Promising investigational drug candidates in phase I and phase II clinical trials for mesothelioma

Introduction: Malignant mesothelioma is a rare and lethal malignancy primarily affecting the pleura and peritoneum. Mesothelioma incidence is expected to increase worldwide and current treatments remain ineffective, leading to poor prognosis. Within this article potential targets to improve the quality of life of the patients and assessment of further avenues for research are discussed. Areas covered: This review highlights emerging therapies currently under investigation for malignant mesothelioma with a specific focus on phase I and phase II clinical trials. Three main areas are discussed: immunotherapy (immune checkpoint blockade and cancer vaccines, among others), multitargeted therapy (such as targeting pro-angiogenic genes) and gene therapy (such as suicide gene therapy). For each, clinical trials are described to detail the current or past investigations at phase I and II. Expert opinion: The approach of applying existing treatments from other cancers does not show significant benefit, with the most promising outcome being an increase in survival of 2.7 months following combination of chemotherapy with bevacizumab. It is our opinion that the hypoxic microenvironment, the role of the stroma, and the metabolic status of mesothelioma should all be assessed and characterised to aid in the development of new treatments to improve patient outcomes

Immunotherapy advances for mesothelioma treatment.

INTRODUCTION Mesothelioma is a rare type of cancer that is strongly tied to asbestos exposure. Despite application of different modalities such as chemotherapy, radiotherapy and surgery, patient prognosis remains very poor and therapies are ineffective. Much research currently focuses on the application of novel approaches such as immunotherapy towards this disease. Areas covered: The types, stages and aetiology of mesothelioma are detailed, followed by a discussion of the current treatment options such as radiotherapy, surgery, and chemotherapy. A description of innate and adaptive immunity and the principles and justification of immunotherapy is also included. Clinical trials for different immunotherapeutic modalities are described, and lastly the article closes with an expert commentary and five-year view, the former of which is summarised below. Expert commentary: Current efforts for novel mesothelioma therapies have been limited by attempting to apply treatments from other cancers, an approach which is not based on a solid understanding of mesothelioma biology. In our view, the influence of the hostile, hypoxic microenvironment and the gene expression and metabolic changes that resultantly occur should be characterised to improve therapies. Lastly, clinical trials should focus on overall survival rather than surrogate endpoints to avoid bias and inaccurate reflections of treatment effects

What can independent research for mesothelioma achieve to treat this orphan disease?

Introduction: Malignant pleural mesothelioma (MPM) is a rare neoplasm with a poor prognosis, as current therapies are ineffective. Despite the increased understanding of the molecular biology of mesothelioma, there is still a lack of drugs that dramatically enhance patient survival. Area Covered: This review discusses recent and complete clinical trials supported by the NIH, other U.S. Federal agencies, universities and organizations found on clinicaltrials.gov. Firstly, chemotherapy-based trials are described, followed by immunotherapy and multitargeted therapy. Then we introduce drug repositioning and the use of drug docking as tools to find new interesting molecules. Finally, we highlight potential molecular pathways that may play a role in mesothelioma biology and therapy. Expert Opinion: Numerous biases are present in the clinical trials due to a restricted number of cases, inappropriate endpoints and inaccurate stratification of patients which delay the finding of a treatment for MPM. The most crucial issue of independent research for MPM is the lack of more substantive funding to translate these findings to the clinical setting. However, this approach is not necessarily scientific given the low mutational load of mesothelioma relative to other cancers, and therefore patients need a more solid rationale to have a good chance of successful treatmen

Myelodysplastic syndromes: advantages of a combined cytogenetic and molecular diagnostic workup

In this study we present a new diagnostic workup for the myelodysplastic syndromes (MDS) including FISH, aCGH, and somatic mutation assays in addition to the conventional cytogenetics (CC). We analyzed 61 patients by CC, FISH for chromosome 5, 7, 8 and PDGFR rearrangements, aCGH, and PCR for ASXL1, EZH2, TP53, TET2, RUNX1, DNMT3A, SF3B1 somatic mutations. Moreover, we quantified WT1 and RPS14 gene expression levels, in order to find their possible adjunctive value and their possible clinical impact. CC analysis showed 32% of patients with at least one aberration. FISH analysis detected chromosomal aberrations in 24% of patients and recovered 5 cases (13.5%) at normal karyotype (two 5q- syndromes, one del(7) case, two cases with PDGFR rearrangement). The aGCH detected 10 "new" unbalanced cases in respect of the CC, including one with alteration of the ETV6 gene. After mutational analysis, 33 patients (54%) presented at least one mutation and represented the only marker of clonality in 36% of all patients. The statistical analysis confirmed the prognostic role of CC either on overall or on progression-free-survival. In addition, deletions detected by aCGH and WT1 over-expression negatively conditioned survival. In conclusion, our work showed that 1) the addition of FISH (at least for chr. 5 and 7) can improve the definition of the risk score; 2) mutational analysis, especially for the TP53 and SF3B1, could better define the type of MDS and represent a "clinical warning"; 3) the aCGH use could be probably applied to selected cases (with suboptimal response or failure)

p53 modeling as a route to mesothelioma patients stratification and novel therapeutic identification

