Sun Laboratory

1. Why 90% drug development fails and how to improve it?

This project aims to enhance drug development success and efficiency through the STAR-guided drug design of dual targeting PI3Kγ/Sting, PI3Kγ inhibitors, and STING agonists/antagonists for immunotherapy of cancer and autoimmune disease.

The 90% failure rate of drug development has not improved over the past 40 years despite significant improvement at each step of cancer drug development. It is impractical to add more testing/criteria to the already lengthy and costly drug development process, which takes 10-15 years and costs $1-2 billion per approved drug. The current strategies to the problem, including AI-driven solutions, may fall into the “survivorship bias” trap, which overly focuses on many unimportant peripheral problems but overlooks the root causes of the failures. We propose the STAR-guided drug design system (structure-tissue/cell selectivity-activity-relationship) to enhance both success rate and efficiency. This system addresses the three overlooked interdependent factors: (a) On-/off-target driven potency/specificity (PS) and on/off-target tissue/cell selectivity (PS) in disease tissues at clinically relevant doses that determine clinical efficacy. (b) on-/off-target-driven PS and TS in normal organs at clinically relevant doses that influence adverse effects (on/off-target toxicity). (c) Optimal clinical doses, as determined by both PS and TS, that balance efficacy and safety. STAR system prioritizes STAR class I drugs with high efficacy/high safety/high success rates, contrasting with the current emphasis on STAR class II/IV drugs with low efficacy/low safety/low success rates.

2. Why most anticancer nanomedicines do not enhance clinical efficacy and how to improve it?

This project develops albumin based nanomedicines to enhance clinical efficacy of immuno-oncology drugs (STING agonists and PI3Kγ inhibitors) by targeting immune cells in the lymphatic system and tumors for cancer immunotherapy.

Anticancer nanomedicines hope to act like biological missiles targeting tumors to improve efficacy and minimizing toxicity in normal organs. However, despite their outstanding efficacy in preclinical animal cancer models, most anticancer nanomedicines have not demonstrated superior clinical efficacy, sparking decades long debate on current design nanomedicine design strategies. We propose a drug/nanocarrier-specific nanomedicine design strategy to improve their clinical success: (1) Cancer-specific, identifying features of cancer types that can be used for targeted drug delivery; (2) Cell-specific, understanding the cell types to which drugs need to be delivered; (3) Drug-specific, identifying the intrinsic shortcomings of the delivered drugs that need to be overcome; and (4) Nanocarrier-specific, evaluating specific nanocarriers to overcome the specific limitations of the delivered drugs.

3. How to improve anticancer efficacy of neoantigen mRNA or peptide cancer vaccines?

This project develops SARS-CoV-2 B epitope-guided neoantigen peptide or mRNA cancer vaccine to enhance their anticancer efficacy by activating CD4/CD8 T cell immunity through B cell-mediated antigen presentation.

Cancer neoantigen vaccines typically rely on dendritic cell/macrophage-dependent antigen presentation to activate CD4/CD8 T cell antitumor immunity. Emerging evidence suggested B cell-mediated antigen presentation also plays a vital role in anticancer immunotherapy. It is not known whether incorporating B cell-mediated antigen presentation into current neoantigen vaccines could enhance their anticancer efficacy. We developed an innovative SARS-CoV-2 B Epitope-Guided peptide and mRNA neoantigen vaccines to enhance their efficacy in melanoma, pancreatic, and breast cancers, by more effectively activating CD4/CD8 T cell antitumor immunity through B cell mediated antigen presentation.

4. What are the differences of microbiome, bile salts, and drug release in different regions of human GI tract?

This project investigates the differences of the microbiome, bile salts, and drug release among the human stomach, small intestine, and colon, as well as studies how these differences influence drug product development and disease states.

During oral drug product development, optimizing in vitro and in vivo drug release in the human gastrointestinal (GI) tract is crucial. Bile salts in the GI tract, which change under fasting and fed conditions, influence drug release, disease states, and the microbiome. Additionally, the human GI tract’s microbiome plays a role in regulating disease conditions and drug treatments. We directly measured drug release in various regions of the human GI tract (stomach, duodenum, jejunum, and ileum) for immediate-release, modified-release, and locally-acting drug products. We also compared the profiles of 15 bile salts in different regions of the human small intestine under fasting and fed conditions. Lastly, we examined the distinct microbiome profiles in different regions of the human small intestine and colon.