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Jolanta Grembecka

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Primary Appointment: Pathology Department
Primary PIBS Dept.: Molecular and Cellular Pathology
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 DESCRIPTION OF RESEARCH
  The research focus of Dr. Jolanta Grembecka is discovery and development of small molecules for targeted therapies in cancer. Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with proteins involved in cancer cell division and spread. By focusing on inhibiting proteins involved in molecular and cellular changes that are specific to cancer, targeted cancer therapies are more effective and much less harmful to normal cells than other types of treatment, including chemotherapy and radiotherapy.

We are particularly interested in development of small molecules targeting protein-protein interactions involved in leukemogenesis. Currently, we are working on identification of small molecules inhibiting MLL fusion proteins which could reverse the oncogenic potential of MLL fusions that are involved in both acute myeloid and acute lymphoblastic leukemias. The oncogenic activity of MLL fusions is dependent on association with menin and LEDGF (Lens Epithelium Derived Growth Factor), which results in upregulation of Hox genes expression and leads to leukemogenic transformation. We are developing small molecules which inhibit the menin-MLL-LEDGF complex, downregulate Hox genes expression, and block the oncogenic potential of MLL fusions. If successful, such compounds can be used as a potential therapeutic strategy for acute leukemias with MLL rearrangements and other leukemias with high expression of Hox genes. Furthermore, such compounds can be applied as chemical probes to study the mechanism of MLL-associated leukemogenesis.
Our group is also interested in development of small molecules targeting other proteins involved in oncogenesis. This includes Cdc25 phosphatases, which activate cyclin-dependent kinases (Cdks) by dephosphorylating critical phospho-tyrosine and phospho-threonine residues on these proteins. Cdc25s enhance cell proliferation and oncogenesis, and overexpression of Cdc25A and/or B occurs in several types of primary human cancers, including breast cancers. Therefore, selective inhibition of Cdc25 phosphatases might result in novel anti-cancer agents.

We are using different strategies for identification of lead compounds, including fragment-based approach, high throughput screening, and virtual screening. A collection of biochemical, biophysical, computational, structural biology and medicinal chemistry methods is being used for lead identification and optimization. Furthermore, we use cell biology methods for functional assays to evaluate compound effectiveness in human cancer cell lines. Close collaboration with biologist to test the effect of our compounds in mouse models of leukemia constitutes an integral part of our research.