Currently running grants with participation by the Toxicogenomics Unit
AZV NW25-03-00150: Biocompatible nanomedicines with optimized pharmacokinetics for the modern treatment of pancreatic tumors
Co-investigator: Prof. RNDr. Pavel Souček CSc.
Principal investigator: RNDr. Tomáš Etrych, Ph.D., DrSc.
Project duration: 2025-2028
Abstract: Pancreatic cancer (PaC) is one of the most aggressive forms of cancer, with a steadily rising incidence. In the Czech Republic, 23 new cases per 100,000 inhabitants are reported annually, which is the third-highest incidence rate in the world. The incidence and mortality curves are virtually identical, and the prognosis for patients with PaC is extremely poor, partly due to the limited efficacy of current chemotherapy. In preliminary experiments, we have demonstrated that the conventional cytostatic agent gemcitabine (Gem) exhibits a significantly prolonged half-life and higher antitumor activity in vivo when covalently bound to a polymeric carrier. This project focuses on in vivo verification of the efficacy and potential toxicity of newly developed, effective polymer-based nanotherapeutics for the treatment of PaC. The nanotherapeutics are being developed and designed to prolong the half-life of Gem in circulation and ensure its controlled release within the tumor. Another objective is to develop nanotherapeutics containing paclitaxel (Ptx) and to investigate the potential synergy of nanotherapeutics delivering both Gem and Ptx simultaneously. These nanotherapeutics utilize biodegradable, biocompatible, and water-soluble polymeric carriers to enhance accumulation in tumors. The main objective of the project is to test the biological activity of these nanotherapeutics in vivo based on previous data obtained from in vitro studies. Various structures of polymeric carriers, drug loads, and release kinetics will be tested. Testing will include CDX models derived from pancreatic carcinoma cells (e.g., Paca44, BxPC3, or PANC-1) and PDX models derived directly from tumor fragments from PaC patients.
AZV NU24-09-00505: Molecular Classification in Relation to the Prevention of Endometrial Cancer Recurrence and Lifestyle Factors
Co-investigator: Mgr. Karolína Šeborová, PhD
Principal investigator: prof. MUDr. Michael Halaška, PhD, Fakultní nemocnice Královské Vinohrady
Project duration: 2024-2027
Abstract: Endometrial cancer (EC) is one of the most common cancers among women worldwide, with a significantly rising incidence, particularly in developed countries. One reason for the increase in the incidence of this disease is the rising prevalence of obesity, which is the greatest risk factor for its development. Other important risk factors include hypertension, diabetes mellitus, and the general aging of the population. These risk factors are not only associated with a higher risk of developing the disease but also, for example, with postoperative complications that affect patients’ quality of life after surgery. The molecular classification of endometrial cancer, which has been introduced into clinical practice in recent years, currently helps physicians make treatment decisions for individual patients and predict their prognosis. As part of this project, we would like to focus on the relationship between this molecular classification and genomic mutation signatures identified through whole-exome sequencing, as well as their association with lifestyle risk factors for endometrial cancer (obesity—BMI, hypertension, diabetes mellitus), including in relation to the extent of staging lymphadenectomy. The identification and detailed analysis of dominant mutation profiles associated with a specific molecular subtype of endometrial cancer (EC) and their influence by the presence of risk lifestyle factors may have a significant impact on both disease progression and the prevention of recurrence. A potential relationship between the mutation profile and the extent of staging lymphadenectomy may aid in deciding the extent of this surgical procedure, which subsequently affects patients’ quality of life, particularly in patients with a high BMI. Given the widespread prevalence of risk-associated lifestyle factors in the developed world, a detailed understanding of the relationships between the genetic profile, its changes, and the presence of these risk factors—which can have a potentially significant impact on treatment success—is absolutely essential for the treatment of cancer and the prevention of its development.
MŠMT LUAUS 23164: Targeted taxane derivatives as a potential therapeutic option for the treatment of resistant and highly aggressive forms of cancer
Co-investigator: RNDr. Radka Václavíková, PhD
Principal investigator: Mgr. Jaroslav Truksa, PhD, 3. lékařská fakulta Univerzity Karlovy
Project duration: 2023-2027
Abstract: In this project, we will collaborate with an international partner to study the efficacy of new biotin- and folate-conjugated experimental taxane cytostatics, specifically developed for this project. We will also study the efficacy of regimens that combine these taxane conjugates with conventional cytostatics in various ways, using both in vitro and in vivo models. Furthermore, we plan to perform a completely unique molecular profiling of the response of both in vitro and in vivo models to these regimens, using modern next-generation sequencing technologies and mass spectrometry. Monitoring the relationships between the efficacy of new regimens and complex changes in cellular regulation at the transcriptome- and proteome-wide levels will enable us to identify molecular factors that predict the development of resistance and new cellular targets suitable for further development of targeted and more effective treatments for solid tumors. Selected cellular targets, identified through transcriptome and proteome profiling, will subsequently be studied in solid tumor tissue samples obtained directly from patients. Furthermore, we plan to perform molecular modeling of the binding and transport of new taxane derivatives via ABCB1 (P-glycoprotein) and other ABC transporters, which play a significant role in the mechanism of taxane resistance.
COST ACTION 24162: Adaptive and acquired resistance in gastrointestinal cancers-contemporary and emerging resolutions (AdResCanCER)
Principal investigator: Dr. Luka Bočkor (Institute for Anthropological Research, Croatia)
Member: Mgr. Karolína Šeborová, PhD
Project duration: 2025-2029
Abstract: Gastrointestinal (GI) cancers (cancer of the esophagus, stomach, colon, rectum, pancreas, and liver) constitute a group of diseases with high incidence and mortality rates, and their treatment is complicated by the development of chemoresistance. The exact mechanism of the adaptive changes underlying chemoresistance in gastrointestinal tumors remains unclear, although various internal and external factors may play a role in this process. The proposed AdResCanCER initiative will serve as a platform that, for the first time, brings together researchers, early-career scientists, clinicians, and small and medium-sized enterprises active in the field of GI-related basic and clinical oncology, molecular biology, drug discovery and development, and bioinformatics, with the aim of strengthening excellent research into understanding and overcoming chemoresistance in gastrointestinal tract tumors, enabling the generation of advanced knowledge, skills, and technology transfer, promoting a high level of training for young researchers, and facilitating the development of new clinically relevant therapeutic solutions and monitoring tools for recurrent gastrointestinal tract tumors. The main objectives of the AdResCanCER project include: 1) creating a platform to connect researchers from various disciplines, clinicians, regulatory authorities, and the general public; 2) optimizing and standardizing the generation and use of research and clinical data and various analytical procedures in the -OMICS field; 3) ensuring the rational design, development, and evaluation of new drugs and compounds targeting resistance phenotypes; and 4) actively collaborating with regulatory authorities, policymakers, and patient organizations in formulating activities aimed at promoting the right approach at the right time in the treatment of gastrointestinal tract cancers.
Participation in this European project through the Ministry of Education, Youth and Sports (MŠMT) project: “Integrated Research on Biomarkers and Preclinical Testing of Drugs to Overcome Drug Resistance in Pancreatic and Colorectal Cancers” in two working groups: WG1 (Genetic and Epigenetic Mechanisms) and WG3 (Therapeutic Approaches).