Genomic Analyses across Six Cancer Types Identify Basal-like Breast Cancer as a Unique Molecular Entity

To improve our understanding of the biological relationships among different types of cancer, we have characterized variation in gene expression patterns in a set of 1,707 samples representing 6 human cancer types (breast, ovarian, brain, colorectal, lung adenocarcinoma and squamous cell lung cancer). In the unified dataset, breast tumors of the Basal-like subtype were found to represent a unique molecular entity as any other cancer type, including the rest of breast tumors, while showing striking similarities with squamous cell lung cancers. Moreover, gene signatures tracking various cancer- and stromal-related biological processes such as proliferation, hypoxia and immune activation were found expressed similarly in different proportions of tumors across the various cancer types. These data suggest that clinical trials focusing on tumors with common profiles and/or biomarker expression rather than their tissue of origin are warranted with a special focus on Basal-like breast cancer and squamous cell lung carcinoma

Syncope Time Frames for Adverse Events after Emergency Department Presentation: An Individual Patient Data Meta-Analysis

Background and Objectives: Knowledge of the incidence and time frames of the adverse events of patients presenting syncope at the ED is essential for developing effective management strategies. The aim of the present study was to perform a meta-analysis of the incidence and time frames of adverse events of syncope patients. Materials and Methods: We combined individual patients’ data from prospective observational studies including adult patients who presented syncope at the ED. We assessed the pooled rate of adverse events at 24 h, 72 h, 7–10 days, 1 month and 1 year after ED evaluation. Results: We included nine studies that enrolled 12,269 patients. The mean age varied between 53 and 73 years, with 42% to 57% females. The pooled rate of adverse events was 5.1% (95% CI 3.4% to 7.7%) at 24 h, 7.0% (95% CI 4.9% to 9.9%) at 72 h, 8.4% (95% CI 6.2% to 11.3%) at 7–10 days, 10.3% (95% CI 7.8% to 13.3%) at 1 month and 21.3% (95% CI 15.8% to 28.0%) at 1 year. The pooled death rate was 0.2% (95% CI 0.1% to 0.5%) at 24 h, 0.3% (95% CI 0.1% to 0.7%) at 72 h, 0.5% (95% CI 0.3% to 0.9%) at 7–10 days, 1% (95% CI 0.6% to 1.7%) at 1 month and 5.9% (95% CI 4.5% to 7.7%) at 1 year. The most common adverse event was arrhythmia, for which its rate was 3.1% (95% CI 2.0% to 4.9%) at 24 h, 4.8% (95% CI 3.5% to 6.7%) at 72 h, 5.8% (95% CI 4.2% to 7.9%) at 7–10 days, 6.9% (95% CI 5.3% to 9.1%) at 1 month and 9.9% (95% CI 5.5% to 17) at 1 year. Ventricular arrhythmia was rare. Conclusions: The risk of death or life-threatening adverse event is rare in patients presenting syncope at the ED. The most common adverse events are brady and supraventricular arrhythmias, which occur during the first 3 days. Prolonged ECG monitoring in the ED in a short stay unit with ECG monitoring facilities may, therefore, be beneficial

Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer

Purpose Transforming growth factor-beta (TGF-β) signaling plays a key role in epithelial-mesenchymal transition (EMT) of tumors, including malignant glioma. Small molecule inhibitors (SMI) blocking TGF-β signaling reverse EMT and arrest tumor progression. Several SMIs were developed, but currently only LY2157299 monohydrate (galunisertib) was advanced to clinical investigation. Design The first-in-human dose study had three parts (Part A, dose escalation, n = 39; Part B, safety combination with lomustine, n = 26; Part C, relative bioavailability study, n = 14). Results A preclinical pharmacokinetic/pharmacodynamic (PK/PD) model predicted a therapeutic window up to 300 mg/day and was confirmed in Part A after continuous PK/PD. PK was not affected by co-medications such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors. Changes in pSMAD2 levels in peripheral blood mononuclear cells were associated with exposure indicating target-related pharmacological activity of galunisertib. Twelve (12/79; 15 %) patients with refractory/relapsed malignant glioma had durable stable disease (SD) for 6 or more cycles, partial responses (PR), or complete responses (CR). These patients with clinical benefit had high plasma baseline levels of MDC/CCL22 and low protein expression of pSMAD2 in their tumors. Of the 5 patients with IDH1/2 mutation, 4 patients had a clinical benefit as defined by CR/PR and SD ≥6 cycles. Galunisertib had a favorable toxicity profile and no cardiac adverse events. Conclusion Based on the PK, PD, and biomarker evaluations, the intermittent administration of galunisertib at 300 mg/day is safe for future clinical investigation

A framework for genomic biomarker actionability and its use in clinical decision making

The increasing scope and availability of genetic testing options for patients suffering from cancer has raised questions about how to use results of molecular diagnostics to inform patient care. For some biomarkers (e.g. BRAF mutations in melanoma), standards exist that outline treatments for individuals harboring aberrations in the biomarker; however for the vast majority of genomic abnormalities, few guidelines exist. Clinical decision making and the therapeutic approach for a patient with a given cancer characterized by aberrations in different genes may be aided by the use of a biomarker actionability framework that provides levels of evidence regarding whether and how a molecular abnormality can be considered a therapeutically relevant biomarker. A gene may be considered theoretically actionable if it has a basis of actionability, such that clinically available drugs can target a gene product that drives the cancer or is differentially expressed in tumor versus normal elements. Herein, we discuss a possible framework for developing guidelines for actionability, as they relate to genomically-based cancer therapeutics

