Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies.

Brain cancer is a formidable challenge for drug development, and drugs derived from many cutting-edge technologies are being tested in clinical trials. We manually characterized 981 clinical trials on brain tumors that were registered in ClinicalTrials.gov from 2010 to 2020. We identified 582 unique therapeutic entities targeting 581 unique drug targets and 557 unique treatment combinations involving drugs. We performed the classification of both the drugs and drug targets based on pharmacological and structural classifications. Our analysis demonstrates a large diversity of agents and targets. Currently, we identified 32 different pharmacological directions for therapies that are based on 42 structural classes of agents. Our analysis shows that kinase inhibitors, chemotherapeutic agents, and cancer vaccines are the three most common classes of agents identified in trials. Agents in clinical trials demonstrated uneven distribution in combination approaches; chemotherapy agents, proteasome inhibitors, and immune modulators frequently appeared in combinations, whereas kinase inhibitors, modified immune effector cells did not as was shown by combination networks and descriptive statistics. This analysis provides an extensive overview of the drug discovery field in brain cancer, shifts that have been happening in recent years, and challenges that are likely to come. SIGNIFICANCE STATEMENT: This review provides comprehensive quantitative analysis and discussion of the brain cancer drug discovery field, including classification of drug, targets, and therapies.

Extracellular vesicles in cancer nanomedicine.

To date, a lot of nanotechnological optitions are available for targeted drug delivery. Extracellular vesicles (EVs) are membrane structures that cells use for storage, transport, communication, and signaling. Recent research has focused on EVs as natural nanoparticles for drug delivery. This review sheds light on the application of EVs in cancer therapy, such as targeted chemotherapy, gene therapy, and vaccine development. Aspects of biogenesis, isolation, targeting, and loading of EVs are discussed in detail.

Feasibility of Targeting Glioblastoma Stem Cells: From Concept to Clinical Trials.

OBJECTIVE: Glioblastoma is a highly aggressive and invasive brain and Central Nervous System (CNS) tumor. Current treatment options do not prolong overall survival significantly because the disease is highly prone to relapse. Therefore, research to find new therapies is of paramount importance. It has been discovered that glioblastomas contain a population of cells with stem-like properties and that these cells are may be responsible for tumor recurrence. METHODS: A review of relevant papers and clinical trials in the field was conducted. A PubMed search with related keywords was used to gather the data. For example, "glioblastoma stem cells AND WNT signaling" is an example used to find information on clinical trials using the database ClinicalTrials.gov. RESULTS: Cancer stem cell research has several fundamental issues and uncertainties that should be taken into consideration. Theoretically, a number of treatment options that target glioblastoma stem cells are available for patients. However, only a few of them have obtained promising results in clinical trials. Several strategies are still under investigation. CONCLUSION: The majority of treatments to target cancer stem cells have failed during clinical trials. Taking into account a number of biases in the field and the number of unsuccessful investigations, the application of the cancer stem cells concept is questionable in clinical settings, at least with respect to glioblastoma.

Evaluation of free and total fluoride concentration in mouthwashes via measurement with ion-selective electrode.

