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Updated: Apr 5, 2026
Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
Published on: March 30, 2018
Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived
Keiki Sugimoto1, Fumihiko Hayakawa2, Satoko Shimada3
11] Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan [2] Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan.
Abstract:
Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, especially in the points of rapid growth rate and microenvironment independency. Consequently, the majority of conventional anti-cancer drugs are less sensitive to slow growing cells and do not target microenvironmental support, although most primary cancer cells grow slower than cell lines and depend on microenvironmental support. Here, we developed a novel high throughput drug screening system using patient-derived xenograft (PDX) cells of lymphoma that maintained primary cancer cell phenotype more than cell lines. The library containing 2613 known pharmacologically active substance and off-patent drugs were screened by this system. We could find many compounds showing higher cytotoxicity than conventional anti-tumor drugs. Especially, pyruvinium pamoate showed the highest activity and its strong anti-tumor effect was confirmed also in vivo. We extensively investigated its mechanism of action and found that it inhibited glutathione supply from stromal cells to lymphoma cells, implying the importance of the stromal protection from oxidative stress for lymphoma cell survival and a new therapeutic strategy for lymphoma. Our system introduces a primary cancer cell phenotype into cell-based phenotype screening and sheds new light on anti-cancer drug development.
Insights
A new drug screening system using patient-derived xenograft cells improves cancer drug discovery. Pyruvinium pamoate showed high efficacy by blocking lymphoma cell support from stromal cells.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Cell lines are limited models for cancer drug discovery due to differences in growth rate and microenvironment dependency.
- Conventional anti-cancer drugs often fail against slow-growing cancers that rely on microenvironmental support.
Purpose of the Study:
- To develop a high throughput drug screening system using patient-derived xenograft (PDX) cells to better model primary cancer phenotypes.
- To identify novel anti-cancer compounds effective against lymphoma by screening a library of known drugs and pharmacologically active substances.
Main Methods:
- Developed a novel high throughput drug screening system utilizing patient-derived xenograft (PDX) cells of lymphoma.
- Screened a library of 2613 known pharmacologically active substances and off-patent drugs.
- Investigated the mechanism of action of promising compounds, including pyruvinium pamoate.
Main Results:
- Identified numerous compounds with higher cytotoxicity than conventional anti-tumor drugs.
- Pyruvinium pamoate demonstrated the highest activity and confirmed anti-tumor effects in vivo.
- Discovered that pyruvinium pamoate inhibits glutathione supply from stromal to lymphoma cells, highlighting the role of stromal protection.
Conclusions:
- The novel PDX-based screening system accurately reflects primary cancer phenotypes, offering a more effective approach for drug discovery.
- Pyruvinium pamoate represents a promising therapeutic strategy for lymphoma by targeting the essential glutathione supply from stromal cells.
- This study emphasizes the importance of microenvironment interactions in cancer survival and provides a new avenue for anti-cancer drug development.
