The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with ...advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and -2 mutations which are each present in around 10–20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.
In the environment, cells from microorganisms can communicate to each other through the secretion of signal molecules, so-called autoinducers, which accumulate in the medium as the population density ...grows. When the concentration of these molecules reaches a threshold, different genes are induced or repressed, and processes such as sporulation, pathogenesis or symbiosis are initiated. These mechanisms, known as quorum sensing (QS), were first discovered in bacteria, and more recently have been identified in fungi. The model eukaryote organism for this kind of studies is the dimorphic pathogenic yeast Candida albicans. However, QS mechanisms have been described in a variety of fungi with clinical or biotechnological interest. Hence, the study of these mechanisms may be useful to prevent fungal infections, and interesting for its exploitation in industrial biotechnology.
•Biliary tract cancers (BTCs) are poor-prognosis malignancies.•Precision medicine in BTC is currently focused on IDH/FGFR, benefiting a minority.•New strategies for improving outcomes in patients ...with BTC are required.•DDR-deficiency (pre-existent/induced) could be central to new treatment strategies.
Biliary tract cancers (BTCs), including cholangiocarcinoma, gallbladder cancer and ampullary cancers, are poor-prognosis malignancies. Most patients are diagnosed with advanced disease, when treatment is limited to palliative chemotherapy. First line chemotherapy is usually administered in the form of cisplatin and gemcitabine. Benefit from second line chemotherapy is still to be confirmed. Even though new systemic treatment targets have been recognised, especially in patients with intrahepatic cholangiocarcinoma (e.g. IDH and FGFR), there is an urgent need for novel treatment strategies. Genomic profiling of BTC is progressively becoming a reality which allows a better understanding of their biology and potential new targets. This review provides an insight into DNA Damage Repair (DDR) mechanisms, prevalence of DDR-deficient tumours in BTC, and the potential role of DDR in cancer development. Some form of DDR deficiency is expected to be present in around 25% of patients with BTC, and this knowledge could be exploited to potentially increase response to currently-available treatment strategies (chemotherapy, radiotherapy or immunotherapy). For patients with DDR-proficient tumours, drug inhibition of DDR could be instituted.
Quorum sensing (QS) is a sophisticated cell-to-cell signalling mechanism that allows the coordination of important processes in microbial populations. The AI-1 and AI-2 autoinducer systems are among ...the best characterized bacterial QS systems at the genetic level.
In this study, we present data derived from in silico screening of QS proteins from bacterial genomes available in public databases. Sequence analyses allowed identifying candidate sequences of known QS systems that were used to build phylogenetic trees. Eight categories were established according to the number of genes from the two major QS systems present in each genome, revealing a correlation with specific taxa, lifestyles or metabolic traits. Many species had incomplete QS systems, encoding the receptor protein but not the biosynthesis of the quorum sensing molecule (QSMs). Reconstruction of the evolutionary history of the LuxR family and prediction of the 3D structure of the ancestral protein suggested their monomeric configuration in the absence of the signal molecule and the presence of a cavity for its binding.
Here we correlate the taxonomic affiliation and lifestyle of bacteria from different genera with the QS systems encoded in their genomes. Moreover, we present the first ancestral reconstruction of the LuxR QS receptors, providing further insight in their evolutionary history.
(QS) is a sophisticated cell to cell signaling mechanism mediated by small diffusible molecules called "autoinducers." This phenomenon is well studied in bacteria, where different QS systems are ...described that differ between Gram-negative and Gram-positive bacteria. However, a common system to these groups was discovered, the autoinducer 2. QS has implications in biofilm formation, where the application of metagenomic techniques to study these phenomena may be useful to understand the communication networks established by the different components of the community, and to discover new targets for microbial control. Here we present an
screening of QS proteins in all publicly available biofilm metagenomes from the JGI database. We performed sequence, conserved motifs, phylogenetic, and three-dimensional structure analyses of the candidates, resulting in an effective strategy to search QS proteins in metagenomes sequences. The number of QS proteins present in each sample, and its phylogenetic affiliation, was clearly related to the bacterial diversity and the origin of the biofilm. The samples isolated from natural habitats presented clear differences with those from artificial habitats. Interesting findings have been made in the abundance of LuxR-like proteins finding an unbalanced ratio between the synthases and the receptor proteins in Bacteroidetes bacteria, pointing out the existence of "cheaters" in this group. Moreover, we have shown the presence of the LuxI/R QS system in bacteria from the Nitrospira taxonomic group. Finally, some undescribed proteins from the HdtS family have been found in Gamma-proteobacteria.
Next generation sequencing (NGS) enables a more comprehensive analysis of bacterial diversity from complex environmental samples. NGS data can be analysed using a variety of workflows. We test ...several simple and complex workflows, including frequently used as well as recently published tools, and report on their respective accuracy and efficiency under various conditions covering different sequence lengths, number of sequences and real world experimental data from rhizobacterial populations of glyphosate-tolerant maize treated or untreated with two different herbicides representative of differential diversity studies.
Alignment and distance calculations affect OTU estimations, and multiple sequence alignment exerts a major impact on the computational time needed. Generally speaking, most of the analyses produced consistent results that may be used to assess differential diversity changes, however, dataset characteristics dictate which workflow should be preferred in each case.
