Inhibition of ABC transporters is considered the most effective way to circumvent multidrug resistance (MDR). In the present study, we evaluated the MDR modulatory potential of ERK5-IN-1, a potent extracelluar...
Thu Mar 12, 2020 02:00
Condition: Chronic Nonspecific Neck PainIntervention: Other: Sagittal Cervical Posture Corrective Orthotic DeviceSponsor: University of SharjahNot yet recruiting
Fri Mar 13, 2020 15:55
Condition: Esophageal AdenocarcinomaInterventions: Procedure: Minimally invasive esophagectomy; Device: daVinci Xi systemSponsor: University Medical Center MainzNot yet recruiting
Fri Mar 13, 2020 15:55
Condition: Moderate to Severe AsthmaIntervention: Drug: KBL693Sponsors: KoBioLabs; Novotech (Australia) Pty LimitedNot yet recruiting
Fri Mar 13, 2020 15:55
Purpose:Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Overexpression of the protein transporter exportin-1 (XPO1) leads to mislocalization of tumor-suppressor proteins (TSP) and their inactivation. Earlier, we showed that blocking XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and analogs) restores the antitumor activity of multiple TSPs leading to suppression of PDAC in vitro and in orthotopic...
Fri Mar 13, 2020 15:05
Purpose:The success of checkpoint blockade against glioblastoma (GBM) has been disappointing. Anti–PD-1 strategies may be hampered by severe T-cell exhaustion. We sought to develop a strategy that might license new efficacy for checkpoint blockade in GBM. Experimental Design:We characterized 4-1BB expression in tumor-infiltrating lymphocytes (TIL) from human GBM. We implanted murine tumor models including glioma (CT2A), melanoma (B16), breast (E0771), and lung carcinomas intracranially and subcutaneously,...
Fri Mar 13, 2020 15:05
Fri Mar 13, 2020 15:05
Purpose:The purpose of this study was to evaluate antigen experienced T cells in peripheral blood lymphocytes (PBL) for responses to p53 neoantigens. Experimental Design:PBLs from patients with a mutated TP53 tumor were sorted for antigen-experienced T cells and in vitro stimulation (IVS) was performed with p53 neoantigens. The IVS cultures were stimulated with antigen-presenting cells expressing p53 neoantigens, enriched for 41BB/OX40 and grown with rapid expansion protocol. Results:T-cell responses...
Fri Mar 13, 2020 15:05
Purpose:Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system...
Fri Mar 13, 2020 15:05
Purpose:5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker of open chromatin and active gene expression. We profiled 5-hmC with Nano-hmC-Seal technology using 10 ng of plasma-derived cell-free DNA (cfDNA) in blood samples from patients with neuroblastoma to determine its utility as a biomarker. Experimental Design:For the Discovery cohort, 100 5-hmC profiles were generated from 34 well children and 32 patients (27 high-risk, 2 intermediate-risk, and 3 low-risk) at various time points during...
Fri Mar 13, 2020 15:05
Purpose:Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody–drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623). Patients and Methods:Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg...
Fri Mar 13, 2020 15:05
Purpose:GOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses. Experimental Design:Plasma samples were analyzed via multiplex ELISA technology...
Fri Mar 13, 2020 15:05
Purpose:ERK1/2 signaling can be dysregulated in cancer. GDC-0994 is an oral inhibitor of ERK1/2. A first-in-human, phase I dose escalation study of GDC-0994 was conducted in patients with locally advanced or metastatic solid tumors. Patients and Methods:GDC-0994 was administered once daily on a 21-day on/7-day off schedule to evaluate safety, pharmacokinetics, and preliminary signs of efficacy. Patients with pancreatic adenocarcinoma and BRAF-mutant colorectal cancer were enrolled in the expansion...
Fri Mar 13, 2020 15:05
Purpose:Neoadjuvant PD-1 blockade is a promising treatment for resectable non–small cell lung cancer (NSCLC), yet immunologic mechanisms contributing to tumor regression and biomarkers of response are unknown. Using paired tumor/blood samples from a phase II clinical trial (NCT02259621), we explored whether the peripheral T-cell clonotypic dynamics can serve as a biomarker for response to neoadjuvant PD-1 blockade. Experimental Design:T-cell receptor (TCR) sequencing was performed on serial peripheral...
