Xenograft-based, platform-independent gene signatures to predict response to alkylating chemotherapy, radiation, and combination therapy for glioblastoma

Shuang G. Zhao, Menggang Yu, Daniel E. Spratt, S. Laura Chang, Felix Y. Feng, Michelle M. Kim, Corey W. Speers, Brett L. Carlson, Ann C. Mladek, Theodore S. Lawrence, Jann N. Sarkaria, Daniel R. Wahl

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Predictive molecular biomarkers to select optimal treatment for patients with glioblastoma and other cancers are lacking. New strategies are needed when large randomized trials with correlative molecular data are not feasible. Methods: Gene signatures (GS) were developed from 31 orthotopic glioblastoma patient-derived xenografts (PDXs), treated with standard therapies, to predict benefit from radiotherapy (RT-GS), temozolomide (Chemo-GS), or the combination (ChemoRT-GS). Independent validation was performed in a heterogeneously treated clinical cohort of 502 glioblastoma patients with overall survival as the primary endpoint. Multivariate Cox analysis was used to adjust for confounding variables and evaluate interactions between signatures and treatment. Results: PDX models recapitulated the clinical heterogeneity of glioblastoma patients. RT-GS, Chemo-GS, and ChemoRT-GS were correlated with benefit from treatment in the PDX models. In independent clinical validation, higher RT-GS scores were associated with increased survival only in patients receiving RT (P = 0.0031, hazard ratio [HR] = 0.78 [0.66-0.92]), higher Chemo-GS scores were associated with increased survival only in patients receiving chemotherapy (P < 0.0001, HR = 0.66 [0.55-0.8]), and higher ChemoRT-GS scores were associated with increased survival only in patients receiving ChemoRT (P = 0.0001, HR = 0.54 [0.4-0.74]). RT-GS and ChemoRT-GS had significant interactions with treatment on multivariate analysis (P = 0.0009 and 0.02, respectively), indicating that they are bona fide predictive biomarkers. Conclusions: Using a novel PDX-driven methodology, we developed and validated 3 platform-independent molecular signatures that predict benefit from standard of care therapies for glioblastoma. These signatures may be useful to personalize glioblastoma treatment in the clinic and this approach may be a generalizable method to identify predictive biomarkers without resource-intensive randomized trials.

Original languageEnglish (US)
Pages (from-to)1141-1149
Number of pages9
JournalNeuro-oncology
Volume21
Issue number9
DOIs
StatePublished - Sep 6 2019

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Glioblastoma
Combination Drug Therapy
Heterografts
Radiotherapy
Genes
Survival
Biomarkers
temozolomide
Therapeutics
Multivariate Analysis
Confounding Factors (Epidemiology)
Standard of Care
Drug Therapy

Keywords

  • Biomarker
  • Glioblastoma
  • Patient-derived xenograft
  • Radiation
  • Signature
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Xenograft-based, platform-independent gene signatures to predict response to alkylating chemotherapy, radiation, and combination therapy for glioblastoma. / Zhao, Shuang G.; Yu, Menggang; Spratt, Daniel E.; Chang, S. Laura; Feng, Felix Y.; Kim, Michelle M.; Speers, Corey W.; Carlson, Brett L.; Mladek, Ann C.; Lawrence, Theodore S.; Sarkaria, Jann N.; Wahl, Daniel R.

In: Neuro-oncology, Vol. 21, No. 9, 06.09.2019, p. 1141-1149.

Research output: Contribution to journalArticle

Zhao, SG, Yu, M, Spratt, DE, Chang, SL, Feng, FY, Kim, MM, Speers, CW, Carlson, BL, Mladek, AC, Lawrence, TS, Sarkaria, JN & Wahl, DR 2019, 'Xenograft-based, platform-independent gene signatures to predict response to alkylating chemotherapy, radiation, and combination therapy for glioblastoma', Neuro-oncology, vol. 21, no. 9, pp. 1141-1149. https://doi.org/10.1093/neuonc/noz090
Zhao, Shuang G. ; Yu, Menggang ; Spratt, Daniel E. ; Chang, S. Laura ; Feng, Felix Y. ; Kim, Michelle M. ; Speers, Corey W. ; Carlson, Brett L. ; Mladek, Ann C. ; Lawrence, Theodore S. ; Sarkaria, Jann N. ; Wahl, Daniel R. / Xenograft-based, platform-independent gene signatures to predict response to alkylating chemotherapy, radiation, and combination therapy for glioblastoma. In: Neuro-oncology. 2019 ; Vol. 21, No. 9. pp. 1141-1149.
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abstract = "Background: Predictive molecular biomarkers to select optimal treatment for patients with glioblastoma and other cancers are lacking. New strategies are needed when large randomized trials with correlative molecular data are not feasible. Methods: Gene signatures (GS) were developed from 31 orthotopic glioblastoma patient-derived xenografts (PDXs), treated with standard therapies, to predict benefit from radiotherapy (RT-GS), temozolomide (Chemo-GS), or the combination (ChemoRT-GS). Independent validation was performed in a heterogeneously treated clinical cohort of 502 glioblastoma patients with overall survival as the primary endpoint. Multivariate Cox analysis was used to adjust for confounding variables and evaluate interactions between signatures and treatment. Results: PDX models recapitulated the clinical heterogeneity of glioblastoma patients. RT-GS, Chemo-GS, and ChemoRT-GS were correlated with benefit from treatment in the PDX models. In independent clinical validation, higher RT-GS scores were associated with increased survival only in patients receiving RT (P = 0.0031, hazard ratio [HR] = 0.78 [0.66-0.92]), higher Chemo-GS scores were associated with increased survival only in patients receiving chemotherapy (P < 0.0001, HR = 0.66 [0.55-0.8]), and higher ChemoRT-GS scores were associated with increased survival only in patients receiving ChemoRT (P = 0.0001, HR = 0.54 [0.4-0.74]). RT-GS and ChemoRT-GS had significant interactions with treatment on multivariate analysis (P = 0.0009 and 0.02, respectively), indicating that they are bona fide predictive biomarkers. Conclusions: Using a novel PDX-driven methodology, we developed and validated 3 platform-independent molecular signatures that predict benefit from standard of care therapies for glioblastoma. These signatures may be useful to personalize glioblastoma treatment in the clinic and this approach may be a generalizable method to identify predictive biomarkers without resource-intensive randomized trials.",
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T1 - Xenograft-based, platform-independent gene signatures to predict response to alkylating chemotherapy, radiation, and combination therapy for glioblastoma

