Molecular Oncology
Cancer is a leading cause of death worldwide, and Hungary has the highest cancer-related mortality rate in the European Union. Efforts to reduce cancer incidence and mortality require multi-pronged efforts aimed at better prevention through the understanding and eliminating environmental and lifestyle risks, earlier and more detailed diagnosis, and improved personalized treatment strategies. Molecular biology research has a central role in answering these important societal needs, and the necessary combination of genetic and biochemical approaches is well supplied by the Institute.
High quality research in the Institute can support the anti-cancer efforts in three fundamental ways. First, a clear understanding of how cancer develops is needed to aid prevention efforts. Cancer is primarily a genetic disease often called ‘a disease of the DNA’, as the defining feature that distinguishes cancer cells from normal body tissue is the presence of somatic oncogenic ‘driver’ mutations. Similar inherited mutations can also increase the risk of developing cancer. A large proportion (in many tissues the majority) of somatic cancer mutations arise due to exposure to environmental agents. Sunlight and cigarette smoke are well characterized, but poor diet and alcohol consumption are also prominent cancer risks in Hungary, therefore their carcinogenic mechanisms and mutagenic constituents must be investigated and taken into account in prevention strategies together with the assessment of the carcinogenicity of environmental chemicals.
Early and accurate diagnosis dramatically improves the outcome of treatment and the patients’ quality of life. Inherited gene defects increase cancer risk, and understanding these will help early, targeted screening efforts that are much more cost-effective than treatment of late disease. Research in the Institute actively focuses on the genetic pathways leading to cancer and can also help characterizing gene variants of uncertain significance that may be enriched in the Hungarian population. The next step of diagnosis is the provision of prognosis and treatment prediction based on molecular properties – biomarkers – of a biological sample. This is a very rapidly progressing and promising area. The Institute wishes to stay in the forefront of using innovative data-intensive ‘omics’ approaches such as genomics, epigenomics and transcriptomics for diagnosis from biopsies and surgical material, and branch out into the use of less invasive methods including the detection of circulating tumor DNA in the blood.
Cancer treatment comprises chemotherapies and targeted biological therapies. Chemotherapies still form the mainstay of treatment due to their established regimens, availability and good initial response. The Institute’s researchers believe that the continued use of chemotherapies is justified and can be improved upon, provided they better understand their side effects, work on more efficient delivery formulations and investigate the mechanisms by which eventual resistance develops. Promising research from the Institute in each of these areas should be continued and expanded in the future to help patients. In many cases, such work is not in the financial interest of the pharmaceutical industry; therefore it must be performed in publicly financed institutions. In contrast, new targeted oncotherapies arise great commercial interest. Here, initial discoveries of targets are usually made in an academic environment, and commercialization follows the route of spinoff companies eventually acquired by big pharma. Through studying the molecular mechanisms of tumorigenesis, researchers will aim to continue identifying targets for modern cancer therapeutics that are designed to exploit the genetic vulnerabilities of loss-of-function mutants or directly interfere with the protein products of oncogenes. The Institute can also take part in the early steps of drug development both directly and in collaboration. Biologically targeted therapies only work on cancers with certain molecular properties; therefore it is essential to couple their development with biomarker research for patient stratification.
Future oncological research in the Institute will be increasingly relevant to healthcare needs, addressing the open questions with the greatest societal impact regarding cancer prevention, diagnosis and treatment.
Molecular regulation of gene expression – searching for new therapeutic opportunities
Precise regulation of gene expression is vital for the proper development and function of every organism, from the start to the end of its life cycle. Dysregulated or uncontrolled gene expression leads to severe developmental disorders and other serious diseases, such as cancer, therefore, detailed knowledge of the regulatory processes is essential for the successful prevention and treatment of such conditions.
With the development of next generation sequencing and gene editing techniques, our knowledge about gene expression regulation experienced an unprecedented expansion, while also revealing a complexity that exceeds previous expectations. Integrating this sudden surge of information into our already existing knowledge and its successful translation to medical purposes present one of the most pressing challenges of modern molecular biology. Only a highly trained expert community can answer these challenges, where researchers experienced in NGS data analysis and experimental techniques can work together in a highly cooperative manner. The Institute of Enzymology stands out in this respect, as the personnel consists of internationally recognized experts of both areas who have already produced invaluable results in the field.
The vision and mission of this subject area are to achieve a deep understanding of the function and co-regulation of complex and interrelated regulatory networks for the development of effective new therapeutic approaches. More specifically, the research conducted within the framework of this area aims to uncover the molecular background of processes, such as the emergence of cancer, the development of tumor drug resistance, autoimmune- and developmental diseases, preeclampsia and different metabolic diseases. The research groups associated with this subject use a diverse array of approaches and techniques that belong to the cutting-edge technologies and respond to the latest discoveries and trends in molecular biology.
The main objectives of this research area are (i) to build a comprehensive understanding of the gene expression regulatory networks related to disease development and progression in order to identify new drug target mechanisms, (ii) to test the identified mechanisms in complex ex vivo model systems and validate their usefulness in drug development and (iii) to develop specific pharmacological strategies, using the obtained information. The main target areas involve diseases that present major challenges for the national healthcare system, like cancer, neurodegenerative and psychological diseases and diabetes. The discoveries made in this area will be directly utilized in collaboration with pharmaceutical companies, especially the Gedeon Richter Plc., in the field of neuropharmacology.
