Systemic therapy of hepatocellular carcinoma: reality and prospects

This article discusses the results of clinical trials and the perspectives for perioperative systemic therapy for liver cancer, as well as the effectiveness of combination with locoregional methods. Special attention is paid to first and second line hepatocellular carcinoma therapy, as already approved in the Russian Federation (multikinase inhibitors, monoclonal antibodies to the vascular endothelial growth factor receptor, checkpoint inhibitors), as well as ongoing clinical trials. Promising combinations of immunotherapy with multikinase and (or) angiogenic inhibitors, potential predictors of the effectiveness of immunotherapy for hepatocellular carcinoma, as well as the features of therapy after orthotopic liver transplantation and against the background of non-compensated liver cirrhosis, are considered.

Antiangiogenic Effect of Alkaloids

Alkaloids are among the natural phytochemicals contained in functional foods and nutraceuticals and have been suggested for the prevention and/or management of oxidative stress and inflammation-mediated diseases. In this review, we aimed to describe the effects of alkaloids in angiogenesis, the process playing a crucial role in tumor growth and invasion, whereby new vessels form. Antiangiogenic compounds including herbal ingredients, nonherbal alkaloids, and microRNAs can be used for the control and treatment of cancers. Several lines of evidence indicate that alkaloid-rich plants have several interesting features that effectively inhibit angiogenesis. In this review, we present valuable data on commonly used alkaloid substances as potential angiogenic inhibitors. Different herbal and nonherbal ingredients, introduced as antiangiogenesis agents, and their role in angiogenesis-dependent diseases are reviewed. Studies indicate that angiogenesis suppression is exerted through several mechanisms; however, further investigations are required to elucidate their precise molecular and cellular mechanisms, as well as potential side effects.

Discovery of Small Molecules that Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies

Angiogenesis is defined as the formation of new blood vessels and is a key phenomenon manifested in a host of cancers during which tyrosine kinases play a crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in cancer angiogenesis, which warrants the urgency of discovering new anti-angiogenic inhibitors that target the signalling pathways. To obtain this objective, a structure-based pharmacophore model was built from the drug target VEGFR-2 (PDB code: 4AG8), complexed with axitinib and was subsequently validated and employed as a 3D query to retrieve the candidate compounds with the key inhibitory features. The model was escalated to molecular docking studies resulting in seven candidate compounds. The molecular docking studies revealed that the seven compounds displayed a higher dock score than the reference-cocrystallised compound. The GROningen MAchine for Chemical Simulations (GROMACS) package guided molecular dynamics (MD) results determined their binding mode and affirmed stable root mean square deviation. Furthermore, these compounds have preserved their key interactions with the residues Glu885, Glu917, Cys919 and Asp1046. The obtained findings deem that the seven compounds could act as novel anti-angiogenic inhibitors and may further assist as the prototype in designing and developing new inhibitors.

Angiogenesis in Pancreatic Cancer: Pre-Clinical and Clinical Studies

Angiogenesis is a crucial event in tumor development and progression, occurring by different mechanisms and it is driven by pro- and anti-angiogenic molecules. Pancreatic cancer vascularization is characterized by a high microvascular density, impaired microvessel integrity and poor perfused vessels with heterogeneous distribution. In this review article, after a brief introduction on pancreatic cancer classification and on angiogenesis mechanisms involved in its progression, the pre-clinical and clinical trials conducted in pancreatic cancer treatment using anti-angiogenic inhibitors will be described. Finally, we will discuss the anti-angiogenic therapy paradox between the advantage to abolish vessel supply to block tumor growth and the disadvantage due to reduction of drug delivery at the same time. The purpose is to identify new anti-angiogenic molecules that may enhance treatment regimen.

Optimizing the delivery of combination therapy for tumors: A mathematical model

We present in this paper a new mathematical model for the scheduling of angiogenic inhibitors in combination with a chemotherapeutic agent for a tumor. Our model takes into account the process of angiogenesis and the quality of the vasculature discriminating between stable blood vessels and unstable blood vessels. We characterize theoretically the optimal controls on drug distribution to minimize the number of cancer cells at the end of the treatment in a free horizon time problem with restrictions on the total amount of drug doses. Finally, we solve the optimal control problem by using numerical simulations, obtaining as a result that, despite the number of the tumor cells decrease with anti-angiogenic treatment, the best results are reached at the end of the chemotherapy treatment.