Published 27. 08. 2021
The research project of Veronika Vymetálková, Ph.D. and her team, are among 16 projects nominated for the Minister's Prize of Medical Research and Development. This is the second nomination of researchers from the IEM CAS in a short time. Last year, Pavel Vodička, M.D., Ph.D., was among the candidates. Both of the nominated researchers work at the Department of the Molecular Biology of Cancer.
At the beginning of September, an official presentation of these projects will take place at the headquarters of the Czech Health Research Council (AZV ČR), at a joint meeting of the AZV ČR Research Board and the AZV ČR Board.
AZV ČR is an organizational component of the state directly under the jurisdiction of the Ministry of Health of the Czech Republic. The agency is a separate accounting unit with the main purpose of supporting applied research in health care in conformity with Act no. 130/2002 Coll., on the Support of Research and Development from Public Funds and the Amendment to Some Related Acts.
Based on a joint vote, the members of the AZV ČR Boards will select projects for proposal to the Minister of Health, who will award the main prize - Minister's Prize or Honorable Mention.
For Veronika Vymetálková, the nomination represents another significant achievement. This year, she was among the 13 finalists of the Czech edition of the international project L'Oréal For Women In Science. At the end of July, she received the Award of the CAS for outstanding results of great scientific significance.
Investigating acquired chemoresistance by profiling genes involved in DNA repair in colon cancer patients
One of the most common causes of colorectal cancer relapse is the development of chemoresistance during chemotherapy. Although not all mechanisms of chemoresistance are yet fully understood, overcoming this obstacle has significant potential to improve the efficacy of chemotherapy and reverse the unfavorable prognosis of cancer patients. This research aimed to identify circulating markers - circulating free DNA (cfDNA) and circulating microRNAs - that may be associated with resistance to widely used chemotherapeutic drugs by non-invasive screening. Identification of these markers could lead to the personalization of treatment and increased success rates. Current trends in oncology aim to divide patients into two groups - those who benefit from chemotherapy and those who do not. However, there is as yet no objective biomarker by which to select patients in this way.
In this project, we have focused on two groups of patients - "good responders" with good response to chemotherapy (i.e. no toxicity or other side effects of chemotherapy, no relapses, no residual cancer and complete response) and "non-responders or poor responders" with acquired chemoresistance, no response and developing toxicity. We prospectively analyzed free circulating DNA (cfDNA) from repeated blood plasma samples (before and after tumor surgery), and further evaluated the ability of the data to predict therapeutic response in patients with colorectal cancer.
Our results revealed that one year after surgery, patients not responding to treatment had a demonstrably pathogenic APC gene mutation in cfDNA. This particular mutation was not found in tumor DNA or cfDNA, analyzed at the time of diagnosis in the same patient. This mutation could signal a change that could help to explain the poor response to therapy. APC is a known tumor suppressor gene that acts as an antagonist of the Wnt signaling pathway and is involved in cell migration and adhesion, transcriptional activation and apoptosis. Another patient, unresponsive to treatment, showed a pathogenic TP53 gene mutation in all cfDNA samples obtained from repeated blood draws and also in tumor DNA. This could be another example of poor therapy response due to the persistence of a non-functional mutant TP53 gene derived from the tumor. One of the physiological functions of the tumor suppressor gene TP53, which is also a transcription factor, is to prevent tumorigenesis.
In another study, we focused on circulating microRNAs in plasma and extracellular vesicles (EVs) in patients with repeated plasma collections, at the time of diagnosis and after treatment. We identified two microRNAs (miR-122-5p and miR-142-5p) that were associated with treatment response. One year after diagnosis, microRNA expression profiles were significantly modified in treatment-responsive patients, whose plasma and EV levels did not differ from those measured in cancer-free individuals. On the other hand, patients who did not respond to therapy continued to be characterized by reduced expression levels in the second sampling, i.e., one year after diagnosis. In vitro studies showed that increased expression of miR-122-5p and miR-142-5p in cell lines derived from intestinal epithelial cells, inhibited their growth and survival. Furthermore, the expression levels of these microRNAs were significantly different in cancer patients compared to healthy subjects. This study provides new evidence that circulating miR-122-5p and miR-142-5p have a high potential for cancer screening and early detection of poor response to treatment, and the ongoing assessment of patient clinical outcomes and treatment plan efficacy.
Identifying biomarkers associated with the therapeutic response could lead to the stratification of colorectal cancer patients into treatment-specific groups, while supporting the transition from a standardized to a personalized therapeutic approach.