Research title: Distinct and redundant functions in PI3K pathway and mechanisms of drug resistance
Research summary: The regulatory modules inside a cell are informed about the environmental conditions through the process of signal transduction. This process in part is facilitated by kinases, which help activate specific transcriptional programs in the nucleus in response to mitogenic stimuli. In principle, a deregulated kinase can lead to an overactive signaling module and ultimately, to cancer. The discoveries in the field have become the basis for development of new drugs that inhibit actions of specific kinases. This class of drugs, called kinase inhibitors, offers extraordinary hope for the future of cancer therapy. Phosphoinositide 3-kinase (PI3K) pathway is activated in a plethora of human cancers. Several hundred inhibitors targeting different components of the pathway are currently in clinical trials. Therefore it is of utmost importance to understand if and how tumors could circumvent PI3K inhibition to sustain survival and proliferation.
In order to obtain a more comprehensive understanding of the PI3K pathway in signaling and cancer;
- We develop cellular models that utilize molecular genetic tools and the CRISPR-Cas9 technology to study gain of function of pathway related oncogenes and loss of tumor suppressor functions in the pathway, e.g. PTEN loss.
- We use retro/lentiviral expression libraries to study mechanisms of functional compensation and drug resistance.
- We utilize quantitative high throughput phosphoproteomics/metabolomics approaches to define functional redundancies and signature features of the PI3K pathway components.
After the establishment and initial characterization of these cellular models, we would like to put these cell biological findings to test utilizing xenograft transplantations in immunocompromised mice. Cells can either be treated in culture with stable RNAi or expression vectors or in host animals with systemic administration of small molecule inhibitors/drugs of interest. In these experiments, tumor burden would be monitored and quantified; any regression or spontaneous remission will be further analyzed by means of immunohistochemistry, immunoblotting and gene expression microarrays.
Research Keywords: Signaling mechanisms, cancer therapy, PI3K pathway, PIK3CA, phosphoproteomics, loss of PTEN, G protein-coupled receptors, Rac1.
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