Current Clinical Pipeline Research Articles

Direct identification of ALK and ROS1 fusions in non-small cell lung cancer from hematoxylin and eosin-stained slides using deep learning algorithms

Anaplastic lymphoma kinase (ALK) and ROS oncogene 1 (ROS1) gene fusions are well-established key players in non-small cell lung cancer (NSCLC). Although their frequency is relatively low, their detection is important for patient care and guides therapeutic decisions. The accepted methods used for their detection are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assay, as well as DNA and RNA-based sequencing methodologies. These assays are expensive, time-consuming, and require technical expertise and specialized equipment as well as biological specimens that are not always available. Here we present an alternative detection method using a computer vision deep learning approach. An advanced convolutional neural network (CNN) was used to generate classifier models to detect ALK and ROS1-fusions directly from scanned hematoxylin and eosin (H&E) whole slide images prepared from NSCLC tumors of patients. A two-step training approach was applied, with an initial unsupervised training step performed on a pan-cancer sample cohort followed by a semi-supervised fine-tuning step, which supported the development of a classifier with performances equal to those accepted for diagnostic tests. Validation of the ALK/ROS1 classifier on a cohort of 72 lung cancer cases who underwent ALK and ROS1-fusion testing at the pathology department at Sheba Medical Center displayed sensitivities of 100% for both genes (six ALK-positive and two ROS1-positive cases) and specificities of 100% and 98.6% respectively for ALK and ROS1, with only one false-positive result for ROS1-alteration. These results demonstrate the potential advantages that machine learning solutions may have in the molecular pathology domain, by allowing fast, standardized, accurate, and robust biomarker detection overcoming many limitations encountered when using current techniques. The integration of such novel solutions into the routine pathology workflow can support and improve the current clinical pipeline.

Insights about clinically approved and Preclinically investigated marine natural products

Abstract Since the early research efforts focusing on bioactive marine substances such as spongouridine, from the marine sponge Cryptotethya crypta, marine natural products (MNPs) have arisen as a robust and sustainable supplier for bioactive drug leads. Marine natural products present definite, unprecedented structural diversifications and varieties of interesting biomedical potentialities with novel mechanisms of action. Until today, eight clinically approved marine natural products-based drugs by two worldwide medical organizations (including U.S. FDA, European Medicines Agency (EMEA)), have been developed for the treatment of different forms of carcinoma, pain, Alzheimer's disease and other current medical challenges. Recent clinical trial analysis disclosed that the current clinical pipeline contains more than twenty listed drug candidates in different clinical trials in phase III, II, or I. Herein, we present recent insights centered to clinically approved and preclinically investigated marine bioactive compounds, as well as sampling techniques, extraction & identification tools, classification of MNPs, some reported biological activities, and challenges faced during MNPs development.

Analysis of the clinical landscape for genetically-modified cellular immunotherapies highlights the need for optimized and consistent manufacturing processes

Background & Aim Genetically-modified cellular immunotherapies, including chimeric antigen receptor T-cells (CAR-T) and natural killer cells (CAR-NK), have generated significant clinical and commercial outcomes due to their unparalleled response rates against cancer. However, the development and manufacture of these advanced therapies face a number of translational bottlenecks that must be addressed to ensure long-term commercial viability. Methods, Results & Conclusion A comprehensive analysis of the current clinical pipeline of genetically-modified cellular immunotherapies will be presented to demonstrate the implications of current manufacturing bottlenecks. This analysis will give a deeper understanding into future manufacturing process needs by highlighting clinical pipeline trends such as, autologous v. allogeneic or immune cell type utilized for therapy. The cost and variability associated with these personalized advanced therapies presents a critical manufacturing and translational challenge. The current clinical pipeline in this field shows the imminent need for manufacturing optimization. However, current manufacturing protocols vary widely, including media used, cytokine concentrations, and starting cell densities. This study will highlight the importance of determining critical manufacturing process parameters. The patient-specific nature of the CAR-T therapies currently on the market is a particular challenge for the field, therefore as much of the process must be controlled in order to decrease overall process variability.