Molecular pharmacology promoting drug discovery and personalised medicine
Rapid advances in biomedical research have provided tools for development of new diagnostic and therapeutic procedures for many diseases of public health importance. Early diagnosis of diseases and personalized treatment strategies are essential for successful therapies that require understanding pathological mechanisms at molecular, cellular and organism level, developing relevant disease models, identifying genetic and non-genetic factors that influence therapies, and translating results to drug development and clinical applications. The Institute is involved in a broad range of genetic, cell biology and pharmacology research, complementing each other in systematic research projects; thus, creating an essential pillar for drug discovery and development as well as for personalized medicine applied in clinical practice. The research projects are structured according to the following main focuses:
- In-depth investigations of the underlying genetic changes, molecular mechanisms in the cells and interactions between the cells are crucial for understanding disease development. By revealing pathological processes, relevant in vitro and in vivo disease models and modelling methods can be established for pharmacological studies screening novel drug-candidates for treatment of various diseases, e.g., cardiovascular, metabolic, oncologic, neurologic and psychiatric disorders, transplantation-related and other immunological problems and obstetrical syndromes associated with cardiometabolic and immunological diseases. Relevant human disease models are essential because of the limitations of classical animal models, which do not necessarily mirror the pathological processes in humans (questionable transferability to humans).
- Accurate diagnosis of various diseases and personalized drug treatment are of high importance for appropriate therapy. Identification of novel biomarkers or improvement of introduced biomarkers for objective distinction of normal physiological and abnormal pathophysiological processes is necessary for reliable and early diagnosis and for prognosis of diseases as well as for design of optimal therapy and monitoring of therapeutic response. In addition to the classical approaches that analyze the associations between genetic variations (mutations, polymorphisms) and disease development, detailed analysis of gene expression (mRNA and protein) and phenotypic changes is crucial for complex diagnostic picture and for pharmacogenetic-based, efficient and safe drug therapy.
- Human primary cell and cell line models as well as genetically engineered cell models have now become basic tools for biomedical research, which are routinely used in the Institute. As novel tools, human cellular and organoid models have been introduced in addition to the classical cell line models for better understanding of cellular signaling pathways and pathological mechanisms, identifying potential drug targets and testing novel therapeutic approaches. Cell-based models are primarily human stem-cell models, whereas organoid models are 3D culture systems derived from stem-cells or patient biopsy samples. Furthermore, while safeguarding scientific quality, alternatives to the use of animals in testing of medicines are encouraged by the regulatory authorities (e.g. EMA, FDA).
Developing relevant human disease models and screening systems, identifying selective and sensitive diagnostic biomarkers, and revealing patient specific pharmacogenetic factors for optimal drug therapy all significantly contribute to the discovery and development of potential therapeutic agents, as well as to efficient clinical applications.
The Institute intends to continue building on the decades of successful approach of curiosity driven biomedical research that aims to contribute to the innovative solutions of various urging public health problems. The goal is to improve patients’ quality of life by identifying new drug targets, developing targeted agents, and developing personalized treatment strategies.
Bioinformatics and artificial intelligence in the service of biomedical research
The mission of the Institute is to create, maintain and develop databases, tools and basic research in the field of bioinformatics that can be used in the three other scientific area in the Institute and ultimately pave the way to save millions of lives. In recent years, bioinformatics and artificial intelligence have played a crucial role in all areas of basic and translational research. As computational approaches are the cheapest, fastest and most widely used to screen drugs, model proteins or protein-protein, protein-ligand interactions, they are the most effective tool to identify mechanisms and drugs that can be tested experimentally. From birth to death, there are many health problems, such as preeclampsia, cancer and aging, which cannot be solved without collecting huge amounts of biological data and computational analysis of these data. Regarding birth, preeclampsia is a serious condition that can occur after the 20th week of pregnancy or after birth and can cause acute and life-long health problems, even death, for both mothers and babies. Various types of cancer can cause early death throughout life, from childhood to old age. As health problems are solved, more and more old people are living in societies (aging society), which brings up new health problems, how to treat diseases that occur in old age, such as Alzheimer’s or Parkinson’s disease.
The vision of curing these diseases hinges on understanding their molecular mechanisms through modeling the structure and interactions of active proteins or establishing causality from the vast pool of publicly available sequencing data related to these conditions. The initial and indispensable steps can be accomplished using bioinformatics tools, which, in terms of cost, stand out as an economical alternative compared to wet lab experiments.
The research conducted at the Institute encompasses the aforementioned tasks not only on publicly available genomic datasets but also focuses on two particularly challenging protein groups: transmembrane proteins and intrinsically unordered proteins. Transmembrane proteins are crucial molecular players in cellular processes, pose significant challenges for wet lab and structural studies due to their dual nature. These proteins are embedded in the double lipid layers surrounding every cell and cell compartment, serving as gatekeepers by facilitating the transport of water-soluble substances across membranes. Given that over 60% of currently available drugs interact with transmembrane proteins, the structural modeling and analysis of these proteins are indispensable for the development of effective medications across various medical disciplines.