Although patients with advanced refractory solid tumors have poor prognosis, the clinical development of targeted protein
kinase inhibitors offers hope for the future treatment of many cancers. In ...vivo and in vitro studies have shown that the oral multikinase inhibitor, sorafenib, inhibits tumor growth and disrupts tumor microvasculature
through antiproliferative, antiangiogenic, and/or proapoptotic effects. Sorafenib has shown antitumor activity in phase II/III
trials involving patients with advanced renal cell carcinoma and hepatocellular carcinoma. The multiple molecular targets
of sorafenib (the serine/threonine kinase Raf and receptor tyrosine kinases) may explain its broad preclinical and clinical
activity. This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell,
hepatocellular, breast, and colorectal carcinomas in the preclinical setting. In particular, preclinical evidence that supports
the different mechanisms of action of sorafenib is discussed. Mol Cancer Ther 2008;7(10):3129–40
Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development ...of hepatocellular carcinomas (HCC). Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. In this study, we investigated the in vitro effects of sorafenib on PLC/PRF/5 and HepG2 HCC cells and the in vivo antitumor efficacy and mechanism of action on PLC/PRF/5 human tumor xenografts in severe combined immunodeficient mice. Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Sorafenib also reduced the phosphorylation level of eIF4E and down-regulated the antiapoptotic protein Mcl-1 in a MEK/ERK-independent manner. Consistent with the effects on both MEK/ERK-dependent and MEK/ERK-independent signaling pathways, sorafenib inhibited proliferation and induced apoptosis in both HCC cell lines. In the PLC/PRF/5 xenograft model, sorafenib tosylate dosed at 10 mg/kg inhibited tumor growth by 49%. At 30 mg/kg, sorafenib tosylate produced complete tumor growth inhibition. A dose of 100 mg/kg produced partial tumor regressions in 50% of the mice. In mechanism of action studies, sorafenib inhibited the phosphorylation of both ERK and eIF4E, reduced the microvessel area (assessed by CD34 immunohistochemistry), and induced tumor cell apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling) in PLC/PRF/5 tumor xenografts. These results suggest that the antitumor activity of sorafenib in HCC models may be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival (Raf kinase signaling-dependent and signaling-independent mechanisms).
In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and ...dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 70% confidence interval CI, 0.59-0.88; stratified log-rank P = .09); median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity FcγRIIIa allele had median PFS of 22.3 months vs 9.8 months in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) vs 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) vs 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd vs Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd vs Bd alone. Registered to ClinicalTrials.gov as NCT01478048.
•Elotuzumab, an immunostimulatory antibody, prolongs PFS with no added clinical toxicity when combined with Bd vs Bd alone in RRMM.•Based on results from this phase 2 study, further investigation of elotuzumab with a proteasome inhibitor in RRMM is warranted.
Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit ...cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) - from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 - was completed in just 11 years, with approval being received approximately 5 years after the initiation of the first Phase I trial.
The interactions of isonicotinamide (INA) with seven common solvents (acetic acid, acetonitrile, acetone, chloroform, ethyl acetate, and methanol) have been studied to examine solute–solvent effects ...on the nucleation of INA from these solvents. In a simple model of 1:1 solute–solvent interactions, the strongest INA–solvent interaction is with acetic acid (binding energy, ΔE bind = −64.05 kJ mol–1) and the weakest is with chloroform (ΔE bind = −24.85 kJ mol–1). This arises since acetic acid and INA form a hydrogen-bonding motif containing two moderate strength N–H···O hydrogen bonds, while chloroform and INA have a single weak C–H···O hydrogen bond. Taking acetic acid, chloroform, and methanol, the solvents with the strongest, the weakest, and an intermediate strength INA–solvent binding energy, the solvation of INA was studied to compare it with the 1:1 model. Acetic acid has the strongest binding energy (−872.24 kJ mol–1) and solvation energy (−341.20 kJ mol–1) with chloroform binding energy (−517.72 kJ mol–1) and solvation energy (−199.05 kJ mol–1). Methanol has intermediate binding energy (−814.19 kJ mol–1) and solvation energies (−320.81 kJ mol–1). These results further confirm the recent the findings which indicate that the key trends in solvent–solute interactions can be determined from a simple and efficient 1:1 dimer model and can be used to predict ease of nucleation with stronger binding energies correlating to slower, more difficult nucleation. A limit of this model is revealed by considering alcohol and acid solvents with longer alkyl chains.
Background
Response patterns with immune checkpoint inhibitors may be different from those with chemotherapy. Therefore, assessment of response to immunotherapy with the Response Evaluation Criteria ...in Solid Tumors (RECIST), version 1.1, could result in premature treatment termination. The randomized, open‐label, phase 3 CheckMate 141 trial (NCT02105636), which evaluated nivolumab in recurrent/metastatic squamous cell carcinoma of the head and neck after platinum therapy, allowed treatment beyond first RECIST‐defined progression (TBP) according to protocol‐specified criteria.
