Toward precision medicine in glioblastoma: the promise and the challenges.
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.
University 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.).
Michael D
MD
Prados
University 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.).
Sara A
SA
Byron
University 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.).
Nhan L
NL
Tran
University 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.).
Joanna J
JJ
Phillips
University 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.).
Annette M
AM
Molinaro
University 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.).
Keith L
KL
Ligon
University 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.).
Patrick Y
PY
Wen
University 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.).
John G
JG
Kuhn
University 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.).
Ingo K
IK
Mellinghoff
University 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.).
John F
JF
de Groot
University 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.).
Howard
H
Colman
University 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.).
Timothy F
TF
Cloughesy
University 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.).
Susan M
SM
Chang
University 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.).
Timothy C
TC
Ryken
University 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.).
Waibhav D
WD
Tembe
University 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.).
Jeffrey A
JA
Kiefer
University 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.).
Michael E
ME
Berens
University 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.).
David W
DW
Craig
University 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.).
John D
JD
Carpten
University 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.).
Jeffrey M
JM
Trent
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002986:Clinical Trials as Topic; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy / Q000639:trends; D009154:Mutation; D057285:Precision Medicine / Q000639:trends*
D000970:Antineoplastic Agents
clinical trial; genomics; glioblastoma; precision medicine; targeted therapy