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Purpose:. Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH – ) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH – to standard RT/TMZ therapy. Patients and Methods:. This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH – ) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH – phase). Eight P-AscH – dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH – doses were escalated in each subject at each cycle until plasma con.
Excitement around and investment in oncology drug development are at unprecedented levels. To maximize the health impact and productivity of this research and development investment, quantitative modeling should impact key decisions in early clinical oncology including Go/No-Go decisions based on early clinical data, and dose selection for late stage studies. See related article by Bottino et al., p. 6633.
Purpose:. Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-naïve patients with advanced/metastatic solid tumors. Patients and Methods:. This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety;
Purpose:. Tumor growth rate (TGR) represents the percentage change in tumor volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR 3m ) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in neuroendocrine tumors (NET). Experimental Design:. Patients from 7 centers with advanced grade (G) 1/2 NETs from the pancreas ℗/small bowel (SB) initiating ST/WW were eligible. Computed tomography (CT)/MRI performed at prebaseline, baseline, and 3(±1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (TGR 3m-BL ; paired T test), and Aim-2: validate TGR 3m ( <0.8%/m vs. ≥0.8%/m) a.
Purpose:. Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary ALK mutations. Here, we investigated utility of plasma genotyping for identifying ALK resistance mutations at relapse on next-generation ALK TKIs. Experimental Design:. We analyzed 106 plasma specimens from 84 patients with advanced ALK -positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify ALK mutations. Results:. By genotyping plasma, we detected an ALK mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectini.
Purpose:. To identify genetic factors associated with risk of stroke among survivors of childhood cancer treated with cranial radiotherapy (CRT). Experimental Design:. We analyzed whole-genome sequencing (36.8-fold) data of 686 childhood cancer survivors of European ancestry [median (range), 40.4 (12.4–64.7) years old; 54% male] from the St. Jude Lifetime Cohort study treated with CRT, of whom 116 (17%) had clinically diagnosed stroke.
Purpose:. Long noncoding RNAs (lncRNA) have essential roles in diverse cellular processes, both in normal and diseased cell types, and thus have emerged as potential therapeutic targets. A specific member of this family, the SWI/SNF complex antagonist associated with prostate cancer 1 ( SChLAP1 ), has been shown to promote aggressive prostate cancer growth by antagonizing the SWI/SNF complex and therefore serves as a biomarker for poor prognosis. Here, we investigated whether SChLAP1 plays a potential role in the development of human glioblastoma (GBM). Experimental Design:. RNA-ISH and IHC were performed on a tissue microarray to assess expression of SChLAP1 and associated proteins in human gliomas. Proteins complexed with SChLAP1 were ident.
Purpose:. Diffuse intrinsic pontine gliomas (DIPG) are the most severe pediatric brain tumors. Although accepted as the standard therapeutic, radiotherapy is only efficient transiently and not even in every patient. The goal of the study was to identify the underlying molecular determinants of response to radiotherapy in DIPG. Experimental Design:. We assessed in vitro response to ionizing radiations in 13 different DIPG cellular models derived from treatment-naïve stereotactic biopsies reflecting the genotype variability encountered in patients at diagnosis and correlated it to their principal molecular alterations. Clinical and radiologic response to radiotherapy of a large cohort of 73 DIPG was analyzed according to their genotype. Using
Purpose:. Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand-binding domain (LBD)-binding antagonists, are inactivated by common resistance mechanisms. It is important to develop next-generation mechanistically distinct drugs to treat castration- and drug-resistant prostate cancers. Experimental Design:. Second-generation AR pan antagonist UT-34 was selected from a library of compounds and tested in competitive AR binding and transactivation assays. UT-34 was tested using biophysical methods for binding to the AR activation function-1 (AF-1) domain. Western blot, gene expression, and proliferation assays were performed in various AR-positive enzalutamide-sensitive and -resistant prostate cancer
BCR-ABL1 transcripts at imatinib cessation were quantified by droplet digital PCR (ddPCR) for 175 patients on the STIM2 trial. Patients with BCR-ABL1 transcripts below a defined cutoff had a 12-month molecular recurrence rate of 46% versus 68% for those above the cutoff. Implications of using ddPCR in forecasting successful imatinib cessation are discussed. See related article by Nicolini et al., p. 6606.
