Basic research: fundamental in the fight against cancer

As part of World Cancer Day, which is celebrated every 4 February, we tell you about the work being carried out by research groups at the Buenos Aires Institute for Research in Biomedicine (IBioBA, CONICET-Max Planck) to provide knowledge about its mechanisms and potential drug or treatment developments.

Who does not feel fear when hearing the word “cancer” from the mouth of a loved one. According to estimates by the World Health Organization (WHO), cancer is between the first and second leading cause of death in people under 70 years of age in most countries. According to the latest report from the Global Cancer Observatory (GLOBOCAN), a total of 19.3 million new cases of cancer and almost 10 million deaths are expected worldwide in 2020. With these numbers, the risk always feels close.

This is why the work of the science and technology system is essential. Although advances in medicine have led to improvements in diagnosis and treatment, the key to understanding and effectively combating this disease lies in basic science: to understand its mechanisms of formation, spread, resistance to therapies and recurrence (when it reappears). Its long-term impact is invaluable: basic science provides the basis for developing more effective therapies and prevention strategies.

Every cell in the body, even during periods of rest or sleep, is active. This activity requires nutrients that are converted into energy and molecules essential for cellular function, known as metabolism. However, in this process, toxic reactive compounds are also generated and can threaten cells and thus health, triggering pathological processes such as cancer. Among these reactive compounds is formaldehyde, which is what Lucas Pontel and his team are working on in the “Cancer Metabolism” laboratory.

In a study published in the journal Nature Communications, Pontel, together with PhD students Carla Umansky and Agustín Morellato, revealed that formaldehyde, in addition to damaging genetic information, attacks cells’ antioxidant defenses. This discovery is particularly relevant in exploring the origin of some human diseases caused by hereditary defects in factors that protect against formaldehyde. It also suggests a direct link between the consumption of foods rich in antioxidant compounds and the possible prevention of tumor development. “The research helps us to understand how our cells suddenly start to divide uncontrollably, losing their identity and giving rise to a tumor process. In this way we will be able to propose interventions and lifestyle changes to help us reduce the incidence of cancer”, says Pontel.

The cellular plasticity area of IBioBA seeks to understand the molecular mechanisms involved in the cellular transformation that gives rise to tumor cells. Cellular plasticity contributes to the heterogeneous cell population of tumors and, consequently, to recurrence after treatment and disease dissemination. The “Tumor stem cells and cellular plasticity” group, led by Carolina Perez-Castro, studies the role of key genes in sustaining tumors, and how to modulate them to slow their growth and ability to metastasize.

The team works with two cancer models: in glioblastoma -a highly aggressive brain tumor for which there is no effective treatment- they were pioneers, together with colleagues at FLENI, in finding that the KANSL2 protein is involved in the formation of these tumors. On the other hand, they study lung cancer -particularly adenocarcinoma- one of the most frequently diagnosed cancers, characterized by high mortality, metastatic potential and recurrence. In this line, together with the Favaloro Foundation University Hospital, last year they published a paper in the journal Biology Direct -whose first authors were the PhD students Melina Muñoz-Bernart and Nicolás Budnik- in which they described that the AHCYL1 protein would have a protective role in this type of tumor, negatively modulating the formation of plastic cells and inhibiting tumor formation. In addition, they observed that AHCYL1 could be explored as a potential biomarker of good prognosis in patients with lung adenocarcinoma.

“Both types of tumors grow silently, i.e. they develop without generating symptoms in their early stages and are often diagnosed once the disease is already advanced. It is therefore essential to understand how deregulated genes in these cancers affect tumor composition and cellular plasticity, and to search for new molecular markers that allow early diagnosis”, explains Perez-Castro. It should be noted that the group is currently studying the mechanisms that these genes use to, in the near future, be able to find an effective therapy through their regulation.

Eduardo Arzt’s “Tumors of the neuroendocrine system” group focuses on understanding the molecular mechanisms that generate this broad group of tumors. They study the role of the RSUME gene – a protein identified by the group in 2007 in a paper published in the journal Cell – in pituitary tumor processes (in which they found that it interacts with and regulates an important protein in the cell cycle, PTTG securin), and in Von Hipppel Lindau (VHL) tumors, such as Renal Clear Cell Carcinomas (RCC).

In a paper published last year in the journal Clinical Genitourinary Cancer, PhD student David Gonilski-Pacin, along with other members of the lab, analyzed data from kidney cancer patients and found that RSUME is overexpressed in tumor tissue, and that this is associated with unfavorable clinic-pathological features and reduced survival. In this way, they found that RSUME is an important factor to be taken into account in the clinic to assess the aggressiveness of renal tumors.

The group also focuses on understanding the mechanisms of cellular senescence, which not only occurs in aging cells, but also in cancer cells, for example, producing resistance to therapy, by mechanisms that the group is currently investigating. “Our group’s research aims to discover new mechanisms and molecules involved that could be targets for new therapies in the future”, says Arzt.

Knowledge gained through basic science not only reveals the fundamental secrets of cancer, but also opens the door to new therapeutic opportunities. Understanding specific molecular processes allows the design of more precise and targeted drugs, minimizing side effects and increasing the efficacy of treatments. The development of a new drug is an arduous task that in successful cases usually takes 10-15 years.

Ricardo Biondi heads the group “Chemical biology of regulatory mechanisms” and in his lab he studies protein kinases, a group of enzymes that are part of the complex mechanisms that cells have to communicate and transmit messages between them. When kinases lose their proper regulation it can lead to diseases such as cancer, diabetes or neurological diseases. In June 2023, they published a paper that was on the cover of the journal Science Signaling in which its first authors -already PhDs- Mariana Sacerdoti and Lissy Gross, together with collaborators, described a peculiarity of the structure of PDK1, a kinase involved in the development of cancer.

In the research, they were able to see that PDK1 has more than one structure – or three-dimensional shape – and that these forms of PDK1 can be modulated with small molecules. In fact, the paper details that a small molecule stabilizes a form of PDK1 that ‘switches off’ one of its functions: the one associated with cancer.

“This is interesting because most of the medicines we take every day, such as aspirin, ibuprofen or omeprazole, are small molecules. The laboratory’s discovery could kick-start the development of small molecule drugs for innovative and targeted therapies to stop tumor growth in the future. In the 20th century, most drug discovery and development was done entirely by the pharmaceutical industry, but today it is increasingly based on discoveries made in academic basic science projects and from early developments in small biotech companies, often spin-offs from academic groups. Such spin-offs can only emerge with strong support from national governments. Without strong state support, we would not have new drugs”, says Biondi.

IBioBA’s Bioinformatics Platform, headed by Patricio Yankilevich, works on the analysis of genomes with the aim of identifying biomarkers associated with diseases, in collaboration with the experimental projects developed at IBioBA and with external research groups. This work, which uses computational tools to analyze biological data, is very useful for the development of diagnostic and treatment techniques for diseases such as cancer.

In this line, Yankilevich has just published a paper in the journal Cancer Immunology, Immunotherapy, in which he developed a genomic analysis program of melanoma tumor models for the discovery of somatic variants, the identification of differentially expressed genes and the prediction of neoantigens.

The main objective of this research was to study the effect of 6-thioguanine (6TG) – a drug used for some types of cancer – in association with immune checkpoint inhibitor (ICI) therapy, which blocks the interaction between inhibitory T-cell receptors and their ligands, to improve the response of patients to ICI treatment. “This work on computational analysis of tumor genomic data serves to systematically explore the characteristics of the different tumor models under investigation and to understand how they react to treatment with different drugs”, says the researcher.