Recently, our group identified a previously unrecognized link between retinoid and rexinoid actions and activation of ubiquitin-proteasome degradation, and identified an alternative degradation program involving ubiquitin-like species, such as the interferon stimulated gene-15 (ISG15). In addition, novel substrates of this pathway were also found, including: PML/RAR-alpha and cyclin D1, among other growth-regulators. These studies provided mechanism that protein degradation pathways can be activated for cancer therapy. Currently, we are studying the role of these proteins in lung tumorigenesis.
Dr. Dmitrovsky’s lab also studies the impact of targeting the cyclin E-CDK2 complex in lung cancer. We have demonstrated that this complex is an active lung cancer target and identified a novel antineoplastic pathway, which we termed anaphase catastrophe. Using murine transgenic models that expressed lung-specific wild-type or proteasome degradation dependent cyclin E species, we observed that lung cancers spontaneously formed in both models and that the onset and frequency of lung carcinogenesis was promoted in the proteasome degradation-resistant lines. In addition, we discovered that the centrosomal protein CP110 is a direct CDK2 target and induces anaphase catastrophe. These studies lead to novel therapeutic strategies to combat lung cancer. Currently, we are exploring novel anti-neoplastic agents to target this pathway.
Our lab is actively involved in translating basic research findings into clinical trials. As an example, we identified cyclin degradation pathways upregulated after rexinoid treatment. This discovery laid the foundation for rexinoid-based lung cancer trials in early stage and advanced lung cancer patients.