Relative bioavailability of three formulations of galunisertib administered as monotherapy in patients with advanced or metastatic cancer

Galunisertib (LY2157299 monohydrate), an inhibitor of the transforming growth factor β (TGFβ) pathway, is currently under investigation in several clinical trials involving multiple tumor types. The primary objective of this study was to assess relative bioavailability of two new galunisertib formulations developed using the roller compaction (RC) dry-milled (RCD) and RC slurry-milled (RCS) processes, compared with the existing formulation developed using the high-sheer wet granulation (HSWG) process. The secondary objective was to report the safety profile after a single dose of the three formulations. Patients with advanced or metastatic cancer were enrolled into this single-center, 3-period, 6-sequence crossover study. Patients were assigned sequentially to 1 of 6 sequences in blocks of 6 to ensure that all 6 sequences have the same number of completers. A patient entering a sequence received a different galunisertib formulation as a single 150 mg dose orally during each of the 3 periods. Each period was separated from the next by a washout interval of at least 48 hours. Pharmacokinetic (PK) parameters, including area under curve (AUC) and C, were computed using standard non-compartmentalized methods of analysis. For comparison of exposures between formulations, log-transformed AUC and C values were analyzed using a linear mixed-effects model. Safety assessments included adverse event monitoring, physical examinations, and laboratory tests. Of the 14 patients who entered and completed the study, 13 patients were included in the final statistical analysis. AUC(0-t), AUC(0-48 h), and AUC(0-∞) for the RC formulations and the HSWG formulation were similar. C was reduced by approximately 22% and t was longer by at least 1.00 h for the RCD and RCS formulations compared with the HSWG formulation. The RC formulations demonstrated a safety profile after a single dose similar to the HSWG formulation. In this relative bioavailability study comparing galunisertib formulations after a single dose, RCD and RCS formulations had similar exposure and safety profile compared with the HSWG formulation

First-in-Human Phase I Study of MP0250, a First-in-Class DARPin Drug Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors.

PURPOSE: A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. PATIENTS AND METHODS: A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. RESULTS: In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. CONCLUSION: MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies

Genomic Analyses across Six Cancer Types Identify Basal-like Breast Cancer as a Unique Molecular Entity

To improve our understanding of the biological relationships among different types of cancer, we have characterized variation in gene expression patterns in a set of 1,707 samples representing 6 human cancer types (breast, ovarian, brain, colorectal, lung adenocarcinoma and squamous cell lung cancer). In the unified dataset, breast tumors of the Basal-like subtype were found to represent a unique molecular entity as any other cancer type, including the rest of breast tumors, while showing striking similarities with squamous cell lung cancers. Moreover, gene signatures tracking various cancer- and stromal-related biological processes such as proliferation, hypoxia and immune activation were found expressed similarly in different proportions of tumors across the various cancer types. These data suggest that clinical trials focusing on tumors with common profiles and/or biomarker expression rather than their tissue of origin are warranted with a special focus on Basal-like breast cancer and squamous cell lung carcinoma

Unraveling the antiviral activity of plitidepsin against SARS-CoV-2 by subcellular and morphological analysis

The pandemic caused by the new coronavirus SARS-CoV-2 has made evident the need for broad-spectrum, efficient antiviral treatments to combat emerging and re-emerging viruses. Plitidepsin is an antitumor agent of marine origin that has also shown a potent pre-clinical efficacy against SARS-CoV-2. Plitidepsin targets the host protein eEF1A (eukaryotic translation elongation factor 1 alpha) and affects viral infection at an early, post-entry step. Because electron microscopy is a valuable tool to study virus-cell interactions and the mechanism of action of antiviral drugs, in this work we have used transmission electron microscopy (TEM) to evaluate the effects of plitidepsin in SARS-CoV-2 infection in cultured Vero E6 cells 24 and 48h post-infection. In the absence of plitidepsin, TEM morphological analysis showed double-membrane vesicles (DMVs), organelles that support coronavirus genome replication, single-membrane vesicles with viral particles, large vacuoles with groups of viruses and numerous extracellular virions attached to the plasma membrane. When treated with plitidepsin, no viral structures were found in SARS-CoV-2-infected Vero E6 cells. Immunogold detection of SARS-CoV-2 nucleocapsid (N) protein and double-stranded RNA (dsRNA) provided clear signals in cells infected in the absence of plitidepsin, but complete absence in cells infected and treated with plitidepsin. The present study shows that plitidepsin blocks the biogenesis of viral replication organelles and the morphogenesis of virus progeny. Electron microscopy morphological analysis coupled to immunogold labeling of SARS-CoV-2 products offers a unique approach to understand how antivirals such as plitidepsin work.This research was funded by Pharma Mar, which commercializes Aplidin/Plitidepsin. The authors also acknowledge the crowdfunding initiative #Yomecorono (https://www.yomecorono.com) and the CBIG consortium supported by Grifols. N.I–U. is supported by grant PID2020-117145RB-I00 from the Spanish Ministry of Science and Innovation. C.R. is supported by grant RTI2018-094445-B-I00 (MCI/AEI/FEDER, UE) from the Spanish Ministry of Science and Innovation.Peer reviewe