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Research areas
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Mechanisms of resistance to monoclonal antibody therapy in B-cell malignancies
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Targeted gene editing and whole-genome knockout screens using CRISPR/Cas9 technology for prediction of novel targeted therapies
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Repurposing of approved drugs for personalized therapy in solid and hematological cancers
Main objectives
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Analysis of molecular mechanisms regulating CD20 expression as the prime target of immunotherapy and elucidation of potential therapy sensitizers
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Generation of diverse cell models gene edited via the CRISPR/Cas9 technique to analyze the functional consequences of mutated genes and suggest potential targets for therapy
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Implementation of different drug and loss-of-function screens (shRNA or CRISPR/Cas9-mediated) to reveal synthetic lethality interactions and to predict targeted therapies specific for individual gene mutations present in solid and hematological cancers
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Development and optimization of tumor therapy using T cells genetically engineered to carry chimeric antigen receptors (CAR-T cell therapy)
Content of research
The focus of modern cancer therapy is set on personalizing the therapy with major emphasis put on developing specific small-molecule compounds targeting key cellular components essential for tumorigenesis. We are in our lab predominantly aiming at identification of novel drug targets that might then be exploited in the clinic as innovative targeted therapies.
We use a plethora of molecular biology and cell biology techniques to elucidate the molecular mechanisms regulating expression of CD20 surface molecule, the prime target of immunotherapy in B cell malignancies that is often downregulated, hence leading to therapy resistance. Better insight into CD20 regulation may reveal novel targets to be pharmacologically exploited for enhancing CD20 expression and thereby improving therapy outcome.
Revolutionary CRISPR/Cas9 technology in conjunction with lentiviral infection is utilized to generate cell models carrying common mutations observed in cancer patients. Functional consequences of these aberrations onto cell signaling and behavior are thoroughly analyzed. Libraries of small-molecule compounds as well as genome-wide CRISPR/Cas9 knockout constructs are employed in order to reveal critical weak-points triggered by individual cell aberrations. The molecular mechanisms underlying observed synthetic lethality interactions are then investigated in detail.
In addition, we are screening libraries of already approved drugs against a variety of diverse patient samples in vitro. This may lead to an elegant drug repurposing, i.e. taking an approved drug and applying it onto a different disease or indication. This has proven to provide a smart way of producing fast and relatively cheap novel treatment options.
We are also establishing and optimizing a breakthrough therapy currently in clinical trials for hematological as well as solid cancers that relies on administering a synthetic chimeric antigen receptor into the patient´s own T lymphocytes. These re-engineered cells are then given back to the patient where they recognize malignant cells specifically through their newly introduced antigen receptor, leading to the tumor cell eradication.
Overall, all our projects aim to decipher the functional changes triggered in malignant cells and to reveal novel cellular vulnerabilities that might be translated into the clinic as unique personalized therapy available to stratified groups of patients.
1. Identification of novel therapies for genetically defined CLL cases through repurposing of already approved drugs
Supervisor: Mgr. Michal Šmída, Dr. rer. nat.
Consultant: prof. RNDr. Šárka Pospíšilová, Ph.D.
Annotation:
Drug repurposing is an elegant way of taking approved drugs and applying them on a novel disease or condition, hence offering novel therapeutic possibilities. B-cell chronic lymphocytic leukemia (CLL) is very heterogeneous disease with a variety of somatic mutations, the therapy of which often fails. To predict novel therapies, we will culture CLL cells, selected to represent the major genetic subtypes carrying different mutations, in a unique in vitro model and screen them against a large library of diverse drugs approved for variety of indications. Measuring cell viability upon drug treatments shall reveal the candidates selectively killing specific CLL subtypes. Careful validation and detailed elucidation of the underlying molecular mechanisms will follow. We will learn novel knowledge about the biology of mutations and signaling pathways altered in CLL. Findings of this project shall lead to a smart drug repurposing and identification of novel options for CLL therapy. Thereby, we may also trigger new clinical trials for the off-label use of identified selective drugs.
Keywords: B-cell chronic lymphocytic leukemia,CLL therapy, selective drugs, drug repurposing