Fri Mar 13, 2020 15:05
Purpose:Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D). Patients and Methods:Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30–400 mg once daily for 14 days; R2, 30–315 mg once daily 3 times/week; or R3, 300–1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease...
Fri Mar 13, 2020 15:05
Purpose:Sessile serrated lesions (SSL) are precursors to colon carcinoma, and their distinction from other polyps, in particular hyperplastic polyps (HP), presents significant diagnostic challenges. We evaluated expression patterns in colonic polyps of previously identified colon carcinoma–associated extracellular matrix (ECM) proteins to identify markers distinguishing SSLs from other polyps. Experimental Design:Gene-expression analyses of ECM proteins were performed using publicly available data...
Fri Mar 13, 2020 15:05
Purpose:Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose–escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137). Patients and Methods:Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ...
Fri Mar 13, 2020 15:05
Harmonic Motion Imaging of Pancreatic Tumor Stiffness Indicates Disease State and Treatment Response
Purpose:Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment. Experimental Design:Harmonic motion imaging (HMI) is a functional ultrasound technique that yields a quantitative relative measurement of stiffness...
Fri Mar 13, 2020 15:05
Purpose:We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment. Patients and Methods:Pretreatment (n = 78) and 8-week on-treatment (n...
Fri Mar 13, 2020 15:05
Purpose:Tumor periphery and lymph nodes of tumor-induced lymphangiogenesis often abundantly express VEGFR-3. In our previous study, we identified a 5-amino acid peptide named TMVP1, which binds specifically to VEGFR-3. The objective of this study was to develop a novel 68Ga-labeled TMVP1 for VEGFR-3 PET imaging and to investigate its safety, biodistribution, and tumor-localizing efficacy in xenograft tumor models and a small cohort of patients with recurrent ovarian and cervical cancer. Experimental...
Fri Mar 13, 2020 15:05
Fri Mar 13, 2020 15:05
Purpose:Recent clinical data demonstrate that tumors harboring MET genetic alterations (exon 14 skip mutations and/or gene amplification) respond to small-molecule tyrosine kinase inhibitors, validating MET as a therapeutic target. Although antibody-mediated blockade of the MET pathway has not been successful in the clinic, the failures are likely the result of inadequate patient selection strategies as well as suboptimal antibody design. Thus, our goal was to generate a novel MET blocking antibody...
Fri Mar 13, 2020 15:05
Purpose:Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer. Experimental Design:Patients with metastatic pancreatic...
Fri Mar 13, 2020 15:05
Fri Mar 13, 2020 15:05
Purpose:Defects in the homologous recombination (HR) repair pathway are of clinical interest due to sensitivity of HR-deficient cells to PARP inhibitors. We were interested in defining PARP vulnerability in patients with metastatic colorectal cancer (mCRC) carrying KRAS and BRAF mutations who display poor prognosis, have limited therapeutic options, and represent an unmet clinical need. Experimental Design:We tested colorectal cancer cell lines, patient-derived organoids (PDO), and patient-derived...
Fri Mar 13, 2020 15:05
Purpose:Cancer antigen–specific T cells are key components in antitumor immune response, yet their identification in the tumor microenvironment remains challenging, as most cancer antigens are unknown. Recent advance in immunology suggests that similar T-cell receptor (TCR) sequences can be clustered to infer shared antigen specificity. This study aims to identify antigen-specific TCRs from the tumor genomics sequencing data. Experimental Design:We used the TRUST (Tcr Repertoire Utilities for Solid...
Fri Mar 13, 2020 15:05
Purpose:Exploration of novel strategies to extend the benefit of PARP inhibitors beyond BRCA-mutant cancers is of great interest in personalized medicine. Here, we identified EGFR amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy. Experimental Design:Selective sensitivity to the PARP inhibitor talazoparib was screened and validated in two sets [test set...
Fri Mar 13, 2020 15:05
Purpose:Natural killer (NK)-cell–based immunotherapy may overcome obstacles to effective T-cell–based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing...
