The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response

Background. Advances from glioma stemlike cell (GSC) research, though increasing our knowledge of glioblas- toma (GBM) biology, do not in uence clinical decisions yet. We explored the translational power of GSC-enriched cultures from patient-derived tumorspheres (TS) in predicting treatment response. Methods. The relationship betweenTS growth and clinical outcome was investigated in 52 GBMs treated with sur- gical resection followed by radiotherapy and temozolomide (TMZ).The effect onTS of radiation (6 to 60 Gy) and of TMZ (3.9 μM to 1 mM) was related with patients’ survival. Results. Generation of TS was an independent factor for poor overall survival (OS) and poor progression-free survival (PFS) (P < .0001 and P = .0010, respectively). Growth rate and clonogenicity ofTS predicted poor OS. In general,TS were highly resistant to both radiation andTMZ. Resistance toTMZ was stronger inTS with high clono- genicity and fast growth (P < .02). Shorter PFS was associated with radiation LD50 (lethal dose required to kill 50% ofTS cells) >12 Gy of matchedTS (P = .0484). A direct relationship was found between sensitivity ofTS toTMZ and patients’ survival (P = .0167 and P = .0436 for OS and PFS, respectively). Importantly, values forTMZ half-maximal inhibitory concentration <50 μM, which are in the range of plasma levels achieved in vivo, identi ed cases with longer OS and PFS (P = .0020 and P = .0016, respectively). Conclusions. Analysis ofTS holds translational relevance by predicting the response of parent tumors to radiation and, particularly, to TMZ. Dissecting the clonogenic population from proliferating progeny in TS can guide thera- peutic strategies to a more effective drug selection and treatment duration.