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

Personnel:

• MSc, Srikar Nagelli

2. Reactivation of PP2A for malignant brain tumors

Glioblastoma (GBM) is a fatal disease in which all oncogene-targeted therapies have thus far failed. GBM therapies are also complicated by challenges related to poor blood-brain barrier permeability which limits many otherwise effective therapies. Protein phosphatase 2A (PP2A) is inhibited in GBM 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 human glioma 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

Personnel:

• PhD, Oxana Denisova
• PhD, Riikka Huhtaniemi

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

Personnel:

• PhD, Anna Aakula
• MSc, Mukund Sharma

4. 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 attractive 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
• Molecular basis of CIP2A protein stabilization via B56 interaction
• Characterization of druggability of CIP2A by small molecules

Personnel:

• PhD, Karolina Pavic
• PhD, Nikhil Gupta

5. Other projects:

• MSc, Umar Butt: Characterization of oncogenic and metastatic properties of SHARPIN (shared supervision with Adjunct professor Jeroen Pouwels)