Claudia Villalobos
Surgery, chemotherapy, and radiotherapy may cease to be the primary choices for combating cancer as scientists worldwide, tirelessly working on various research endeavors, manage to unravel and curb the mechanisms of malignant cell dissemination to sites other than the original tumor (metastasis). These studies aim to generate new knowledge leading to future, more effective, and safer detection methods and treatments.
Such is the case of a group of scientists from the Instituto Politécnico Nacional (IPN), led by Dr. Marlet Themis Martínez Archundia from the Escuela Superior de Medicina (ESM), which focuses its efforts on exploring new uses for molecules or already approved drugs (drug repurposing) by institutions such as the Federal Drug Administration (FDA) that represent viable treatment possibilities against various neoplasms and also inhibit metastatic processes.
With the support of the Consejo Nacional de Humanidades, Ciencias y Tecnologías (Conahcyt), the research team, including ESM researcher Gema Lizbeth Ramírez Salinas and graduate students Melvin Nadir Rosalez and Eridani Fuentes Aguilar, employed bioinformatics techniques to analyze around two thousand compounds and conduct molecular docking studies to predict their affinity with a protein involved in metastasis called Tetraspanin CD-151.
Following this analysis, the researchers conducted filtering and selected 850 compounds for simulations, from which they expect to choose the three or five with the highest potential to initiate experimental studies.
Dr. Martínez Archundia pointed out that the interest in investigating the Tetraspanin CD-151 membrane protein arose because, according to some evidence, it is a protein that could be a candidate to prevent metastasis in breast cancer and glioblastoma (the most frequent, aggressive, and lethal type of brain cancer).
"Despite experimental studies reporting its effect on both types of cancer, we are limited by the fact that this membrane protein does not have a crystallized structure. Therefore, we are working on predicting a three-dimensional model of the protein for the respective molecular docking studies," explained the scientist affiliated with level II of the National System of Researchers (SNII).
Worldwide, 90 percent of cancer deaths are attributed to metastasis. Therefore, unraveling its mechanisms is a top priority.
The polytechnic professor explained that at the molecular level, Tetraspanin CD-151 interacts with an adhesion molecule called Integrin alpha 3 beta 1. The research group aims to prevent the interaction of both proteins, as this union leads to a signaling cascade that causes metastasis.
The site where the interaction of both molecules occurs is known as the QRD motif. At the cellular level, this motif is located in the second extracellular loop of the protein. One of the research objectives is to target this site, conduct molecular docking studies with the proposed drugs, and select the most promising ones that could inhibit metastatic processes," warned the School of Medicine scientist.
The frontier science project authorized by Conahcyt for three years (CF-2023-g-1454) will consist of three stages. The first will involve the bioinformatic study of Tetraspanin CD-151 and the in silico evaluation of potential drugs.
"The goodness of bioinformatics is that even without having the 3D model of the protein yet, it is possible to search for possible drugs that can bind to it, which allows us to advance more quickly in the research," emphasized Dr. Marlet Martínez.
Behind the achievements so far are several years of postdoctoral study by Martínez Archundia at the ESM and one in France, as well as the collaboration of the working team and the guidance of the pioneer scientist in bioinformatics at the IPN, José Correa Basurto.
The second phase will be in vivo and will focus on testing potential drugs on cell lines, as well as choosing the best-performing one to verify the hypothesis that it can indeed represent a viable alternative as a novel pharmacological target. This stage will be carried out in collaboration with Dr. Martha Cecilia Rosales Hernández from the Escuela de Medicina.
Additionally, in the third stage, in collaboration with Dr. Miriam Azucena Hernández Zamora, a researcher at the Escuela Nacional de Ciencias Biológicas (ENCB), toxicological studies will be conducted on fish and microalgae, aiming to ensure the safety of the drugs.
It is a type of tumor that reaches the central nervous system and develops in the spinal cord or brain with invasive growth and poor prognosis.
The greatest challenge in brain cancer is controlling the migration of cancer cells, as this phenomenon generates secondary tumors. The polytechnic expert considered it important to investigate migration mechanisms to generate the basic knowledge that supports new treatments.
In the case of glioblastoma, the survival rate is very low due to the high migration of malignant cells. Unlike neoplasms in other organs or parts of the body, the brain cannot be extracted, making it one of the most challenging cancers to treat. "Hence, contributions that could be made regarding new treatments would represent a significant scientific advance," noted the specialist.
She also reported that, as part of the research, migration assays will be conducted to assess how much the compounds contribute to slowing the proliferation of cancer cells to other organs, thus having the possibility of increasing the survival rate.
Even if the experiments are successful, Dr. Martínez Archundia emphasized that, although these drugs are already approved by the FDA, there would not be authorization to test them on patients. However, by publishing the results in scientific journals, the groundwork can be laid to obtain approval and conduct clinical trials later.
While it is true that scientific results are long-term, it is a fact that bioinformatics has played an important role in obtaining results in recent years, as molecular-level simulation allows for the shortening of experimentation times.
On the other hand, it is important to highlight that, although advances often occur slowly due to the complexity of research, multidisciplinary collaboration contributes to achieving goals more quickly. In this case, in addition to having the support of specialists from the ESM, Dr. Marlet Martínez Archundia also has the support of Dr. Alfonso Dueñas González and Dr. Helena Solleiro Villavicencio, scientists from the National Cancer Institute (Incan) and the Autonomous University of Mexico City (UACM), respectively, who contribute to the generation of frontier knowledge aimed at combating these high-incidence neoplasms (breast cancer) and low-survival-rate (glioblastoma).
Triple-negative metastatic breast cancer is highly aggressive and has a poor prognosis. Although it is associated with low response rates and short survival, chemotherapy is the only treatment option. IPN researchers plan to test the drugs on cell lines of this neoplasm with the aim of halting metastasis.
Selección Gaceta Politécnica #168. (November 30th, 2023). IPN Imagen Institucional: Read the full magazine in Spanish here
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