Methods
In CheckMate 141, patients with RECIST‐defined progression who had a stable performance status and demonstrated clinical benefit without rapid disease progression were permitted to receive TBP with nivolumab at 3 mg/kg every 2 weeks until further progression, which was defined as an additional ≥10% increase in tumor volume. This post hoc analysis evaluated outcomes for patients who received TBP with nivolumab.
Results
Of 240 patients randomized to nivolumab, 146 experienced RECIST‐defined progression. Sixty‐two of these patients received TBP, and 84 discontinued treatment (no TBP). Among the 60 TBP patients evaluable for response, 15 (25%) had no change in their tumor burden, and 15 (25%) had reductions in target lesion size; 3 patients (5%) had reductions >30%. The median overall survival among TBP patients was 12.7 months (95% confidence interval, 9.7‐14.6 months). No new safety signals were observed with TBP. Exploratory analyses of immune cell biomarkers suggested a potential relationship with initial and TBP responses.
Conclusions
Tumor burden reduction was noted in a proportion of patients who received TBP with nivolumab in CheckMate 141. Additional research is warranted to identify factors predictive of a TBP benefit in this population.
In the randomized, open‐label, phase 3 CheckMate 141 trial in patients with recurrent/metastatic squamous cell carcinoma of the head and neck after platinum therapy, patients with a stable performance status and the potential for clinical benefit were permitted to receive treatment beyond first Response Evaluation Criteria in Solid Tumors–defined progression (TBP) with nivolumab; tumor burden reduction was noted in a proportion of these patients. Additional research is warranted to identify factors predictive of benefit with TBP in this population.
Although a theoretical consideration suggests that point-of-care testing (POCT) might be uniquely vulnerable to error, little information is available on the quality error rate associated with POCT. ...Such information would help inform risk/benefit analyses when one considers the introduction of POCT.
This study included 1 nonacute and 2 acute hospital sites. The 2 acute sites each had a 24-h central laboratory service. POCT was used for a range of tests, including blood gas/electrolytes, urine pregnancy testing, hemoglobin A(1c) (Hb A(1c)), blood glucose, blood ketones, screening for drugs of abuse, and urine dipstick testing. An established Quality Query reporting system was in place to log and investigate all quality errors associated with POCT. We reviewed reports logged over a 14-month period.
Over the reporting period, 225 Quality Query reports were logged against a total of 407 704 POCT tests. Almost two-thirds of reports were logged by clinical users, and the remainder by laboratory staff. The quality error rate ranged from 0% for blood ketone testing to 0.65% for Hb A(1c) testing. Two-thirds of quality errors occurred in the analytical phase of the testing process. These errors were all assessed as having no or minimal adverse impact on patient outcomes; however, the potential adverse impact was graded higher.
The quality error rate for POCT is variable and may be considerably higher than that reported previously for central laboratory testing.
Nanotheranostics constitute a novel drug delivery system approach to improving systemic, brain-targeted delivery of diagnostic imaging agents and pharmacological moieties in one rational carrier ...platform. While there have been notable successes in this field, currently, the clinical translation of such delivery systems for the treatment of neurological disorders has been limited by the inadequacy of correlating in vitro and in vivo data on blood-brain barrier (BBB) permeation and biocompatibility of nanomaterials. This review aims to identify the most contemporary non-invasive approaches for BBB crossing using nanotheranostics as a novel drug delivery strategy and current non-animal-based models for assessing the safety and efficiency of such formulations. This review will also address current and future directions of select in vitro models for reducing the cumbersome and laborious mandate for testing exclusively in animals. It is hoped these non-animal-based modelling approaches will facilitate researchers in optimising promising multifunctional nanocarriers with a view to accelerating clinical testing and authorisation applications. By rational design and appropriate selection of characterised and validated models, ranging from monolayer cell cultures to organ-on-chip microfluidics, promising nanotheranostic particles with modular and rational design can be screened in high-throughput models with robust predictive power. Thus, this article serves to highlight abbreviated research and development possibilities with clinical translational relevance for developing novel nanomaterial-based neuropharmaceuticals for therapy in CNS disorders. By generating predictive data for prospective nanomedicines using validated in vitro models for supporting clinical applications in lieu of requiring extensive use of in vivo animal models that have notable limitations, it is hoped that there will be a burgeoning in the nanotherapy of CNS disorders by virtue of accelerated lead identification through screening, optimisation through rational design for brain-targeted delivery across the BBB and clinical testing and approval using fewer animals. Additionally, by using models with tissue of human origin, reproducible therapeutically relevant nanomedicine delivery and individualised therapy can be realised.
The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK ...signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
While resistance to anticoagulant rodenticides is known to occur in many European populations of Norway rat and house mouse, to-date no data is available on the occurrence in Ireland of such ...resistance. No genetic evidence for the occurrence of resistance was found in 65 Norway rat samples analysed, indicative of an absence, or low prevalence, of resistance in rats in at least the Eastern region of the island of Ireland. The presence of two of the most commonly found amino acid substitutions Leu128Ser and Tyr139Cys associated with house mouse resistance to anticoagulant rodenticides was confirmed. The occurrence of two such mutations is indicative of the occurrence of resistance to anticoagulant rodenticides in house mice in the Eastern region of the island of Ireland.
PDF
