One of the biggest health problems in the developing world is that the mortality rate of chronic, non-communicable diseases has increased in parallel with the increase in life expectancy, so the care of cancer diseases is also an increasing problem for health care systems. In Hungary, too, cancer mortality has gradually increased over the past 60 years. Two-thirds of cancer cases occur over the age of 60, and unfortunately approximately 70,000 people are diagnosed with malignant tumor yearly. Today, the use of chemotherapeutics, which are used to inhibit rapidly dividing cells – such as tumor cells – has not yet been displaced from the therapy of human cancer diseases, but personalized targeted therapy and the use of molecules with biological effects are increasingly coming to the fore. With their gradual spread, the survival (recovery) of cancer patients increases significantly, and the patients’ quality of life (symptom-free period) improves, where the social usefulness of which is important to emphasize.
The division and differentiation of the approximately 37 billion cells in the human body are regulated in many cases by signal pathways operating through receptor tyrosine kinases. The most important regulators of these signaling pathways are the GTP-binding RAS proteins, which are mutated in human tumors, but especially in lung, colon and pancreatic cancer. In such cases, the cells break away from the physiological regulation dependent on growth factors and begin to divide indefinitely, and then a tumor may develop. Recently, the investigation of mutant RAS proteins has become a key issue in oncology, because the presence of the KRAS mutation is one of the main causes of resistance to classical chemotherapeutics and new targeted molecular therapy drugs.
The consortium plans are to identify effective inhibitors for the inhibition of mutant KRAS proteins, based on partly already known and partly still to be determined 3D spatial structure information, using the most modern fragment-based molecular design method. The biochemical and antitumor effects of the synthesized potential inhibitors will be tested on in vitro and in vivo models of human tumors and then selected according to their effectiveness. The second objective of the project is to identify and develop effective inhibitors that affect the newly discovered tyrosine regulatory pathway of the KRAS protein by keeping the active, GTP-bound RAS in a phosphorylated state, i.e. inactivating it. As the third goal of the project, we intend to use allele-specific covalent inhibitors in combination with active substances. These compounds alone have not previously been shown to be effective, however, recent data suggest that combination therapy may be beneficial in certain oncogenic RAS-expressing tumors.
The Consortium is led by the Natural Science Research Center, its members are Semmelweis University, Eötvös Loránd University of Science and KINETO Lab Ltd.
The Consortium competes with the best international research groups because we believe that, based on our research experience, we are capable of designing, synthesizing and screening compounds that inhibit oncogenic KRAS using the most modern innovative methods.