Novel antibiotics effective against gram-positive and -negative multi-resistant bacteria with limited resistance.

Antibiotics are a medical wonder, but an increasing frequency of resistance among most human pathogens is rendering them ineffective. If this trend continues, the consequences for public health and for the general community could be catastrophic. The current clinical pipeline, however, is very limited and is dominated by derivatives of established classes, the “me too” compounds. Here, we have exploited our recent identification of a bacterial toxin to transform it into antibiotics active on multidrug-resistant (MDR) gram-positive and -negative bacterial pathogens. We generated a new family of peptidomimetics—cyclic heptapseudopeptides—inspired from a natural bacterial peptide. Out of the 4 peptides studied, 2 are effective against methicillin-resistant Staphylococcus aureus (MRSA) in mild and severe sepsis mouse models without exhibiting toxicity on human erythrocytes and kidney cells, zebrafish embryos, and mice. These new compounds are safe at their active doses and above, without nephrotoxicity. Efficacy was also demonstrated against Pseudomonas aeruginosa and MRSA in a mouse skin infection model. Importantly, these compounds did not result in resistance after serial passages for 2 weeks and 4 or 6 days’ exposure in mice. Activity of heptapseudopeptides was explained by the ability of unnatural amino acids to strengthen dynamic association with bacterial lipid bilayers and to induce membrane permeability, leading to bacterial death. Based on structure determination, we showed that cationic domains surrounded by an extended hydrophobic core could improve bactericidal activity. Because 2 peptide analogs, Pep 16 and Pep19, are effective against both MRSA and P. aeruginosa in severe sepsis and skin infection models, respectively, we believe that these peptidomimetics are promising lead candidates for drug development. We have identified potential therapeutic agents that can provide alternative treatments against antimicrobial resistance. Because the compounds are potential leads for therapeutic development, the next step is to start phase I clinical trials.

The current state and future directions of RNAi-based therapeutics.

The RNA interference (RNAi) pathway regulates mRNA stability and translation in nearly all human cells. Small double-stranded RNA molecules can efficiently trigger RNAi silencing of specific genes, but their therapeutic use has faced numerous challenges involving safety and potency. However, August 2018 marked a new era for the field, with the US Food and Drug Administration approving patisiran, the first RNAi-based drug. In this Review, we discuss key advances in the design and development of RNAi drugs leading up to this landmark achievement, the state of the current clinical pipeline and prospects for future advances, including novel RNAi pathway agents utilizing mechanisms beyond post-translational RNAi silencing.

Can Some Marine-Derived Fungal Metabolites Become Actual Anticancer Agents?

Marine fungi are known to produce structurally unique secondary metabolites, and more than 1000 marine fungal-derived metabolites have already been reported. Despite the absence of marine fungal-derived metabolites in the current clinical pipeline, dozens of them have been classified as potential chemotherapy candidates because of their anticancer activity. Over the last decade, several comprehensive reviews have covered the potential anticancer activity of marine fungal-derived metabolites. However, these reviews consider the term “cytotoxicity” to be synonymous with “anticancer agent”, which is not actually true. Indeed, a cytotoxic compound is by definition a poisonous compound. To become a potential anticancer agent, a cytotoxic compound must at least display (i) selectivity between normal and cancer cells (ii) activity against multidrug-resistant (MDR) cancer cells; and (iii) a preferentially non-apoptotic cell death mechanism, as it is now well known that a high proportion of cancer cells that resist chemotherapy are in fact apoptosis-resistant cancer cells against which pro-apoptotic drugs have more than limited efficacy. The present review thus focuses on the cytotoxic marine fungal-derived metabolites whose ability to kill cancer cells has been reported in the literature. Particular attention is paid to the compounds that kill cancer cells through non-apoptotic cell death mechanisms.