AU - Zhao, Shuang G.

AU - Yu, Menggang

AU - Spratt, Daniel E.

AU - Chang, S. Laura

AU - Feng, Felix Y.

AU - Kim, Michelle M.

AU - Speers, Corey W.

AU - Carlson, Brett L.

AU - Mladek, Ann C.

AU - Lawrence, Theodore S.

AU - Sarkaria, Jann N.

AU - Wahl, Daniel R.

PY - 2019/9/6

Y1 - 2019/9/6

N2 - Background: Predictive molecular biomarkers to select optimal treatment for patients with glioblastoma and other cancers are lacking. New strategies are needed when large randomized trials with correlative molecular data are not feasible. Methods: Gene signatures (GS) were developed from 31 orthotopic glioblastoma patient-derived xenografts (PDXs), treated with standard therapies, to predict benefit from radiotherapy (RT-GS), temozolomide (Chemo-GS), or the combination (ChemoRT-GS). Independent validation was performed in a heterogeneously treated clinical cohort of 502 glioblastoma patients with overall survival as the primary endpoint. Multivariate Cox analysis was used to adjust for confounding variables and evaluate interactions between signatures and treatment. Results: PDX models recapitulated the clinical heterogeneity of glioblastoma patients. RT-GS, Chemo-GS, and ChemoRT-GS were correlated with benefit from treatment in the PDX models. In independent clinical validation, higher RT-GS scores were associated with increased survival only in patients receiving RT (P = 0.0031, hazard ratio [HR] = 0.78 [0.66-0.92]), higher Chemo-GS scores were associated with increased survival only in patients receiving chemotherapy (P < 0.0001, HR = 0.66 [0.55-0.8]), and higher ChemoRT-GS scores were associated with increased survival only in patients receiving ChemoRT (P = 0.0001, HR = 0.54 [0.4-0.74]). RT-GS and ChemoRT-GS had significant interactions with treatment on multivariate analysis (P = 0.0009 and 0.02, respectively), indicating that they are bona fide predictive biomarkers. Conclusions: Using a novel PDX-driven methodology, we developed and validated 3 platform-independent molecular signatures that predict benefit from standard of care therapies for glioblastoma. These signatures may be useful to personalize glioblastoma treatment in the clinic and this approach may be a generalizable method to identify predictive biomarkers without resource-intensive randomized trials.

AB - Background: Predictive molecular biomarkers to select optimal treatment for patients with glioblastoma and other cancers are lacking. New strategies are needed when large randomized trials with correlative molecular data are not feasible. Methods: Gene signatures (GS) were developed from 31 orthotopic glioblastoma patient-derived xenografts (PDXs), treated with standard therapies, to predict benefit from radiotherapy (RT-GS), temozolomide (Chemo-GS), or the combination (ChemoRT-GS). Independent validation was performed in a heterogeneously treated clinical cohort of 502 glioblastoma patients with overall survival as the primary endpoint. Multivariate Cox analysis was used to adjust for confounding variables and evaluate interactions between signatures and treatment. Results: PDX models recapitulated the clinical heterogeneity of glioblastoma patients. RT-GS, Chemo-GS, and ChemoRT-GS were correlated with benefit from treatment in the PDX models. In independent clinical validation, higher RT-GS scores were associated with increased survival only in patients receiving RT (P = 0.0031, hazard ratio [HR] = 0.78 [0.66-0.92]), higher Chemo-GS scores were associated with increased survival only in patients receiving chemotherapy (P < 0.0001, HR = 0.66 [0.55-0.8]), and higher ChemoRT-GS scores were associated with increased survival only in patients receiving ChemoRT (P = 0.0001, HR = 0.54 [0.4-0.74]). RT-GS and ChemoRT-GS had significant interactions with treatment on multivariate analysis (P = 0.0009 and 0.02, respectively), indicating that they are bona fide predictive biomarkers. Conclusions: Using a novel PDX-driven methodology, we developed and validated 3 platform-independent molecular signatures that predict benefit from standard of care therapies for glioblastoma. These signatures may be useful to personalize glioblastoma treatment in the clinic and this approach may be a generalizable method to identify predictive biomarkers without resource-intensive randomized trials.

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KW - Glioblastoma

KW - Patient-derived xenograft

KW - Radiation

KW - Signature

KW - Temozolomide

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