Current Medicinal Chemistry - Volume 27, Issue 29, 2020

Background: Biliary Tract Cancers (BTC) are rare malignancies with a poor prognosis. There are many challenges encountered in treating these patients in daily practice as well as in clinical, translational and basic research. Objective: This review summarises the most relevant challenges in clinical and translational research in BTCs and suggests potential solutions towards an improvement in quality of life and outcomes of patients diagnosed with such malignancies. Findings: The main challenge is the low number of patients with BTCs, complicated by the aggressive natural behaviour of cancer and the lack of funding sources for research. In addition, the clinical characteristics of these patients and the specific cancer-related complications challenge clinical research and clinical trial recruitment. It is worth highlighting that BTCs are a group of different malignancies (cholangiocarcinoma, gallbladder cancer and ampullary cancer) rather than a unique homogeneous disease. These subgroups differ not only in molecular aspects, but also in clinical and demographic characteristics. In addition, tailored imaging and quality of life assessment are required to tackle some of the issues specific to BTCs. Finally, difficulties in tissue acquisition both in terms of biopsy size and inclusion of sufficient tumour within the samples, may adversely impact translational and basic research. Conclusion: Increasing awareness among patients and clinicians regarding BTC and the need for further research and treatment development may address some of the main challenges in BTC research. International collaboration is mandatory to progress the field.

Sarcomas are tumours of mesenchymal origin, which can arise in bone or soft tissues. They are rare but frequently quite aggressive and with a poor outcome. New approaches are needed to characterise these tumours and their resistance mechanisms to current therapies, responsible for tumour recurrence and treatment failure. This review is focused on the potential of three-dimensional (3D) in vitro models, including multicellular tumour spheroids (MCTS) and organoids, and the latest data about their utility for the study on important properties for tumour development. The use of spheroids as a particularly valuable alternative for compound high throughput screening (HTS) in different areas of cancer biology is also discussed, which enables the identification of new therapeutic opportunities in commonly resistant tumours.

Hepatocellular carcinoma (HCC) is a frequent and increasing cause of cancerrelated deaths worldwide. Reversing this trend is complicated by the varied aetiological factors leading to liver cirrhosis resulting in molecular genetic and clinical heterogeneity, combined with frequent presentation at advanced stage. Large-scale genomic studies have identified alterations in key signalling pathways for HCC development and progression, but these findings have not yet directly influenced patient management in the clinical setting. Despite these translational challenges, a small number of anti-angiogenic systemic therapy agents have succeeded in recent randomized trials enriching the repertoire of available treatments for advanced HCC. In addition, the early promise of immune checkpoint inhibition is now on the cusp of delivering changes to standard systemic therapy algorithms. This review focuses on recent translational and clinical developments that have advanced current practice and explores the challenges encountered in attempting to improve the outcomes and experience of patients diagnosed with advanced HCC.

Thyroid cancer is the most common endocrine malignancy and it accounts for 1% of all newly diagnosed tumors. Approximately 10% of patients with differentiated thyroid carcinomas (DTC) and 30% with medullary thyroid carcinoma (MTC) could not be cured with locoregional treatment and could develop metastatic disease. In addition, one of the most aggressive solid tumors can arise from the thyroid gland, the anaplastic thyroid carcinoma, with a median overall survival of less than 6 months. Currently, only four drugs are approved for the treatment of DTC and MTC and several unmet needs are focusing the scientific discussions, including the resistant setting, the off-target side effects that may reduce the efficacy and the molecular knowledge-based combinations. In this review, we aimed to discuss the current molecular landscape and treatment of thyroid cancers, and the ongoing clinical and translational research lines focusing on new drugs and drug combinations to improve the inhibition of driver mutations, such as BRAF and RET, and how systemic therapies that improved outcomes of other cancer types, like immunotherapy and peptide receptor radionuclide therapy, may play a role in the future management of advanced thyroid cancers.

Neuroendocrine tumours (NETs) represent a range of neoplasms that may arise from any (neuro)endocrine cell situated in any part of the human body. As any other rare diseases, NETs face several difficulties in relation to research. This review will describe some of the main challenges and proposed solutions faced by researchers with expertise in rare malignancies. Some of the most common challenges in clinical and translational research are enumerated in this review, covering aspects from clinical, translational and basic research. NETs being a heterogeneous group of diseases and a limited sample size of clinical and translational research projects are the main challenges. Challenges with NETs lay over the disparities between healthcare models to tackle rare diseases. NETs add an extra layer of complexity due to a numerous group of different entities. Prospective real-world data trials are an opportunity for rare cancers with the revolution of electronic health technologies. This review explores potential solutions to these challenges that could be useful not only to the NET community but also to other rare tumours researchers.

