Research in the Lu Laboratory centers on the multi-functional transcription factor nuclear factor κB (NF-κB). As a hallmark in many cancers and a key link between inflammation and cancer, the pivotal transcription factor NF-κB is a “hot” target for disease treatment. The research of Tao Lu, PhD, focuses on addressing how NF-κB is regulated and how this regulation contributes to tumorigenesis. Ultimately, these studies may provide a rational basis for the design of new strategies for treating NF-κB-activated cancers and inflammatory disorders.
Research in the Lu Lab utilizes a broad range of advanced research techniques and experimental models to discover novel aspects of NF-κB regulation and new genes for drug resistance, with the hope of identifying innovative biomarkers, therapeutic targets in cancer and other NF-κB related diseases, and ultimately, lead to the development of new medicines to treat these devastating diseases.
Epigenetic Regulation of NF-kB in cancer and inflammatory disease
The lab has discovered that the histone modifying enzymes, such as protein arginine methyltransferase 5 (PRMT5) (ref. 1, 2) and the F-box leucine repeat rich protein 11 (FBXL11) (ref. 2-4), a known histone H3 lysine 36 (H3K36) demethylase are novel regulators of NF-κB. Currently, these researchers are studying the role of these histone modifying enzymes in cancer. Specifically, we have adapted the AlphaLISA technique into a high throughput screen (HTS) platform to identify PRMT5 small molecule inhibitors. This work has resulted in an International Patent Application (5) regarding “Small molecule protein arginine methyltransferase 5 (PRMT5) inhibitors and methods of treatment”. The lead compound and its derivatives may serve as the basis for new medicine development to combat cancer, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and breast cancer (BC) (6, 7).
Furthermore, since elevated NF-κB activity has been widely observed in both chronic inflammatory bowel disease (IBD) and colitis-associated colon cancer (CAC), and is believed to be a key link between IBD and CAC, therefore, NF-κB is widely considered to be an attractive therapeutic target for CAC. The lab team has successfully established genetically engineered mouse models to investigate the role of FBXL11 in CAC and other inflammation related diseases, such as diabetes and atherosclerosis.
Using Validation-based insertional mutagenesis (VBIM) technique to discover novel genes
VBIM is a powerful genetic approach for gene discovery (3, 8). We have employed this innovative approach to identify novel regulators of NF-κB. These regulators may have great potential to serve as new biomarkers and therapeutic targets for cancer. Furthermore, understanding the underlying molecular mechanisms regarding how these novel regulators control NF-κB activity may help to devise innovative therapeutic strategies to control NF-κB activity in cancer.
Additionally, the Lu Lab is utilizing VBIM technique to discover carboplatin and paclitaxel resistance genes in cancer. Once identified, targeting these genes may help to overcome chemoresistance to carboplatin or paclitaxel, thus, improving their efficacies for cancer treatment. Finally, discovery of novel drug resistance genes may help physicians to design more precise treatment to each individual cancer patient.