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 for the above two interconnected problems: (a) Potency/specificity to on/off-targets that determines tumor efficacy at clinical doses. (b) On/off-target tissue/cell selectivity that influences adverse effects (on/off-target toxicity) in normal organs at clinical doses. (c) Optimal clinical doses that balances efficacy and safety as determined by potency/specificity and tissue/cell selectivity. The STAR system categorizes drugs into four classes based above three factors. STAR system prioritizes STAR class I drugs with high clinical success potential, contrasting with the current emphasis on class II/IV drugs with high failure rates.

 

We are currently using STAR-guided drug design system to optimize dual targeting compounds to inhibit PI3K/activate Sting, PI3K gamma inhibitors and STING agonists for cancer immunotherapy, as well as JAK inhibitors and STING inhibitors for treating autoimmune disease.

Can machine learning overcome the 95% failure rate and reality that only 30% of approved cancer drugs meaningfully extend patient survival? Duxin Sun, Christian Macedonia, Zhigang Chen, Sriram Chandrasekaran, Kayvan Najarian, Simon Zhou7, Tim Cernak, Vicki L. Ellingrod, H.V. Jagadish, Bernard Marini, Manjunath Pai, Angela Violi, Jason C. Rech, Shaomeng Wang, Yan Li1, Brian Athey, Gilbert S. Omenn. J Med Chem, 2024, Sep 10, in press, 10.1021/acs.jmedchem.4c01684

Why 90% of Clinical Drug Development Fails and How to Improve It? Duxin Sun, Wei Gao, Hongxiang Hu, Simon Zhou. Acta Pharmaceutic Sinica B, 2022, 12, 3049

Dual Targeting of STING and PI3Kγ Eliminates Regulatory B Cells to Overcome STING Resistance for Pancreatic Cancer Immunotherapy. Chengyi Li, Shuai Mao, Hongyi Zhao, Miao He, Meilin Wang, Zhongwei Liu, Hanning Wen, Zhixin Yu, Bo Wen, Mahamadou Djibo, Jinsong Tao, Yingzi Bu, Wei Gao,  Duxin Sun (Under revision in Nature Cancer 2024). bioRxiv doi: https://doi.org/10.1101/2024.02.14.580378

A gastrointestinal (GI) locally-activating Janus Kinae (JAK) inhibitor to treat ulcerative colitis. Yingzi Bu, Mohamed Dit Mady Traore, Luchen Zhang, Lu Wang, Zhongwei Liu, Duxin Sun. J Biol Chem, 2023, 299: 105467 DOI:https://doi.org/10.1016/j.jbc.2023.105467

Machine learning prediction of on/off target-driven clinical adverse events. Albert Cao, Luchen Zhang, Yingzi Bu, and Duxin Sun. Pharmaceutical Research, August, 2024, DOI https://doi.org/10.1007/s11095-024-03742-x

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

This project develops albumin based anticancer nanomedicines to enhance clinical efficacy of immuno-oncology drugs 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 found two key issues affecting their clinical efficacy: (1) EPR, while present in all animal and human tumors, may not always lead to the increased nanomedicine accumulation compared to free drugs depending on cancer models. (2) Long blood circulation may reduce nanomedicine clearance by the mononuclear phagocyte system (MPS), but could negatively affect efficacy and alter, rather than reduce, toxicity.

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.

Currently, we are employing these new strategies to design albumin based nanomedicines of PI3K inhibitors and Sting agonists to target immune cells in the lymphatic system and tumors to enhance cancer immunotherapy.

The latest manuscripts

What Went Wrong with Anticancer Nanomedicine Design and How to Make It Right. Sun D, Zhou S, Gao W. ACS Nano. 2020 Oct 27;14(10):12281-12290.

Reappraisal of anticancer nanomedicine design criteria in three types of preclinical cancer models for better clinical translation. Luan X, Yuan H, Song Y, Hu H, Wen B, He M, Zhang H, Li Y, Li F, Shu P, Burnett JP, Truchan N, Palmisano M, Pai MP, Zhou S, Gao W, Sun D. Biomaterials. 2021 Aug;275:120910.

Albumin nanoparticle containing a PI3Kγ inhibitor and paclitaxel in combination with α-PD1 induces tumor remission of breast cancer in mice. Yudong Song, Luke Bugada, Ruiting Li, Hongxiang Hu, Luchen Zhang, Chengyi Li, Hebao Yuan, Krishani Rajanayake, Nathan Truchan, Fei Wen, Wei Gao, and Duxin Sun. Science Translational Medicine, 2022, 14 (643): onlineDOI: 10.1126/scitranslmed.abl3649

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. Despite B cells being professional APCs, these vaccines do not utilize B cell-mediated antigen presentation due to the longstanding debate for the role of B cell immunity in cancer. 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 CD4 and CD8 T cell immunity to improve 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.

The latest manuscripts

Antigen-Clustered Nanovaccine Achieves Long-Term Tumor Remission by Promoting B/CD 4 T Cell Crosstalk. Chengyi Li, Ryan Clauson, Luke F. Bugada, Bing He, Hongwei Chen, Hongxiang Hu, Polina Chuikov, Ke Fang, Brett D. Hill, Syed M. Rizvi, Yudong Song, Kai Sun, Daniel Huynh, Marilia Cascalho, Lana Garmire, Leo Yu Lei, Irina Grigorova, Fei Wen, Wei Gao, Duxin Sun. ACS Nano 2024, 18: 9584-9604

SARS-CoV-2 B Epitope-Guided Neoantigen NanoVaccines Enhance Tumor-Specific CD4/CD8 T Cell Immunity Through B Cell Antigen Presentation. Chengyi Li, Shuai Mao, Zera Montemayor, Mohamed Dit Mady Traore, Alejandra Duran, Fang Ke, Mahamadou Djibo, Hanning Wen, Wei Gao, Duxin Sun. https://www.biorxiv.org/content/10.1101/2024.07.18.604163v1. 

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.

We have 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.

Spatial and Temporal Analysis of the Stomach and Small-Intestinal Microbiota in Fasted Healthy Humans. Seekatz AM, Schnizlein MK, Koenigsknecht MJ, Baker JR, Hasler WL, Bleske BE, Young VB, Sun D. mSphere. 2019 Mar 13;4(2):e00126-19.

In Vivo Dissolution and Systemic Absorption of Immediate Release Ibuprofen in Human Gastrointestinal Tract under Fed and Fasted Conditions. Koenigsknecht MJ, Baker JR, Wen B, Frances A, Zhang H, Yu A, Zhao T, Tsume Y, Pai MP, Bleske BE, Zhang X, Lionberger R, Lee A, Amidon GL, Hasler WL, Sun D. Mol Pharm. 2017 Dec 4;14(12):4295-4304. 

Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract. Yu A, Baker JR, Fioritto AF, Wang Y, Luo R, Li S, Wen B, Bly M, Tsume Y, Koenigsknecht MJ, Zhang X, Lionberger R, Amidon GL, Hasler WL, Sun D. Mol Pharm. 2017 Feb 6;14(2):345-358.