1. Deregulated phosphatases in human breast cancer

Despite of huge advancements on breast cancer therapy, certain breast cancer subtypes still lack any targeted therapies, or develop resistance to existing therapies. Leveraging on yet uncapitalized potential of phosphatases as breast cancer tumor suppressors and oncoproteins, we have several ongoing projects to address the relevance of phosphatase-mediated phosphoregulation in human breast cancer development and in therapy resistance.

Specific projects:

• Role of CIP2A as a TNBC driver
• Druggable phosphatases in HER2 inhibitor resistance
• Systemic characterization of TNBC phosphoproteomes and drug resistance
• Novel small molecule approaches for breast cancer brain metastasis

2. Reactivation of PP2A for overcoming kinase inhibitor tolerance in brain tumors

Glioblastoma (GBM) and Medulloblastoma (MB) are fatal diseases in which all oncogene-targeted therapies have thus far failed. Brain tumor therapies are also complicated by challenges related to poor blood-brain barrier (BBB) permeability which limits many otherwise effective therapies. Protein phosphatase 2A (PP2A) is inhibited in brain tumors by non-genetic mechanisms and is thus amendable for reactivation. In addition, we have recently demonstrated that combination of PP2A reactivation and multikinase inhibition results in profound synergistic cell killing of GB and MB cells in vitro and in vivo.

Specific projects:

• In vivo therapeutic potential of pharmacological reactivation of PP2A in glioblastoma
• Characterization of targets for synthetic lethal cell killing of glioblastoma stem cells
• Novel small molecule approaches for breast cancer brain metastasis

3. PP2A-mediated control of epigenetics and gene expression

Epigenetic complexes are known to be critically involved in cancer initiation and progression. However, it is very poorly understood how functions of epigenetic complexes and gene expression mechanisms are regulated via phosphorylation-dependent signaling. Our recent results indicate a pivotal role for PP2A in determining phosphorylation of several key epigenetic complex components and in various steps of gene expression.

Specific projects:

• Global impact of PP2A in chromatin remodeling and transcription
• Transcription regulation by PP2A inhibitor proteins
• PP2A-regulated epigenetic proteins in KRAS-mutant lung cancer

4. Species-specific cellular transformation mechanism

Malignant cellular transformation is a multi-stage process where oncogene activation and tumor suppressor inhibition co-operate. Previous studies have firmly established that in mouse cells, an oncogene (e.g. RAS) can transform the cells in combination with inhibition of only one tumor suppressor, whereas RAS-mediated transformation of human cells requires inhibition of Protein Phosphatase 2A (PP2A). However, even after 20 years, the species-specific requirement of PP2A inhibition for cellular transformation remains as an unsolved major question in human cancer biology. Medically solving this question is very relevant as PP2A inhibition has a major role in protecting cancer cells from cell death and in driving cancer drug resistance

Specific projects:

• Generation of step-wise transformation models in cells from multiple species
• Comprehensive multi-omics analysis to identify targets that are dependent on PP2A inhibition upon transformation of human cells
• Screening of drug sensitivities between transformed cells from different species
• Validation of target mechanisms mediating human specific requirement for PP2A inhibition for cellular transformation

5. CIP2A structure-function analysis

CIP2A is an oncogenic PP2A inhibitor protein overexpressed in most human cancer types. CIP2A inhibition effectively limits tumor growth both in xenograft and knock-out mouse models.  Transgenic CIP2A overexpression also induces Alzheimer´s disease phenotypes in mouse brain and behavioural changes typical for Alzheimer´s disease onset. Together these characteristics make CIP2A as a very attracting drug target protein. Thereby, we are currently focusing on understanding of molecular mechanisms of CIP2A-mediated PP2A inhibition and characterization of potential druggability of CIP2A.

Specific projects:

• Structural characterization of CIP2A-PP2A interaction mechanisms
• Characterization of druggability of CIP2A by small molecules