When estimating bacterial diversity, ESPRIT as well as the web-based workflow, RDP pyrosequencing pipeline, produced good results in all circumstances, however, its computational requirements can make method-combination workflows more attractive, depending on sequence variability, number and length.
With the aim of improving patient selection for phase I trials, we previously performed a retrospective analysis of 212 phase I oncology patients where we were able to develop a prognostic score ...predicting overall survival (OS). This prospective study was performed to test the validity of the prognostic score.
On the basis of our retrospective multivariate analysis, three factors were associated with poor survival (albumin < 35 g/L, lactate dehydrogenase LDH > upper limit of normal ULN, and > two sites of metastases). We integrated these into a prognostic score ranging from 0 to 3 and analyzed this score in a prospectively selected cohort of 78 patients enrolled onto phase I trials.
All patients had progressive disease before study entry. The median age was 56 years (range, 18 to 79 years). After a median follow-up time of 27.3 weeks, patients with a prognostic score of 0 to 1 (n = 43) had superior OS (33.0 weeks; 95% CI, 24 to 42 weeks) compared with patients with a score of 2 to 3 (n = 35; 15.7 weeks; 95% CI, 11 to 21 weeks). Our multivariate analysis confirmed that our prognostic score was an independent marker for OS, with a hazard ratio of 1.4 (95% CI, 1.02 to 1.9; P = .036).
This is the first prospective analysis confirming that a prognostic score based on objective markers, including albumin less than 35 g/L, LDH more than ULN, and more than two sites of metastasis, is a helpful tool in the process of patient selection for phase I trial entry.
The hepatocyte growth factor/c-MET axis is implicated in tumor cell proliferation, survival, and angiogenesis. ARQ 197 is an oral, selective, non-adenosine triphosphate competitive c-MET inhibitor. A ...phase I trial of ARQ 197 was conducted to assess safety, tolerability, and target inhibition, including intratumoral c-MET signaling, apoptosis, and angiogenesis.
Patients with solid tumors amenable to pharmacokinetic and pharmacodynamic studies using serial biopsies, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and circulating endothelial cell (CEC) and circulating tumor cell (CTC) enumeration were enrolled.
Fifty-one patients received ARQ 197 at 100 to 400 mg twice per day. ARQ 197 was well tolerated, with the most common toxicities being grade 1 to 2 fatigue, nausea, and vomiting. Dose-limiting toxicities included grade 3 fatigue (200 mg twice per day; n = 1); grade 3 mucositis, palmar-plantar erythrodysesthesia, and hypokalemia (400 mg twice per day; n = 1); and grade 3 to 4 febrile neutropenia (400 mg twice per day, n = 2; 360 mg twice per day, n = 1). The recommended phase II dose was 360 mg twice per day. ARQ 197 systemic exposure was dose dependent and supported twice per day oral dosing. ARQ 197 decreased phosphorylated c-MET, total c-MET, and phosphorylated focal adhesion kinase and increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) staining in tumor biopsies (n = 15). CECs decreased in 25 (58.1%) of 43 patients, but no significant changes in DCE-MRI parameters were observed after ARQ 197 treatment. Of 15 patients with detectable CTCs, eight (53.3%) had ≥ 30% decline in CTCs after treatment. Stable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), ≥ 4 months was observed in 14 patients, with minor regressions in gastric and Merkel cell cancers.
ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non-small-cell lung cancer, is ongoing.
Ovarian cancer remains one of the leading causes of cancer deaths. Thus, new biomarkers predictive of response to the standard paclitaxel-carboplatin treatment are needed to improve chemotherapy ...strategies. MicroRNAs have the potential to modify drug outcomes. Based on this, we have demonstrated in this study that patients with a high expression of the miR-200 family show low levels of β-tubulin class III in ovarian carcinoma. In addition, we have established the clinical relevance of these microRNAs for ovarian cancer patients' treatment response and survival. In a well-characterized series of 72 ovarian carcinomas, the expressions of miR-141, miR-200a, miR-200b, miR-200c, and miR-429 were quantified by quantitative reverse transcription-PCR, and the protein content of β-tubulin isotypes I, II, and III was determined by immunohistochemistry. The relationship between these microRNAs, β-tubulin expression, response to paclitaxel-based treatment, progression-free survival (PFS) and overall survival was determined. While isotype I had constant high levels, protein expression of β-tubulins II and III was mutually exclusive. Low tumoral miR-200 expression was significantly associated with high β-tubulin III protein content (P values range, 0.047-<0.0001), and patients without complete response (CR) had lower miR-200c levels than patients with CR (hazard ratio (HR)=1.43, 95% confidence interval (CI)=1.02-1.99, P=0.037, multivariate analysis). Additionally, low miR-200 family expression had a trend toward poor PFS (HR>2.0, P values 0.051, 0.054, and 0.079 for miR-200c, miR-141, and miR-429 respectively, multivariate analysis). In conclusion, miR-200 family members affect the final β-tubulin III protein content of ovarian carcinomas. Furthermore, these microRNAs might constitute the biomarkers of response to paclitaxel-based treatments and relapse/progression of advanced stage ovarian carcinoma patients.
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