The aim of the project: Development of an assessment method for evaluating the effectiveness of anticancer therapy with a combination of D-isoascorbic acid (D-VC) and arsenic trioxide in KRAS-mutated metastatic colorectal cancer using ctDNA liquid biopsy technology
Project Description: Colorectal cancer (CRC) is one of the leading causes of death worldwide. The annual increase in CRC morbidity and mortality rates requires the introduction of new diagnostic methods and the development of new approaches to effective therapy. To date, the standard approach to anti-cancer therapy for CRC is anti-EGFR therapy with drugs aimed at blocking the transmission of epidermal growth factor receptor (EGFR) activation signals via the RAS/MAPK-dependent signaling pathway, which inhibits the proliferative activity of tumor cells and metastasis mechanisms. At the same time, an independent predictive marker of tumor response to EGFR inhibitor therapy is the mutation of codon 12/13 of the KRAS oncogene. Liquid biopsy is a modern tool in cancer screening based on the study of residual amounts of tumor cell DNA in the bloodstream using molecular genetic testing of driver mutations, including in the KRAS gene. The advantage of the method, as opposed to traditional biopsy, is its non-invasiveness. In addition, the method has a wide range of possible applications, including early diagnosis of cancer, monitoring disease progression and assessing the effectiveness of treatment in real time. Therefore, in our study, the use of liquid biopsy method to evaluate the efficacy of anticancer therapy in KRAS-mutant CRC using ctDNA biomarker will help to monitor the efficacy of drug treatment and promptly identify patients who do not respond to therapy at an early stage
PI: Akbota Aitkulova
Co-PI: Dos Sarbasov
Diana Samatkyzy
Tomiris Kadenova
Co-PI: Dos Sarbasov
Diana Samatkyzy
Tomiris Kadenova
Realisation Period: 2024-2026
Expected results: The results obtained during the implementation of the project will be covered in at least 3 (three) articles and (or) reviews in peer-reviewed scientific publications in the scientific direction of the project, indexed in the Science Citation Index Expanded and included in the 1st (first), 2nd (second) and (or) 3rd (third) quartile by impact factor in the Web of Science database and (or) having a CiteScore percentile in Scopus database of at least 60 (sixty), and at least 1 (one) article or review in a peer-reviewed foreign or domestic publication recommended by CQASE ME RK. In addition, within the framework of the project, it is planned to obtain a patent for an invention of the Patent Office of the Republic of Kazakhstan. Commercialization of the obtained scientific results is not planned.
The target consumers of the results obtained will be medical institutions in Kazakhstan. The results obtained during the implementation of the project will be used to monitor the effectiveness of antitumor therapy of the drug D-VC/ATO at the molecular level in patients with CRC. The introduction of the liquid biopsy method into clinical practice in Kazakhstan will allow for early diagnosis and detection of cancer, improve therapy approaches and reduce the risks and limitations associated with the invasive method. In turn, this will contribute to the implementation of strategic programs to combat cancer and improve the health and longevity of the population of Kazakhstan
The target consumers of the results obtained will be medical institutions in Kazakhstan. The results obtained during the implementation of the project will be used to monitor the effectiveness of antitumor therapy of the drug D-VC/ATO at the molecular level in patients with CRC. The introduction of the liquid biopsy method into clinical practice in Kazakhstan will allow for early diagnosis and detection of cancer, improve therapy approaches and reduce the risks and limitations associated with the invasive method. In turn, this will contribute to the implementation of strategic programs to combat cancer and improve the health and longevity of the population of Kazakhstan
Methodology: Study cohort includes patients from Phase I/II clinical trial of the efficacy, tolerability and safety of intravenous D-isoascorbic acid (D-VC) with arsenic trioxide in patients with advanced/metastatic colorectal cancer who tolerated the standard drug therapy. Blood samples will be collected and separated into plasma by centrifugation, and circulating tumor DNA will be isolated at intervals: before/during and after 1.3 6 and 12 months after completion of therapy. Further, during anti-cancer therapy, an assessment of dynamic changes in the level of cfDNA in the blood will be carried out for the presence of mutations of the 12/13 codon of the KRAS gene using digital PCR. Statistical analysis will be performed using R statistics, SPSS, GraphPad software packages. Descriptive statistics and Mann-Whitney U tests will be used to evaluate clinical and biochemical variables associated with baseline ctDNA levels. Comparison of ROC curves will be performed to evaluate the sensitivity and specificity of the test. Kaplan-Meier survival plots will be generated to assess patient survival after therapy
Contacts: akbota.aitkulova@nu.edu.kz