Fri Mar 13, 2020 15:05
Purpose:Therapies directed to specific molecular targets are still unmet for patients with triple-negative breast cancer (TNBC). Deubiquitinases (DUB) are emerging drug targets. The identification of highly active DUBs in TNBC may lead to novel therapies. Experimental Design:Using DUB activity probes, we profiled global DUB activities in 52 breast cancer cell lines and 52 patients' tumor tissues. To validate our findings in vivo, we employed both zebrafish and murine breast cancer xenograft models....
Fri Mar 13, 2020 15:05
Purpose:Despite the therapeutic success of existing HER2-targeted therapies, tumors invariably relapse. This study aimed at identifying new mechanisms responsible for HER2-targeted therapy resistance. Experimental Design:We have used a platform of HER2-targeted therapy–resistant cell lines and primary cultures of healthy and tumor-associated fibroblasts (TAF) to identify new potential targets related to tumor escape from anti-HER2 therapies. Results:We have shown that TAFs promote resistance...
Fri Mar 13, 2020 15:05
Purpose:Immune checkpoint inhibitors (ICI) benefit only a minority of treated patients with cancer. Identification of biomarkers distinguishing responders and nonresponders will improve management of patients with cancer. Because the DC-HIL checkpoint differs from the PD1 pathway in expression and inhibitory mechanisms, we examined whether DC-HIL expression regulates ICI responsiveness. Experimental Design:Plasma samples were collected from patients with advanced non–small cell lung carcinoma (NSCLC)...
Fri Mar 13, 2020 15:05
Purpose:Patients with head and neck squamous cell carcinoma (HNSCC) who actively smoke during treatment have worse survival compared with never-smokers and former-smokers. We hypothesize the poor prognosis in tobacco smokers with HNSCC is, at least in part, due to ongoing suppression of immune response. We characterized the tumor immune microenvironment (TIM) of HNSCC in a retrospective cohort of 177 current, former, and never smokers. Experimental Design:Tumor specimens were subjected to analysis...
Fri Mar 13, 2020 15:05
Purpose:We evaluated the role of everolimus in the prevention of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) progression. Experimental Design:The effects of everolimus on breast cancer cell invasion, DCIS formation, and DCIS progression to IDC were investigated in a 3D cell culturing model, intraductal DCIS xenograft model, and spontaneous MMTV-Her2/neu mouse model. The effect of everolimus on matrix metalloproteinase 9 (MMP9) expression was determined with Western blotting...
Fri Mar 13, 2020 15:05
Purpose:One of the main limitations to anticancer radiotherapy lies in irreversible damage to healthy tissues located within the radiation field. "FLASH" irradiation at very high dose-rate is a new treatment modality that has been reported to specifically spare normal tissue from late radiation-induced toxicity in animal models and therefore could be a promising strategy to reduce treatment toxicity. Experimental Design:Lung responses to FLASH irradiation were investigated by qPCR, single-cell...
Fri Mar 13, 2020 15:05
Purpose:Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at the time of diagnosis remains unclear. Experimental Design:We sequenced samples from 314 consecutive, newly diagnosed patients with CLL...
Fri Mar 13, 2020 15:05
Purpose:Emerging evidence indicates that castration-resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor (AR) or its V7 splice variant (AR-V7) and commonly becomes resistant to endocrine therapy. The aim of this work is to evaluate the function of a kinesin protein, KIF4A, in regulating AR/AR-V7 in prostate cancer endocrine therapy resistance. Experimental Design:We examined KIF4A expression in clinical prostate cancer specimens by IHC. Regulated pathways...
Fri Mar 13, 2020 15:05
On April 4, 2019, the FDA approved a supplemental new drug application for palbociclib (IBRANCE), to expand the approved indications in women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant, to include men. Palbociclib was first approved in 2015 for use in combination with letrozole for the treatment of estrogen receptor–positive, HER2-negative advanced breast cancer as initial endocrine-based...
Fri Mar 13, 2020 15:05
Careful study of T-cell clonal dynamics in patients with non–small cell lung cancer treated with neoadjuvant nivolumab suggests that successful trafficking of clones from a proliferative burst in the periphery to the tumor associates with major pathologic response. Integration of these findings with functional analysis may augment current therapeutic strategies. See related article by Zhang et al., p. 1327
Fri Mar 13, 2020 15:05
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου