Job Information
- Organisation/Company: CEITEC MU
- Research Field: Biological sciences; Chemistry » Biochemistry
- Researcher Profile: First Stage Researcher (R1)
- Application Deadline: 30 Sep 2026 - 21:50 (UTC)
- Country: Czech Republic
- Type of Contract: Temporary
- Job Status: Full-time
- Offer Starting Date: 1 Feb 2027
- Is the job funded through the EU Research Framework Programme? Not funded by a EU programme
Offer Description
Doctoral study program: Biomedical Sciences
Form of study: doctoral full time
Supervisor: Mgr. Miroslav Boudny, Ph.D.
Consultant: Prof. Marek Mraz, MSc., MD, Ph.D.
Topic title: DNA damage response inhibitors in high-risk hematological malignancies
Annotation:
The DNA damage response (DDR) safeguards genome integrity. Tumor cells frequently harbor DDR aberrations and sustain high replication stress from oncogene activation and rapid proliferation, making them dependent on the residual DDR machinery for survival — a therapeutically exploitable vulnerability. The ataxia telangiectasia and Rad3-related (ATR) kinase and its effector checkpoint kinase 1 (CHK1) form a central axis of the DDR that maintains genome integrity and coordinates the replication-stress response, and DDR inhibition has emerged as an attractive strategy for high-risk hematological malignancies (Boudny and Trbusek, Cancer Treatment Reviews, 2020). Our previous studies have demonstrated the efficacy of a newly developed CHK1 inhibitor in TP53-mutated chronic lymphocytic leukemia (Boudny et al., Haematologica, 2019).
Building on these foundations, this project focuses on rational DDR-targeted combination strategies in high-risk leukemias and lymphomas (e.g., AML, ALL, RS). Important questions remain open: which disease subgroups are most vulnerable, what drives sensitivity and resistance, and how DDR-targeted agents can be most effectively combined with current treatments.
The candidate will (i) evaluate the efficacy and synergy of selected DDR-targeted combinations and characterize their molecular basis in cell lines; (ii) test whether recurrent DDR defects characteristic of certain hematological malignancies (e.g., TP53 or ATM loss) confer sensitivity to ATR/CHK1 inhibition using CRISPR engineering; (iii) identify predictive biomarkers of response (replication-stress level, DDR pathway activation, oncogenic drivers, ATM/TP53 status) and define resistance mechanisms; and (iv) evaluate combinations with established targeted therapies, particularly BH3-mimetics (venetoclax) or B-cell receptor signaling inhibitors. Techniques include drug-sensitivity/synergy testing, flow cytometry, immunoblotting, qPCR, DNA fiber assays, CRISPR/Cas9 editing, and RNA sequencing with bioinformatic analysis. Key observations will be validated on primary patient cells or in mouse models.
Recommended literature:
- Boudny M, Trbusek M. ATR-CHK1 pathway as a therapeutic target for acute and chronic leukemias. Cancer Treatment Reviews, 2020, https://doi.org/10.1016/j.ctrv.2020.102026.
- Boudny M, et al. Novel CHK1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells. Haematologica, 2019;104(12):2443–2455, https://haematologica.org/article/view/9168.
- Kwok M, et al. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood, 2016;127(5):582–595, https://doi.org/10.1182/blood-2015-05-644872.
- Kwok M, et al. DNA damage response defects in hematologic malignancies: mechanistic insights and therapeutic strategies. Blood, 2024, https://doi.org/10.1182/blood.2023019963
Research area: Cancer biology
Keywords: DNA damage response, replication stress, ATR, CHK1, synthetic lethality, high-risk hematological malignancies, targeted therapy
Funding of the PhD candidate:
Part-time salary (min. 0,5 FTE) on AZV/GACR grants + doctoral scholarship + CEITEC PhD School scholarship. Guaranteed net income after taxes of min. 29.400 CZK.
Requirements for candidate:
- Master’s degree in Molecular biology, Biochemistry, or similar field of study
- Experience of working in a laboratory
- The ability of collective work as well as independent project planning
- Desire to learn new things
Start date: February 2027 or sooner
Sign-up link: https://www.ceitec.eu/dna-damage-response-inhibitors-in-high-risk-hematological-malignancies/t11789
Where to apply
Website: https://www.ceitec.eu/dna-damage-response-inhibitors-in-high-risk-hematological-malignancies/t11789
Work Location(s)
Number of offers available: 1
Company/Institute: CEITEC MU
Country: Czech Republic
City: Brno
Postal Code: 625 00
Street: Kamenice 753/5
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