In 2015 we developed a powerful methodology for growing primary patient tumor tissue in a three-dimensional culture condition as tumor organoids (Nat. Med. 2015, 11:1364-71). These tumor organoids – “mini tumors” – recreate histoarchitecture, differentiation status and epigenetic status of the matched patient tumor. Importantly, these patient-derived tumor organoids maintain both inter-tumor and intra-tumor heterogeneity for all the above traits. We can established tumor organoids with >80% take-rate. They can be serially passaged, genetically modified, test for drug response and used for establishing xenograft models. We believe that these tumor organoids are a robust platform for target validation and target discovery efforts. Using this technology, we have discovered that inhibition of a chromatin regulating enzyme, EZH2, blocks growth of some, but not all pancreatic tumor-derived organoid culture. This finding raises the possibility that EZH2 inhibitors (EZH2i) are likely to be a therapeutic drug for treating patients with pancreatic cancer, a possibility that we are pursuing for clinical translation.
Every patient’s tumor is unique for its molecular traits, hence, matching patients to therapies is likely to improve our chances to control cancer. The ability to grow a patient’s tumor ex vivo for pre-clinical or co-clinical (analysis performed in conjunction with clinical care) is emerging to be a powerful strategy to match the patient tumor genotype to the clinical response phenotype. The tumor organoid technology has created an unprecedented opportunity to keep primary patient tumors cells alive for extended periods of time and use them to design treatment plans, one patient at a time.
Huang, L., Holtzinger A., Jagan, I., BeGora, , Lohse, I., Ngai, N., Nostro, C., Wang, R., Muthuswamy, L.B., Crawford, H.C., Cheryl Arrowsmith, C., Kalloger, S.E., Renouf, D.J., Connor, A., Cleary, S., Schaeffer, D.F., Roehrl, M., Tsao, M., Gallinger, S., Keller, G., and Muthuswamy, S.K. (2015) Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell– and patient-derived tumor organoids. Nat Med. 2015 Nov;21(11):1364-71. PMID: 26501191