Research
Our research is focused around uncovering coding and non-coding RNAs, involved in resistance to targeted therapies in cancer. In particular, we are focusing on microRNAs modulating refractoriness to Tyrosine Kinase Inhibitor (TKI) treatment in lung cancer, and how to deliver microRNA-based drugs into lung tumor models.
MicroRNAs suppress target genes by nucleotide pairing to the 3’UTR of messenger RNAs, thereby tuning gene expression with each microRNA able to regulate numerous genes.
During recent years, microRNA therapies have come under the development for a wide variety of diseases, including cancer. Delivery of microRNAs can be carried out using synthesized mimic-, or inhibitory molecules. The mimic molecule approach is based on introducing a synthetic molecule that is identical to a microRNA lost in cancer, while the inhibitory approach relies on specifically blocking microRNAs aberrantly expressed in cancer.
Due to the promiscuous nature of microRNAs, delivery of microRNA drugs provides an ability to target multiple factors in single or overlapping signaling pathways. Hence, modulation of microRNAs may be particularly interesting when targeting refractory cancers.
We have established multiple methods in the laboratory to systematically uncover RNAs, including microRNAs, of specific importance for therapy refractoriness. Moreover, we have experience in formulating RNA-molecules into lipid nanoparticle vehicles for systemic in vivo delivery.
Projects
RNAs in treatment-refractory lung adenocarcinomas
The majority of all lung cancers are classified as lung adenocarcinomas. A fraction of these cancers harbor mutations in receptor tyrosine kinases (RTKs), including EGFR and ALK, making them amenable for targeted therapy through tyrosine kinase inhibitors (TKIs). TKIs targeting these RTKs display superior efficacy in the clinic compared to chemotherapy and have quickly been established as standard of care for lung cancer patients with activating mutations in specific RTKs. Although most patients respond in a favorable way to TKI-treatment, therapy resistance eventually emerges. Our aim in this project is to uncover diagnostic profiles as well as therapeutic molecular candidates among coding and non-coding RNAs of specific importance for TKI resistance in lung adenocarcinomas.
The role of microRNAs in cell-cycle driven cancers
One of the main physiological alterations in cancer is self-sufficiency in growth signals. Growth signaling induces expression of cyclins, which subsequently recruit and activate their kinase partners, cyclin-dependent kinases (CDKs). Together, they form complexes that govern DNA-synthesis and cell division. Analysis across human tumors has revealed that cyclins and CDKs belong to the most frequently amplified genes across human cancer, including in lung cancers. Conversely, endogenous cell cycle inhibitory genes belong to the most frequently lost in cancers. We recently demonstrated that specific microRNAs, enriched in targeting multiple cell-cycle components, were highly efficacious in targeting refractory cancer types in vitro and in vivo, including triple negative breast cancers and KRAS-driven lung cancers. Our aim in this project is to expand on our previous findings to uncover microRNAs of particular importance for the cell cycle machinery in lung adenocarcinomas.