They study an antifascin drug to treat colorectal cancer

Given this, research is essential to offer solutions to this condition worldwide. Aware of this fact, the IMIB Molecular Pathology and Pharmacogenetics Research group at the Santa Lucía University General Hospital in Cartagena has launched the 'Preclinical study with a new antifascin drug for the treatment of colorectal cancer'. In his work of researching medicine strategies to apply the appropriate medication to each patient, he has included the study of fascin, since it is found in large quantities in a subtype of colorectal cancer with a poor prognosis, called serrated adenocarcinoma. Fascin is a key protein in the organization of the cytoskeleton (the scaffolding of the cell), since it participates in the formation of structures that allow cell movement.

Due to the fundamental role of fascin in the advancement of tumor cells, this protein becomes a target for blocking the movement capacity of tumors that contain it in large quantities, reducing the risk of developing metastasis. “Fascin appears in high quantities in colorectal cancer, but also in others with a poor prognosis such as triple-negative breast cancer, so the strategy of blocking this protein could be useful in several types of cancer,” indicates the coordinator of Research, Ginés Luengo Gil.

In this context, strategies aimed at inhibiting fascin with chemical compounds can constitute an effective pharmacological therapy in numerous types of cancer. Given this reality, the project arises as a result of years of basic and translational research carried out by this team and collaborators such as the group led by Dr. Horacio Pérez Sánchez at UCAM and Dr. Irene Luque at the University of Granada, in addition to Dr. José Manuel Villalgordo Soto, CEO of the Murcian company Eurofins Villapharma Research. «After screening with a library of 10,000 compounds, we discovered that both the antidepressant imipramine and the antiretroviral raltegravir show the ability to block fascin. In fact, some of the compounds with antifascin activity, such as imipramine, are already in clinical trials, one of these clinical trials being led by the research group. From this screening of compounds we have found very promising results with another of them, a compound that shares similar binding properties to imipramine,” adds the coordinator.

Dr. Pablo Conesa Zamora also participates in this project as co-PI, and the researchers doctors José García Solano, Ana María Hurtado López, Silvia Montoro García, Begoña Alburquerque González and Ana Belén Arroyo Rodríguez; and as collaborators Fátima Postigo Corrales, Ana Albaladejo González and Daniel Torres Moreno.

The process

This research group has been characterizing this protein in the context of colorectal cancer for many years, managing to go from very basic aspects of knowledge to non-commercial clinical trials, developing patents and licensing them to companies. «Our experience in the field and the cohesion of the inter and multidisciplinary team allow us to obtain high performance with this 'screening' strategy and 'in silico', 'in vitro' and 'in vivo' studies, to finally reach the trials. clinical,” says Gil.

The compound they want to test, synthesized by the Murcian company Eurofins Villapharma, was proposed by Dr. Horacio Pérez as a potential antifascin agent, because it has binding properties similar to imipramine, a repositioning drug with which they are currently developing the clinical trial. . «In our group we have already demonstrated that this compound has fascination binding capacity and antitumor properties 'in vitro' thanks to collaborations with the Center for Magnetic Resonance (CERM) in Florence, the Leibniz Institute of Molecular Pharmacology in Berlin and with the Institute of Genetics and Molecular and Cellular Biology (IGBMC) of Strasbourg,” he adds. With this approach, they seek to find a compound with less effect at the central nervous system level and greater antitumor effect.

Thanks to this research process, they now have enough synthetic compound to begin developing the two preclinical objectives of the proof of concept: on the one hand, to demonstrate that the compound is safe in mice by escalating the dose to concentrations similar to those of the imipramine and, on the other hand, demonstrate that it has an antitumor effect on colorectal cancer lines that express fascinan.

During the study, mice will be exposed to the chemical through daily oral administration for 28 consecutive days. Toxicological parameters will be monitored, such as changes in body weight, food and water consumption, clinical signs of toxicity, effects on organs and tissues, and other relevant parameters. At the end of the exposure period, a detailed evaluation of the organs and tissues will be performed to determine any toxic effects, so this study will provide critical information on the short-term toxicity of the compound, which may help establish the reference dose. and safe levels of exposure in humans. Therefore, the data obtained in this study may be useful in risk assessment and in making regulatory decisions related to the use and exposure of the compound.

On the other hand, the study of the antitumor effect 'in vivo' includes a test group and a control group with monitoring of growth or regression of tumor size at least twice a week, measuring tumor size and a weekly measurement by luminescence imaging.

Currently, 'mass balance' studies have already been carried out: absorption, distribution, metabolism and elimination (ADME). The objective of these studies is to understand and characterize the pharmacokinetic (PK) profile of the investigational medication, knowing how the body processes the drug. «We want to start testing in the murine model in the coming weeks. We hope that the compound is safe in the animal model and, given that we have demonstrated an antitumor effect 'in vitro', we also hope that it will have an antitumor effect 'in vivo', although we cannot say much more at the moment,” concludes Gil.