Prothymosin alpha (ProTα) is a highly acidic polypeptide, ubiquitously expressed in almost all mammalian cells and tissues and consisting of 109 amino acids in humans. ProTα is known to act both, intracellularly, as an anti-apoptotic and proliferation mediator, and extracellularly, as a biologic response modifier mediating immune responses similar to molecules termed as “alarmins”. Antibodies and immunochemical techniques for ProTα have played a leading role in the investigation of the biological role of ProTα, several aspects of which still remain unknown and contributed to unraveling the diagnostic and therapeutic potential of the polypeptide. This review deals with the so far reported antibodies along with the related immunodetection methodology for ProTα (immunoassays as well as immunohistochemical, immunocytological, immunoblotting, and immunoprecipitation techniques) and its application to biological samples of interest (tissue extracts and sections, cells, cell lysates and cell culture supernatants, body fluids), in health and disease states. In this context, literature information is critically discussed, and some concluding remarks are presented.

Background: The development of modern nanomedicine greatly depends on the involvement of novel materials as drug delivery system. In order to maximize the therapeutic effects of drugs and minimize their side effects, a number of natural or synthetic materials have been widely investigated for drug delivery. Among these materials, biomimetic self-assembling peptides (SAPs) have received more attention in recent years. Considering the rapidly growing number of SAPs designed for drug delivery, a summary of how SAPs-based drug delivery systems were designed, would be beneficial. Method: We outlined research works on different SAPs that have been investigated as carriers for different drugs, focusing on the design of SAPs nanomaterials and how they were used for drug delivery in different strategies. Results: Based on the principle rules of chemical complementarity and structural compatibility, SAPs such as ionic self-complementary peptide, peptide amphiphile and surfactant-like peptide could be designed. Determined by the features of peptide materials and the drugs to be delivered, different strategies such as hydrogel embedding, hydrophobic interaction, electrostatic interaction, covalent conjugation or the combination of them could be employed to fabricate SAPs-drug complex, which could achieve slow release, targeted or environment-responsive delivery of drugs. Furthermore, some SAPs could also be combined with other types of materials for drug delivery, or even act as drug by themselves. Conclusion: Various types of SAPs have been designed and used for drug delivery following various strategies, suggesting that SAPs as a category of versatile nanomaterials have promising potential in the field of nanomedicine.

Background: Antioxidants are multifaceted molecules playing a crucial role in several cellular functions. There is by now a well-established knowledge about their involvement in numerous processes associated with aging, including vascular damage, neurodegenerative diseases and cancer. An emerging area of application has been lately identified for these compounds in relation to the recent findings indicating their ability to affect biofilm formation by some microbial pathogens, including Staphylococcus aureus, Streptococcus mutans, and Pseudomonas aeruginosa. Methods: A structured search of bibliographic databases for peer-reviewed research literature was performed using a focused review question. The quality of retrieved papers was appraised using standard tools. Results: One hundred sixty-five papers extracted from pubmed database and published in the last fifteen years were included in this review focused on the assessment of the antimicrobial and antibiofilm activity of antioxidant compounds, including vitamins, flavonoids, non-flavonoid polyphenols, and antioxidant polymers. Mechanisms of action of some important antioxidant compounds, especially for vitamin C and phenolic acids, were identified. Conclusions: The findings of this review confirm the potential benefits of the use of natural antioxidants as antimicrobial/antibiofilm compounds. Generally, gram-positive bacteria were found to be more sensitive to antioxidants than gram-negatives. Antioxidant polymeric systems have also been developed mainly derived from functionalization of polysaccharides with antioxidant molecules. The application of such systems in clinics may permit to overcome some issues related to the systemic delivery of antioxidants, such as poor absorption, loss of bioactivity, and limited half-life. However, investigations focused on the study of antibiofilm activity of antioxidant polymers are still very limited in number and therefore they are strongly encouraged in order to lay the foundations for application of antioxidant polymers in treatment of biofilm-based infections.