The COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease is an emerging and urgent global public health issue. In this lecture, we will describe how we used our expertise from cancer target therapy to target SARS-CoV-2. For example, we established SARS-CoV2 -related assays including Mpro, Furin, TMPRSS2, Vpp, etc and screened multiple compound libraries. Several positive candidate drugs have drug/protein structure resolved. And currently, we are seeking clinical collaboration to move these drugs for clinical trials (AJCR 2020 & 2021).
Our group’s research focus is centered on resistance mechanism to anti-PD-1/PD-L1 treatment, development of effective novel combination immunotherapy and methodology to enhance PD-L1 detection in clinical setting. Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumor-associated immune escape. The following are progresses and their significance. A highly translational study identified a link between the ubiquitination and glycosylation pathways that regulate the immunosuppressive activity of PD-L1 (Nature Communications 2016). We showed that glycosylation of PD-L1 is required for its protein stability and interaction with PD-1. To this end, in collaboration with StCube Pharmaceuticals Inc., we have developed monoclonal antibodies against glycosylation-specific PD-L1. Impressive therapeutic effect was observed through antibody-drug-conjugate approach (Cancer Cell 2018 & Cancer Res 2020).
We demonstrated that metformin-activated AMPK kinase downregulates PD-L1 through phosphorylation of Ser-195, which alters glycosylation of PD-L1 and functionally mimics anti-PD-L1 to block PD-L1/PD-1 interaction. It exhibited a highly potent synergistic effect of combination therapy of metformin, a drug that has been treated patients with diabetes and anti-CTLA4. The therapeutic efficacy could reach to the survival rate of 50-70% in different syngeneic mouse models which were treated by this combination therapy (Molecular Cell 2018). We discovered that epithelial-mesenchymal transition (EMT) enhances PD-L1 in cancer stem-like cells (CSCs) by the EMT/��-catenin/STT3-PD-L1 signaling axis. Etoposide, a commonly used anti-cancer chemotherapy drug is able to suppress this signaling axis, resulting in downregulation of PD-L1 to sensitize cancer cells to anti-Tim 3 therapy (Nature Comm 2018). Furthermore, our group has conducted a series of vigorous studies to identify additional potential targets to overcome PD-1/PD-L1 resistance and develop effective combination therapy including c-MET inhibitors (Gastroenterology 2019), IL-6/JAK1 pathway (J Clin Invest 129:3324, 2019), Galectin-9 (Nature Comm 2021) and Tyro 3 (J Clin Invest 2021) in various cancer types. These findings provide potential therapeutic strategies to enhance cancer immune therapy efficacy by targeting PD-L1 stabilization to combat multiple cancer types.
Similar to most of cell surface proteins, PD-L1 is heavily glycosylated; and therefore, this posttranslational modification makes it difficult to accurately detect PD-L1 expression and has been a puzzle to use PD-L1 expression to stratify patients for treatment. We developed a method to resolve this issue by removing the glycan moieties from cell surface antigens via enzymatic digestion. We demonstrated that 1) improved PD-L1 detection after deglycosylation is associated with response to anti-PD-1/PD-L1 therapy as well as increased PD-L1 signal after deglycosylation is beneficial to therapeutic selection; 2) antigen retrieval by protein deglycosylation improves predictive ability of PD-L1 as a biomarker for immunotherapy (Cancer Cell 2019). Previously, we identified TNFα as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1) (Cancer Cell 2016). We have further discovered a novel PD-L1 function that is independent of its role in immune checkpoint (Nature Cell Biology 2020)--PD-L1 in the nucleus harbors a nuclear transcriptional activity and promotes tumor pyroptosis downstream of TNFα.
In addition to cancer immunotherapy, our group has several exciting findings on targeted therapies for lung and GI (including HCC and pancreatic) cancers. Our group opens a new field in demonstrating important aspects of ribonuclease family members in cancer, i.e. a specific ribonuclease could serve as a ligand to growth factor receptors including RNase 5-EGFR in pancreatic cancer (Cancer Cell 2018) , RNase 7-ROS1 in HCC (J of Hepatol 2020) and RNase1-EphA4 in breast cancer (Nature Comm 2021). We identified a novel kinase-resistant and expression-sensitive mechanism of EGFR that activates PKC delta in non-small cell lung cancer (NSCLC) that are resistant to EGFR TKIs including Osimertinib, the most recently approved third generation EGFR TKI (Cancer Cell 2018). In our recent report (Nature 2020), we discovered that activated AKT in human hepatocellular carcinoma (HCC) cells phosphorylates cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), converting the tumor suppression function of PCK1 into oncogenic function of p-PCK1 in HCC. This report unravels the importance of the protein kinase activity of PCK1 in the activation of sterol regulatory element-binding proteins (SREBPs), lipogenesis and the development of HCC; and identifies the inhibition of the protein kinase activity of PCK1 as a potential treatment strategy in human HCC. We will summarize the molecular mechanism and share our recent development to identify drugs that selectively target at p-PCK1 but not at PCK1. |
