Central Nervous System
SS 13 - CNS 2 - Gliomas
94 - Development and Validation of Xenograft-Based Platform-Independent Gene Signatures That Predict Response to Alkylating Chemotherapy, Radiation, and Combination Therapy in Glioblastoma.
Monday, October 22
11:05 AM - 11:15 AM
Location: Room 004
Shuang Zhao, MD, MSE
PFS Genomics: President: Employee; University of Michigan: Resident: Employee
GenomeDx Biosciences: Travel Expenses
Celgene: Patent/License Fees/Copyright; GenomeDx Biosciences: Patent/License Fees/Copyright; PFS Genomics: Patent/License Fees/Copyright
PFS Genomics: President, Board Member
Development and Validation of Xenograft-Based Platform-Independent Gene Signatures That Predict Response to Alkylating Chemotherapy, Radiation, and Combination Therapy in Glioblastoma.
S. G. Zhao1, P. Decker2, D. E. Spratt1, S. W. L. Chang3, F. Y. Feng4, M. M. Kim1, C. Speers5, J. Eckel-Passow2, B. Carlson6, A. C. Tuma2, T. S. Lawrence1, M. Yu7, J. N. Sarkaria2, and D. R. Wahl8; 1Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 2Mayo Clinic, Rochester, MN, 3University of California - San Francisco, San Francisco, CA, 4UCSF Department of Urology, San Francisco, CA, 5Veteran Affairs Hospital Ann Arbor, Ann Arbor, MI, 6Mayo Clinic, Rocheser, MN, 7Department of Statistics, University of Wisconsin School of Medicine and Public Health, Madison, WI, 8University of Michigan, Ann Arbor, MI
Many prognostic biomarkers have been developed in oncology. However, very few prospectively validated predictive biomarkers exist, and none in radiation oncology. We leveraged a novel methodology to generate multiple predictive biomarkers for patients with glioblastoma (GBM) to personalize the use of adjuvant therapy.
Transcriptome-wide RNAseq data was generated from 31 GBM orthotopic patient-derived xenografts (PDXs) that were treated with radiation (RT), alkylating chemotherapy (chemo), and ChemoRT. Gene signatures were developed to predict treatment benefit in the PDXs (RT, Chemo, and ChemoRT gene signatures are termed RT-GS, Chemo-GS and ChemoRT-GS). Independent validation of the signatures was then performed in the TCGA GBM dataset (n=502) with overall survival as the primary endpoint. Multivariate Cox regression analysis (MVA) to adjust for treatment selection bias was used to assess the interaction between the signature and treatment, in order evaluate if the signatures were predictive for treatment response.
PDX models recapitulated the molecular heterogeneity, subtypes, and varied treatment response of GBM patients. RT-GS, Chemo-GS and ChemoRT-GS were all highly correlated with treatment response in the PDXs. In independent validation using the TCGA, higher RT-GS scores were associated with increased survival only in the patients that received RT (p=0.0031, HR=0.88 [0.81-0.96]), higher Chemo-GS scores were associated with increased survival only in the patients that received chemo (p<0.0001, HR=0.81 [0.74-0.9]), and higher ChemoRT-GS scores were associated with increased survival only in the patients that received chemo+RT (p=0.0001, HR=0.9 [0.86-0.95]). None of the three signatures were associated with improved survival in the patients that did not receive the specific therapy. Furthermore, RT-GS and ChemoRT-GS both had significant interaction terms with treatment on MVA (RT-GS: p=0.0009; ChemoRT: p=0.02). Notably, the Chemo-GS had improved performance compared to MGMT promoter methylation (p=0.097, HR=0.87 [0.74-1.02]) in chemo treated patients.
We successfully developed and validated three transcriptomic signatures that predict benefit from current standard of care adjuvant therapies for GBM. These signatures represent the first molecular predictors for RT and chemo+RT response in GBM that are predictive of treatment response, rather than merely prognostic. Furthermore, Chemo-GS outperforms MGMT promoter methylation, the current clinical gold standard. This novel PDX-driven approach shows promise in being able to model treatment response clinically and may be generalizable to other tumor types. These gene signatures represent a significant advance towards personalizing therapies for patients with GBM, and efforts toward prospective validation are ongoing.
Author Disclosure: S.G. Zhao: Employee; PFS Genomics. Travel Expenses; GenomeDx Biosciences. Patent/License Fees/Copyright; Celgene, PFS Genomics, GenomeDx Biosciences. P. Decker: None. D.E. Spratt: None. S.L. Chang: Independent Contractor; UCSF. Stock Options; PFS Genomics. Patent/License Fees/Copyright; GenomeDx Biosciences. President and board member; PFS Genomics. F.Y. Feng: Research Grant; GenomeDx. Advisory Board; GenomeDx, Dendreon, Sanofi. Travel Expenses; GenomeDx. Liaison, GU Translational Research Program; Radiation Therapy Oncology Group. President and Founder; PFS Genomics. M.M. Kim: Research Grant; EpicentRx. C. Speers: Stock; PFS Genomics. Patent/License Fees/Copyright; PFS Genomics. J. Eckel-Passow: None. B. Carlson: None. T.S. Lawrence: royalties; Lippincott, Williams and Wilkins. Honoraria; Massachusetts General Hospital, Pfizer Oncology Innovation Summit, Sidney Kimmel Foundation for Cancer Research. Consultant; Pfizer Oncology Innovation Summit. Advisory Board; ASTRO Radiation Oncology Institute, Dana Farber Cancer Institute, Massachusetts General Hospital, Sidney Kimmel Compreh Cancer Ctr at Johns Hopkins, Sidney Kimmel Foundation for Cancer Research, St. Jude Children's Research Hospital, University of Wisconsin Comprehensive Cancer Ctr. Travel Expenses; AACR, ASTRO Radiation Oncology Institute, Dana Farber Cancer Institute, Lippincott, Williams and Wilkins, Massachusetts General Hospital, Pfizer Oncology Innovation Summit, RSNA, Sidney Kimmel Compreh Cancer Ctr at Johns Hopkins, Sidney Kimmel Foundation for Cancer Research, St. Jude Children's Research Hospital, University of Wisconsin Comprehensive Cancer Ctr. Patent/License Fees/Copyright; Pi Squared Therapeutics. Editor, Cancer Discovery; AACR. Member, Editorial Advisory Board, Cancer Today; AACR. Senior Editor, Cancer Research; AACR. Member, External Advisory Board for Lung SPORE; Dana Farber Cancer Institute. Co-Editor of Principles and Practices of Oncology; Lippincott, Williams and Wilkins. Member, NCI Board of Scientific Advisors; NCI - BSA. President; ROI. Member, External Advisory Board for the Cancer Ctr; Sidney Kimmel CCC at Johns Hopkins University. Member of the Medical Advisory Board; Sidney Kimmel Foundation for Cancer Research. Vice-Chair, St. Jude Scientific Advisory Board; St. Jude Children's Research Hospital. Member, V Foundation Scientific Advisory Board; V Foundation for Cancer Research. M. Yu: None. J. Sarkaria: Research Grant; Basilea, Beigene, Eli LIlly, Genentech, Sanofi-Aventis. board member; Society of NeuroOncology. D.R. Wahl: Stock; Lycer Inc.