The ubiquitin proteasome system (UPS) plays a pivotal role in most cellular processes. The multitude of genes dedicated to functions associated with the ubiquitin proteasome system, comprising over 4% of all coding proteins, indicates its extensive use as a regulatory system. Emerging data suggests roles for the UPS outside of the known housekeeping function in protein turnover, highlighting that more has to be done to understand the complex nature of the UPS and its functions in the cell. In our laboratory, we study the UPS starting from basic cellular functions and progress towards understanding its involvement in human diseases, ranging from muscle atrophies to cancer. In order to characterize the UPS in different cellular environments, our efforts are concentrated on developing novel molecular and chemical tools/assays to gain insight into this complex process. Another aim is to look developing biotechnologies around ligand protein integration(s). A core focus we have with translational potential is to “hijack” the UPS for targeted protein degradation with small molecules, which have the potential to create novel therapeutic strategies. Using this approach, we can hopefully unlock the “undruggable” proteome and create a better strategy to combat diseases where therapeutic options are limited by conventional drug discovery approaches. One such targeted degradation tactic is with bifunctional molecules that recruit UPS components to degrade a target protein – more commonly referred to as PROTACs (proteolysis-targeting chimeras). While conventional small molecules must block the aberrant activity of a target protein, PROTACs serve to eliminate the protein altogether by routing it to the proteasome for degradation using the ubiquitin system. Since PROTACs deplete the targeted protein by degradation, much in the same way that functional genetics approaches (e.g. RNAi and CRISPR/Cas9) do, we will then be able to correlate molecular changes and predict cellular phenotypes much better – something which traditional therapeutics are usually unable to fully recapitulate. Furthermore, as traditional small molecules are always plagued with off-target effects, PROTACs can significantly improve on the predictability from gene-to-function studies by mimicking the effects seen in traditional genetic ablation studies.
Project 12 – Molecular and chemical approaches to unravel hormonal signaling in BC and target tissues
Hypothesis: Molecular biosensors for hormone receptors can create an understanding between level of binding of hormones to receptors and the phenotypic outcome.
Background and Significance: The presence of HR agonists within the tumor microenvironment has emerged as an important factor in breast and skin cancer development and progression. Yet little is known about how and where in the tissue hormones and different agonists and antagonists interact with their cognate receptors. Thus, using state-of-the-art molecular and chemical biology techniques, novel biosensors for HR agonists will be produced enabling one to precisely detect hormone levels in cancer cells and to screen for new therapeutic agents that targeting (ER), PgR and AR through degradation. The first clinical trials with proteolysis-targeting chimeras for hormone receptors (AR and ER) started in 2019 and the emerging drug-modality of degradation-based pharmaceuticals are growing to open up drug for targets that was not available for conventional drug development.
Objectives: The overall objective is to establish molecular and chemical tools to increase understanding about hormone receptor signaling for breast and skin cancer prevention: (1) to set up state-of-the-art hormone receptor target engagement systems that can be used to characterize on-target and phenotypic data of test compounds for use by the research network. (2) Validate the biosensors in vitro using hormone sensitive cell lines. (3) Determine binding of different progestins used in hormonal contraception to the PgR and AR in ex vivo and xenograft models in collaboration with C:Brisken. (4) To perform high-throughput screening and lead optimization for novel binders/inhibitors (such as proteolysis-targeting chimeras [PROTACs]) targeting the hormone receptors with developed hormone receptor target engagement systems – representing new therapeutic modalities.