Background Malignant pleural mesothelioma (MPM) is an orphan disease that is difficult to treat using traditional chemotherapy, an approach which has been effective in other types of cancer. Most chemotherapeutics cause DNA damage leading to cell death. Recent discoveries have highlighted a potential role for the p53 tumor suppressor in this disease. Given the pivotal role of p53 in the DNA damage response, here we investigated the predictive power of the p53 interactome model for MPM patients’ stratification. Methods We used bioinformatics approaches including omics type analysis of data from MPM cells and from MPM patients in order to predict which pathways are crucial for patients’ survival. Analysis of the PKT206 model of the p53 network was validated by microarrays from the Mero-14 MPM cell line and RNA-seq data from 71 MPM patients, whilst statistical analysis was used to identify the deregulated pathways and predict therapeutic schemes by linking the affected pathway with the patients’ clinical state. Results In silico simulations demonstrated successful predictions ranging from 52 to 85% depending on the drug, algorithm or sample used for validation. Clinical outcomes of individual patients stratified in three groups and simulation comparisons identified 30 genes that correlated with survival. In patients carrying wild-type p53 either treated or not treated with chemotherapy, FEN1 and MMP2 exhibited the highest inverse correlation, whereas in untreated patients bearing mutated p53, SIAH1 negatively correlated with survival. Numerous repositioned and experimental drugs targeting FEN1 and MMP2 were identified and selected drugs tested. Epinephrine and myricetin, which target FEN1, have shown cytotoxic effect on Mero-14 cells whereas marimastat and batimastat, which target MMP2 demonstrated a modest but significant inhibitory effect on MPM cell migration. Finally, 8 genes displayed correlation with disease stage, which may have diagnostic implications. Conclusions Clinical decisions related to MPM personalized therapy based on individual patients’ genetic profile and previous chemotherapeutic treatment could be reached using computational tools and the predictions reported in this study upon further testing in animal models

Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines

Malignant pleural mesothelioma (MPM) is a cancer of the pleural cavity resistant to chemotherapy. The identification of novel therapeutic targets is needed to improve its poor prognosis. Following a review of literature and a screening of specimens we found that platelet-derived growth factor receptor beta (PDGFRB) is over-expressed, but not somatically mutated, in MPM tissues. We aimed to ascertain whether PDGFRB is a MPM-cancer driver gene. The approaches employed included the use of gene silencing and the administration of small molecules, such as crenolanib and imatinib (PDGFR inhibitors) on MPM cell lines (IstMes2, Mero-14, Mero-25). Met5A cells were used as non-malignant mesothelial cell line. PDGFRB-silencing caused a decrease in the proliferation rate, and a reduced colony formation capacity, as well as an increase of the share of cells in sub-G1 and in G2 phase, and increased apoptotic rate of MPM cell lines. Loss of migration ability was also observed. Similar, or even further enhanced, results were obtained with crenolanib. Imatinib showed the least effective activity on the phenotype. In conclusion, our study highlights PDGFRB as target with a clear role in MPM tumorigenesis and provided a rationale to explore further the efficacy of crenolanib in MPM patients, with promising results

Individuazione di un profilo d'espressione di microRNA in pazienti con Mielofibrosi Primaria (PMF) arruolati all'interno di un protocollo di fase III del farmaco sperimentale INC424 (Ruxolitinib)