Purpose:. To investigate the efficacy of the combination of the FLT3 inhibitors midostaurin or gilteritinib with the Bcl-2 inhibitor venetoclax in FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) and the underlying molecular mechanism. Experimental Design:. Using both FLT3-ITD cell lines and primary patient samples, Annexin V-FITC/propidium iodide staining and flow cytometry analysis were used to quantify cell death induced by midostaurin or gilteritinib, alone or in combination with venetoclax.
Purpose:. Treatment of BRAF V600E -mutant melanomas with MAPK inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand nonmutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi. Experimental Design:. By screening proteins expressed on the cell surface of melanoma cells, we identified the fatty acid transporter CD36 as the most consistently upregulated protein upon short-term treatment with MAPKi. We further investigated the effects of MAPKi on fatty acid metabolism using in vitro and in vivo models and analyzing patients' pre- and on-treatment tumor.
Purpose:. Patients with anaplastic lymphoma kinase ( ALK )–rearranged non–small-cell lung cancer (NSCLC) inevitably develop resistance to ALK inhibitors. New diagnostic strategies are needed to assess resistance mechanisms and provide patients with the most effective therapy. We asked whether single circulating tumor cell (CTC) sequencing can inform on resistance mutations to ALK inhibitors and underlying tumor heterogeneity in ALK -rearranged NSCLC. Experimental Design:. Resistance mutations were investigated in CTCs isolated at the single-cell level from patients at disease progression on crizotinib ( n = 14) or lorlatinib ( n = 3). Three strategies including filter laser-capture microdissection, fluorescence activated cell sorting, and the.
Purpose:. The success of checkpoint blockade has led to a significant increase in the development of a broad range of immunomodulatory molecules for the treatment of cancer, including agonists against T-cell costimulatory receptors, such as OX40. Unlike checkpoint blockade, where complete and sustained receptor saturation may be required for maximal activity, the optimal dosing regimen and receptor occupancy for agonist agents is less well understood and requires further study. Experimental Design:. We integrated both preclinical and clinical biomarker data sets centered on dose, exposure, receptor occupancy, receptor engagement, and downstream pharmacodynamic changes to model the optimal dose and schedule for the OX40 agonist antibody BMS-98.
Purpose:. High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and HER2 -positive breast cancer.
Purpose:. Intratumoral injection of oncolytic adenovirus Delta-24-RGDOX induces efficacious antiglioma immunity in syngeneic glioma mouse models. We hypothesized that localized treatment with the virus is effective against disseminated melanomas. Experimental Design:. We tested the therapeutic effect of injecting Delta-24-RGDOX into primary subcutaneous (s.c.) B16-Red-FLuc tumors in s.c./s.c. and s.c./intracranial (i.c.) melanoma models in C57BL/6 mice. Tumor growth and in vivo luciferase-expressing ovalbumin-specific (OT-I/Luc) T cells were monitored with bioluminescence imaging. Cells were profiled for surface markers with flow cytometry. Results:. In both s.c./s.c. and s.c./i.c. models, 3 injections of Delta-24-RGDOX significantly inhibited.
Purpose:. The heterogeneity of androgen receptor (AR)-activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatment-naïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications. Experimental Design:. Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery ( n = 5,239) and validation ( n = 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data ( n = 1,170)
Purpose:. In this study, we addressed the underlying mechanisms for the association between enzalutamide (ENZ) treatment and neuroendocrine prostate cancer (NEPC), and the critical involvement of MYCN, and loss of RB1 function in neuroendocrine differentiation (NED) of prostatic epithelial cells, and the development of NEPC.

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