BACKGROUND: The aim of this study was to compare free fluoride concentration and total fluoride concentration in mouthwashes. METHODS: Fluorine-containing mouthwashes from various companies and manufacturers (Colgate Total Plax Classic Mint®, Colgate-Palmolive, New York, USA; Colgate Total Plax Gentle Mint®, Colgate-Palmolive, New York, USA; Colgate Total Plax Fresh Mint®, Colgate-Palmolive, New York, USA; Oral B Advantage®, Procter&Gamble, Cincinnati, USA; Reach Fresh Mint®, Johnson&Johnson, New Brunswick, USA; Foramen®, Laboratorios Foramen, Guarnizo, Spain; Lacalut Sensitive®, Dr. THEISS, Homburg, Germany; Sensodyne®, GlaxoSmithKline, London, UK; Vesna F®, Vita, Saint Petersburg, Russia; Lacalut Fresh®, Dr. THEISS, Homburg, Germany) were selected as study objects. Fluoride measurements were carried out using the fluoride selective electrode. RESULTS: Free fluoride:total fluoride ratio was more than 80% for six samples (Colgate Total Plax Gentle Mint® - 88%, Colgate Total Plax Fresh Mint® - 99%, Oral B Advantage® - 92%, Reach Fresh Mint® - 92 and 89% for the mouthwash of another batch, Lacalut Sensitive® - 94%) and less than 63% for three samples (Colgate Total Plax Classic Mint® - 56%, Foramen® - 62%, Vesna F® - 61%). Two samples had more than 70% and less than 80% of unbound fluoride, respectively (Sensodyne® - 77%, another batch of Oral B Advantage® mouthwash - 74%). Rinse containing sodium monofluorophosphate (Na2PO3F) (Vesna F®) had more than 50% of free fluoride, while the rinse containing amine fluoride (AmF) (Lacalut Sensitive®) had 94%. The difference in the free fluoride:total fluoride ratio can be explained by binding of fluoride ions by components contained in mouthwashes, such as coloring agents and polymeric compounds. The lowest concentration of free fluoride ions (0.000093 mol/L) was observed for aluminum fluoride (AlF3) rinse (Lacalut Fresh®), while the total fluoride amount was not determined due to possible generation of strong fluoride complexes. This implies that fluoride ions will not be uptaken by tooth tissue and may even be washed away from it, compromising the efficacy of mouthwashes. CONCLUSIONS: The differences in free fluoride: total fluoride ratio between analyzed mouthwashes reveal a need to develop a method for evaluation of free fluorides in mouthwashes for proper updating of national and international guidelines.

The Role of Melanin to Dissociate Oxygen from Water to Treat Retinopathy of Prematurity.

BACKGROUND: Retinopathy of Prematurity (ROP) is a potentially blinding disorder that commonly afflicts premature infants who are born prior to 31weeks of gestation or with a body weight less than 1250 grams (about 2.75 pounds). Another risk factor is excessive oxygen in incubators, which can lead to blindness. A compounding factor is that survival rates for premature infants are rising with concomitantly more cases of ROP. We have reported an unsuspected intrinsic property of melanin to dissociate water. This capability can be considered an alternative treatment option for adult and neonatal diseases. It is known that exogenous surfactant administration suppresses bronchopulmonary dysplasia and consequent death, randomized, controlled trials with various respiratory interventions did not show any significant reductions in morbidity and mortality rates. During a descriptive study about the three leading causes of blindness in the world, the ability of melanin to transform light energy into chemical energy through the dissociation of water molecule was unraveled. Initially, during 2 or 3 years; we tried to link together our findings with the widely accepted metabolic pathways already described in molecular pathway databases, which have been developed to collect and organize the current knowledge on metabolism scattered across a multitude of scientific evidence. OBSERVATIONS: The current report demonstrates the main problems that afflict premature babies with an emphasis on the growth of abnormal vessels in the retina, the explanation for which is unknown until date. We also reported a case of a baby who suffered digestive and respiratory problems with a brain haemorrhage that was successfully treated by laser photocoagulation. We hypothesise that most likely this effect was due to the melanin level and melanin itself produces oxygen via dissociating with water molecules. CONCLUSION: We postulate that the intrinsic effect of melanin may easily convert visible and invisible light into chemical energy via a water dissociation reaction similar to the one in plant's chlorophyll, and markedly elevated with diagnosis and treatment of the complications related to premature babies.

How Cancer Cells Resist Chemotherapy: Design and Development of Drugs Targeting Protein-Protein Interactions.

BACKGROUND: Resistance toward chemotherapeutics is one of the main obstacles on the way to effective cancer treatment. Personalization of chemotherapy could improve clinical outcome. However, despite preclinical significance, most of the potential markers have failed to reach clinical practice partially due to the inability of numerous studies to estimate the marker's impact on resistance properly. OBJECTIVE: The analysis of drug resistance mechanisms to chemotherapy in cancer cells, and the proposal of study design to identify bona fide markers. METHODS: A review of relevant papers in the field. A PubMed search with relevant keywords was used to gather the data. An example of a search request: drug resistance AND cancer AND paclitaxel. RESULTS: We have described a number of drug resistance mechanisms to various chemotherapeutics, as well as markers to underlie the phenomenon. We also proposed a model of a rational-designed study, which could be useful in determining the most promising potential biomarkers. CONCLUSION: Taking into account the most reasonable biomarkers should dramatically improve clinical outcome by choosing the suitable treatment regimens. However, determining the leading biomarkers, as well as validating of the model, is a work for further investigations.