Yao-An Shen

Although CSCs constitute only 0.1–2% of tumor masses, they are major drivers of resistance, recurrence, and metastasis. Our research team has invented a behavioral isolation technique that effectively isolates expandable, stable, and high-purity cancer stem cell (CSC) line banks. 

From core-to-surface investigations of CSCs, we identified three quintessential targets, including unique nuclear transcription factors, metabolic engines, and cell surface neoantigens in CSCs. In light of the fact that pre-B-cell leukemia transcription factor 1 (PBX1) is a critical transcription factor in CSCs and regulates stemness, chemoresistance, and metastasis, we have developed the first-in-class small molecular PBX1 inhibitors. These inhibitors effectively undermine PBX1’s DNA-binding activity, thereby reducing its ability to bolster CSC traits. 

Secondly, CSCs may switch their metabolic engine to glycolysis or glutaminolysis depending on the tumor microenvironment or stresses. We found glutaminase (GLS) inhibitors demonstrate synergistic effects with chemotherapeutic drugs in CSCs that rely on glutaminolysis, hence augmenting their resistance to chemotherapy, whereas GLS inhibitors can counteract the metabolic compensation of CSCs. Another strategy to effectively target CSCs from a metabolic perspective is to optimize drug delivery to CSCs located in hypoxic regions, which lack blood vessels to deliver the drugs. We utilized glucosamine-labeled liposomes that exploit the glucose transporter 1 (GLUT1)-mediated transcytosis to hypoxic tumor environments and attract sugarholic CSCs to uptake high levels of drugs. 

Thirdly, cancer patients exhibit diminished immune cell activity and a reduced ability to detect tumor cells. Without antigen training in immune cell manufacturing, they are unable to properly recognize and eliminate cancer cells. We have created anti-CSC immunotherapy using the CSC neoantigens to train T cells via dendritic cells, which can reduce the possibility of subsequent recurrence and metastasis. 

Overall, these multifaceted approaches not only seek to advance therapeutic strategies against CSCs but also to establish a strong foothold in the growing market for cell therapies and related innovative combination strategies, aiming to solve unmet medical conundrums with CSC-targeted therapies.