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Toward precision medicine in glioblastoma: the promise and the challenges
Michael D Prados1, Sara A Byron1, Nhan L Tran1
1University of California San Francisco, San Francisco, California (M.D.P, J.J.P., A.M.M., S.M.C.); Translational Genomics Research Institute, Phoenix, Arizona (S.A.B., N.L.T., W.D.T., J.A.K., M.E.B., D.W.C., J.D.C., J.M.T.); Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (K.L.L., P.Y.W.); University of Texas Health Science Center, San Antonio, Texas (J.G.K.); Memorial Sloan-Kettering Cancer Center, New York, New York (I.K.M.); The University of Texas M.D. Anderson Cancer Center, Houston, Texas (J.F.d.G.); University of Utah Huntsman Cancer Institute, Salt Lake City, Utah (H.C.); University of California Los Angeles, Los Angeles, California (T.F.C.); Iowa Spine and Brain Institute, Waterloo, Iowa (T.C.R.).
Abstract:
Integrated sequencing strategies have provided a broader understanding of the genomic landscape and molecular classifications of multiple cancer types and have identified various therapeutic opportunities across cancer subsets. Despite pivotal advances in the characterization of genomic alterations in glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. In this review, we highlight potential reasons why targeting single alterations has yielded limited clinical efficacy in glioblastoma, focusing on issues of tumor heterogeneity and pharmacokinetic failure. We outline strategies to address these challenges in applying precision medicine to glioblastoma and the rationale for applying targeted combination therapy approaches that match genomic alterations with compounds accessible to the central nervous system.
Insights
Targeting single genetic changes in glioblastoma has failed due to tumor complexity. Combination therapies that overcome tumor heterogeneity and reach the brain offer new precision medicine strategies for this brain cancer.
Area of Science:
- Genomics
- Molecular Biology
- Neuro-oncology
Background:
- Integrated sequencing reveals cancer's genomic landscape and molecular subtypes.
- Glioblastoma genomic characterization has advanced, yet targeted therapies show limited efficacy, leading to poor patient survival.
Purpose of the Study:
- To review reasons for limited clinical efficacy of single-alteration targeted agents in glioblastoma.
- To outline strategies for precision medicine in glioblastoma, focusing on combination therapy.
Main Methods:
- Literature review of glioblastoma genomic alterations and targeted therapies.
- Analysis of challenges including tumor heterogeneity and pharmacokinetic limitations.
Main Results:
- Single-target therapies in glioblastoma have shown minimal efficacy.
- Tumor heterogeneity and poor drug penetration into the central nervous system are key challenges.
Conclusions:
- Precision medicine for glioblastoma requires addressing tumor heterogeneity.
- Targeted combination therapies, considering central nervous system accessibility, are a promising strategy.
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