, sCD44var (v6), in saliva samples of patients with laryngeal carcinoma in our tumoral biobank, to evaluate possible correlations with clinical-anamnestic and prognostic data. METHODS: Study design was retrospective. Salivary samples of 66 patients with laryngeal cancer recruited from January 2012 to December 2013 were selected from our tumoral biobank. For each salivary sample was performed the determination of solCD44 and its isoform v6, sCD44var (v6), by ELISA. Qualitative and quantitative results of the test were correlated with clinical and medical history data. For statistical analysis we used the software MedCalc (versione 12.2.1.0). RESULTS: Concentrations of salivary sCD44var v6 were significantly higher according to the size of the primary tumor (T) (p= 0.001), the tumor site glottic or supraglottic-transglottic (p= 0.005) and according to the metastatic lymph node involvement (p= 0005). Furthermore, tumors in advanced disease (stage III-IV) showed values of salivary sCD44var v6 higher than the tumors in early stage, with a statistically significant difference (p= 0.005). CONCLUSIONS: The determination of the levels of salivary solCD44 v6 may represent a promising prognostic test in laryngeal carcinomas.

Soluble CD44 and vascular endothelial growth factor levels in patients with acute primary angle closure.

PURPOSE: Acute elevation of intraocular pressure (IOP) in acute primary angle closure (APAC) can cause huge damage to the variable cells in the eye; however, the mechanisms that connect the two processes still remain unclear. In this study, we aim to evaluate the levels of soluble CD44 (sCD44) and vascular endothelial growth factor (VEGF) in the aqueous humour of acute primary angle closure patients. METHODS: This study included 24 eyes of 24 APAC patients (11 eyes with current APAC and 13 eyes with previous APAC) and 15 eyes of 15 cataract subjects. Clinical data were acquired, and aqueous humour was collected. The levels of sCD44 and VEGF in the aqueous humour were determined by ELISA and magnetic bead immunoassay technique. RESULTS: The concentrations of the sCD44 and VEGF in the current APAC were 9.9 ± 8.8 ng/ml and 2440.2 ± 2107.1 ng/ml, respectively, which were significantly higher when compared to the previous APAC group (p = 0.001) and cataract (p < 0.001); however, there were no significant differences between the group with previous APAC and with cataract. Higher IOP was associated with higher concentration of sCD44 (Rho = 0.617, p = 0.001). The concentration of the VEGF in aqueous humour of APAC patients was closely related to the sCD44 levels (Rho = 0.752, p < 0.001). CONCLUSION: After acute increase of IOP in the APAC, the level of sCD44 and VEGF increased significantly in the aqueous humour. The damage due to high IOP may therefore be mediated through the release of sCD44.

Comparative evaluation of salivary soluble CD44 levels in periodontal health and disease.

CONTEXT: Inflammation, immunoactivation, and malignant diseases are associated with increased plasma levels of soluble CD44 (sCD44). Serum sCD44 has been recognized as a diagnostic marker in smoking-induced diseases. AIM: (1) To assess the levels of salivary sCD44 in periodontal health and disease. (2) To compare the levels of salivary sCD44 in smokers and nonsmokers. (3) To assess if salivary sCD44 levels could be used as a diagnostic marker for periodontitis. SETTING AND DESIGN: A total of 60 patients were divided into three groups viz. Group A - healthy, Group B - aggressive periodontitis and Group C - chronic periodontitis (Subdivided into C1 - chronic periodontitis smokers and C2 - chronic periodontitis nonsmokers). MATERIALS AND METHODS: The plaque index, gingival index (GI), probing depth and clinical attachment level; along with the radiographs were recorded. The saliva sample collected at baseline was stored at -80°C. The sCD44 levels were analyzed using ELISA. STATISTICAL ANALYSIS USED: ANOVA test and Mann-Whitney's test was used to compare readings between all the groups and Pearson correlation was calculated for CD44 and all the clinical parameters in each group. RESULTS: Highest mean sCD44 was recorded in Group C2 followed by Group C1. The GI was positively correlated with CD44 levels in chronic periodontitis group. Contrary to previous reports nonsmokers subjects had higher CD44 levels as compared to smoker. CONCLUSION: Soluble CD44 levels were positively correlated with periodontal disease. Thus, salivary sCD44 could be considered as a one of the biomarker for periodontitis that is, aggressive and chronic periodontitis.