BACKGROUND: Advances from glioma stemlike cell (GSC) research, though increasing our knowledge of glioblastoma (GBM) biology, do not influence clinical decisions yet. We explored the translational power of GSC-enriched cultures from patient-derived tumorspheres (TS) in predicting treatment response. METHODS: The relationship between TS growth and clinical outcome was investigated in 52 GBMs treated with surgical resection followed by radiotherapy and temozolomide (TMZ). The effect on TS 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 of TS predicted poor OS. In general, TS were highly resistant to both radiation and TMZ. Resistance to TMZ was stronger in TS with high clonogenicity and fast growth (P < .02). Shorter PFS was associated with radiation LD50 (lethal dose required to kill 50% of TS cells) >12 Gy of matched TS (P = .0484). A direct relationship was found between sensitivity of TS to TMZ and patients' survival (P = .0167 and P = .0436 for OS and PFS, respectively). Importantly, values for TMZ half-maximal inhibitory concentration <50 μM, which are in the range of plasma levels achieved in vivo, identified cases with longer OS and PFS (P = .0020 and P = .0016, respectively). CONCLUSIONS: Analysis of TS 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 therapeutic strategies to a more effective drug selection and treatment duration.
BACKGROUND: Advances from glioma stemlike cell (GSC) research, though increasing our knowledge of glioblastoma (GBM) biology, do not influence clinical decisions yet. We explored the translational power of GSC-enriched cultures from patient-derived tumorspheres (TS) in predicting treatment response. METHODS: The relationship between TS growth and clinical outcome was investigated in 52 GBMs treated with surgical resection followed by radiotherapy and temozolomide (TMZ). The effect on TS 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 of TS predicted poor OS. In general, TS were highly resistant to both radiation and TMZ. Resistance to TMZ was stronger in TS with high clonogenicity and fast growth (P < .02). Shorter PFS was associated with radiation LD50 (lethal dose required to kill 50% of TS cells) >12 Gy of matched TS (P = .0484). A direct relationship was found between sensitivity of TS to TMZ and patients' survival (P = .0167 and P = .0436 for OS and PFS, respectively). Importantly, values for TMZ half-maximal inhibitory concentration <50 μM, which are in the range of plasma levels achieved in vivo, identified cases with longer OS and PFS (P = .0020 and P = .0016, respectively). CONCLUSIONS: Analysis of TS 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 therapeutic strategies to a more effective drug selection and treatment duration.
Authors: D A Haas-Kogan; S S Kogan; G Yount; J Hsu; M Haas; D F Deen; M A Israel Journal: Int J Radiat Oncol Biol Phys Date: 1999-01-15 Impact factor: 7.038
Authors: Anoop P Patel; Itay Tirosh; John J Trombetta; Alex K Shalek; Shawn M Gillespie; Hiroaki Wakimoto; Daniel P Cahill; Brian V Nahed; William T Curry; Robert L Martuza; David N Louis; Orit Rozenblatt-Rosen; Mario L Suvà; Aviv Regev; Bradley E Bernstein Journal: Science Date: 2014-06-12 Impact factor: 47.728
Authors: L A Hammond; J R Eckardt; S D Baker; S G Eckhardt; M Dugan; K Forral; P Reidenberg; P Statkevich; G R Weiss; D A Rinaldi; D D Von Hoff; E K Rowinsky Journal: J Clin Oncol Date: 1999-08 Impact factor: 44.544
Authors: Heidi S Phillips; Samir Kharbanda; Ruihuan Chen; William F Forrest; Robert H Soriano; Thomas D Wu; Anjan Misra; Janice M Nigro; Howard Colman; Liliana Soroceanu; P Mickey Williams; Zora Modrusan; Burt G Feuerstein; Ken Aldape Journal: Cancer Cell Date: 2006-03 Impact factor: 31.743
Authors: Roberto Pallini; Lucia Ricci-Vitiani; Giuseppe Luigi Banna; Michele Signore; Dario Lombardi; Matilde Todaro; Giorgio Stassi; Maurizio Martini; Giulio Maira; Luigi Maria Larocca; Ruggero De Maria Journal: Clin Cancer Res Date: 2008-12-15 Impact factor: 12.531
Authors: G Marziali; M Signore; M Buccarelli; S Grande; A Palma; M Biffoni; A Rosi; Q G D'Alessandris; M Martini; L M Larocca; R De Maria; R Pallini; L Ricci-Vitiani Journal: Sci Rep Date: 2016-02-09 Impact factor: 4.379
Authors: Jian Chen; Yanjiao Li; Tzong-Shiue Yu; Renée M McKay; Dennis K Burns; Steven G Kernie; Luis F Parada Journal: Nature Date: 2012-08-23 Impact factor: 49.962
Authors: Philippe Diaz; Eric Horne; Cong Xu; Ernest Hamel; Michael Wagenbach; Ravil R Petrov; Benjamin Uhlenbruck; Brian Haas; Parvinder Hothi; Linda Wordeman; Rick Gussio; Nephi Stella Journal: Eur J Med Chem Date: 2018-09-11 Impact factor: 6.514
Authors: Alessandra Palma; Sveva Grande; Lucia Ricci-Vitiani; Anna Maria Luciani; Mariachiara Buccarelli; Mauro Biffoni; Valentina Dini; Giuseppe A P Cirrone; Mario Ciocca; Laura Guidoni; Roberto Pallini; Vincenza Viti; Antonella Rosi Journal: Int J Mol Sci Date: 2020-07-21 Impact factor: 5.923
Authors: Maurizio Martini; Ivana de Pascalis; Quintino Giorgio D'Alessandris; Vincenzo Fiorentino; Francesco Pierconti; Hany El-Sayed Marei; Lucia Ricci-Vitiani; Roberto Pallini; Luigi Maria Larocca Journal: BMC Cancer Date: 2018-05-10 Impact factor: 4.430