La Mielofibrosi Primaria (PMF), è stata classificata nel 2008 dalla World Health Organization (WHO) come neoplasia mieloproliferativa BCR-ABL1- negative (MPNs). Le neoplasie mieloproliferative croniche includono anche la policitemia vera (PV) e la trombocitemia essenziale (ET), malattie caratterizzate dall’alterazione della cellula staminale ematopoietica che porta ad un’eccessiva proliferazione clonale. Studi familiari e la recente scoperta della mutazione V617F del gene JAK2, che si riscontra nel 90% delle PV e nel 30-50% delle ET e delle PMF, suggerisce una predisposizione genetica alle MPNs. La PMF è caratterizzata da un incremento prevalente della serie mieloide e megacariocitaria; nella fase conclamata della malattia tale proliferazione si associa a fibrosi midollare reattiva e ad ematopoiesi extramidollare. Il complesso fenotipo patologico della PMF è anche influenzato da aspetti genetici sconosciuti e da fattori epigenetici. Esistono delle molecole biologiche, i microRNA (miRNA), che hanno un ruolo critico nella regolazione dei networks cellulari e sono quindi candidati di rilievo per il coinvolgimento patogenetico in malattie sistemiche come le neoplasie. I miRNA sono piccole molecole di RNA a singolo filamento non codificanti di circa 21-25 nt, che legando la regione 3’UTR di mRNA di geni target, regolano negativamente la loro traduzione e determinano una diminuzione dei livelli finali della proteina. Il progetto di tesi prende in esame pazienti con PMF già diagnosticata, arruolati all’interno di un protocollo clinico/terapeutico per lo studio di fase III (COMFORT-II) di un farmaco sperimentale (INC424 ruxolitinib). Tali pazienti vengono seguiti dall’inizio della terapia e nei successivi mesi fino ad un intervallo temporale di 3 mesi, necessario per verificare una riduzione della splenomegalia associata alla PMF e ad un complessivo miglioramento dei sintomi ad essa associati. INC424 (ruxolitinib) è stato studiato sulla base dei meccanismi patogenetici della PMF con particolare attenzione alla mutazione del gene JAK2. Questo ha permesso di mettere a punto nuovi farmaci, i cui target molecolari fossero più selettivi e che fornissero una risposta ematologica migliore rispetto ai farmaci meno specifici e di utilizzo più generico. Lo scopo del nostro studio è quello di analizzare il profilo d’espressione dei miRNA in pazienti affetti da PMF e sottoposti a terapia farmacologica con Ruxolitinib (anti-JAK2) al fine di identificare un set di miRNA da utilizzare come biomarcatori nello studio del trattamento farmacologico sia all’inizio della terapia stessa che al monitoraggio di 3 mesi. Nella pratica per ogni paziente arruolato è stata condotta inizialmente l’analisi citogenetica classica con cariotipo convenzionale standard, per individuare l’eventuale presenza di anomalie cromosomiche numeriche e strutturali. In seguito, su una coorte opportunamente selezionata è stata eseguita l’analisi High Throughput di 675 miRNA, tramite quantitative Real Time PCR utilizzando i TaqMan Low Density Arrays. L’analisi dei dati, effettuata mediante utilizzo di software statistici e specifici algoritmi, ci ha permesso di individuare un piccolo pannello di miRNA differentemente espressi in tempi diversi durante la terapia. L’identificazione di questi miRNA potrebbe costituire un valido strumento con potenzialità, non solo diagnostiche ma anche prognostiche. Infatti l’individuazione di miRNA specifici deregolati durante il trattamento farmacologico può fornire al clinico un dato essenziale per il monitoraggio del paziente, la valutazione dei segni clinici e l’eventuale presa in considerazione di trattamenti alternativi. Trattandosi di uno studio preliminare, in cui per pochi pazienti sono state generate quantità considerevoli di dati, i risultati ottenuti necessitano di essere ulteriormente validati su una casistica più ampia, con metodiche più facilmente riproducibili ed interpretabili

Spreading of granular suspensions on a solid surface

International audienceWe examine the spreading of a suspension of non-Brownian spheres suspended in a Newtonian liquid on a solid substrate. We show that the spreading dynamics is well described by the classical Cox-Voinov law provided the value of the fluid viscosity that arises in the capillary number of the problem is adjusted to a value that depends on particle size and volume fraction in a nontrivial way. We demonstrate that this behavior is a signature of the ability of the particles to approach the contact line close enough to affect dissipation

Psychosocial implications of disaster on children and pediatric care

Malignant mesothelioma (MMe) is a cancer with poor prognosis and resistance to standard treatments. Recent reports have highlighted the role of the BRCA1 associated protein 1 gene (BAP1) in the development of MMe. In this study, the chemosensitivity of human mesothelioma cell lines carrying BAP1 wild-type (WT), mutant and silenced was analysed. The BAP1 mutant cells were significantly less sensitive than BAP1 WT cell lines to the clinically relevant drug gemcitabine. Silencing of BAP1 significantly increased resistance of MMe cells to gemcitabine. Cell cycle analysis suggested that gemcitabine induced Sub-G1 phase accumulation of the BAP1 WT cells and increased in the S-phase in both BAP1 WT and mutant cells. Analysis of the role of BAP1 in apoptosis suggested that gemcitabine induced early apoptosis in both BAP1 WT and BAP1 mutant cells but with a much higher degree in the WT cells. Effects on the population of cells in late apoptosis, which can mark necrosis and necroptosis, could not be seen in the mutant cells, highlighting the possibility that BAP1 plays a role in several types of cell death. Significantly decreased DNA damage in the form of double-strand breaks was observed in gemcitabine-treated BAP1 mutant cells, compared to BAP1 WT cells under the same conditions. After BAP1 silencing, a significant decrease in DNA damage in the form of double-strand breaks was observed compared to cells transfected with scramble siRNA. Taken together, the results presented in this manuscript shed light on the role of BAP1 in the response of MMe cells to gemcitabine treatment and in particular in the control of the DNA damage response, therefore providing a potential route for more efficient MMe therap

Protocol for open-label randomized clinical trial of intensive surveillance versus standard postoperative follow-up in patients undergoing surgical resection for oesophageal and gastric cancer

Despite recent improvements in oncological and surgical treatment for patients with oesophageal and gastric cancer, 60 per cent of those with locally advanced disease who are treated with curative intent will develop tumour recurrence and die within 3 years of completing treatment. In the absence of robust scientific evidence, national or international guidelines have failed to reach consensus on the optimal surveillance strategy after primary treatment of oesophageal or gastric cancer.The primary research question of the proposed RCT is: does the routine use of a structured follow-up programme with regular radiological and endoscopic investigations improve survival in patients who have had surgical treatment for oesophageal or gastric cancer with curative intent