HKU Centennial Distinguished Chinese Scholar Public Lecture: Pyroptosis, Inflammatory Diseases, and Drug Development

Modern drug development relies on breakthrough discoveries in basic biomedical research, through which molecular understandings of disease pathogenesis are obtained. These basic findings provide molecular targets or rationales for developing interference molecules or drugs to be tested in clinics.

Taking cancer treatment as an example, it has now entered the immunotherapy era, beginning with the groundbreaking immune checkpoint therapy. In the 1990s, researchers in academia discovered that cancer cells can ‘hide’ from immune cells by using certain checkpoints, such as PD-1 and CTLA-4. These checkpoints act like brakes, stopping the immune system from attacking the cancer. Industry scientists then developed drugs that block these brakes, allowing the immune system to recognise and destroy cancer cells. Since the first checkpoint inhibitor was approved in 2011, more drugs targeting checkpoints like PD-1 and PD-L1 have shown efficacy in treating various cancers.

In the first part of the seminar, Dr Shao will introduce this Nobel Prize-winning work and share his perspective on how basic science can transform medicine and impact our society. Dr Shao will also share his efforts and journey in discovering novel innate immune and pyroptosis pathways and translating these discoveries into innovative drugs for treating inflammatory diseases and cancers. In 2018, Shao’s team identified the ALPK1 immune receptor that recognises a bacterial metabolite called ADP-heptose to induce potent inflammation. They have developed an ALPK1 inhibitor that is entering a phase I clinical trial for inflammatory bowel disease. Their research shows that activating ALPK1 could induce effective antitumour immunity, and an ALPK1-agonising drug is already in clinical trials for solid tumours.

Pyroptosis is a proinflammatory form of cell death. In 2015, Shao’s team identified the gasdermin family of proteins, which, upon activation by various inflammatory insults, could perforate cell membranes and execute pyroptosis. Among the family, GSDMD is activated by canonical inflammasomes and endotoxin-engaged noncanonical inflammasome. GSDMD plays a prevalent role in various chronic and acute inflammatory diseases. An innovative GSDMD inhibitor has been developed, showing great promise in animal models and will soon be tested in sepsis patients. GSDME causes membrane damage or pyroptosis in chemotherapy-treated or virus-infected cells. A GSDME inhibitor has shown excellent efficacy in blocking avian flu-caused cytokine storm and is entering clinics for treating chemotherapy-induced peripheral neuropathy and neurodegeneration diseases like ALS.

Furthermore, Shao’s team has found that pyroptosis of less than 15% tumour cells is sufficient to render tumour clearance by stimulating antitumour immunity, which is being exploited for developing the next-generation cancer immunotherapy.