Implementing targeted therapies in the treatment of glioblastoma: Previous shortcomings, future promises, and a multimodal strategy recommendation

Abstract The introduction of targeted therapies to the field of oncology has prolonged the survival of several tumor types. Despite extensive research and numerous trials, similar outcomes have unfortunately not been realized for glioblastoma. For more than 15 years, the standard treatment of glioblastoma has been unchanged. This review walks through the elements that have challenged the success of previous trials and highlight some future promises. Concurrently, this review describes how institutions, through a multimodal and comprehensive strategy with 4 essential components, may increase the probability of finding a meaningful role for targeted therapies in the treatment of glioblastoma. These components are (1) prudent trial designs, (2) considered drug and target selection, (3) harnessed real-world clinical and molecular evidence, and (4) incorporation of translational research.

[1]  A. Balasubramanian,et al.  Poor correlation between preclinical and patient efficacy data for tumor targeted monotherapies in glioblastoma: the results of a systematic review , 2022, Journal of Neuro-Oncology.

[2]  Jeffrey Helgager,et al.  Entrectinib demonstrates prolonged efficacy in an adult case of radiation-refractory NTRK fusion glioblastoma , 2022, Neuro-oncology advances.

[3]  P. French,et al.  Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas , 2021, Neuro-oncology advances.

[4]  L. Yarmus,et al.  Joining Forces: How to Coordinate Large, Multicenter Randomized Trials. , 2021, Clinics in chest medicine.

[5]  J. Blay,et al.  Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial , 2021, The Lancet Oncology.

[6]  S. Loi,et al.  ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. , 2021, Annals of oncology : official journal of the European Society for Medical Oncology.

[7]  P. Wen,et al.  Leveraging external data in the design and analysis of clinical trials in neuro-oncology. , 2021, The Lancet. Oncology.

[8]  Susan M. Chang,et al.  Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement. , 2021, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  B. Kristensen,et al.  Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and Their Implications for Therapy , 2021, Cancers.

[10]  W. Oh,et al.  PROMISE: a real-world clinical-genomic database to address knowledge gaps in prostate cancer , 2021, Prostate Cancer and Prostatic Diseases.

[11]  Guojing Liu,et al.  Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy , 2021, Frontiers in Oncology.

[12]  Susan M. Chang,et al.  Systematic review of combinations of targeted or immunotherapy in advanced solid tumors , 2021, Journal for ImmunoTherapy of Cancer.

[13]  S. Di Bartolomeo,et al.  Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update , 2021, International journal of molecular sciences.

[14]  N. Etienne-Selloum,et al.  A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials , 2021, Cancers.

[15]  P. Perrini,et al.  Decipher the Glioblastoma Microenvironment: The First Milestone for New Groundbreaking Therapeutic Strategies , 2021, Genes.

[16]  I. Christensen,et al.  A Prognostic Model for Glioblastoma Patients Treated With Standard Therapy Based on a Prospective Cohort of Consecutive Non-Selected Patients From a Single Institution , 2021, Frontiers in Oncology.

[17]  N. Mitsakakis,et al.  Does biomarker use in oncology improve clinical trial failure risk? A large‐scale analysis , 2021, Cancer medicine.

[18]  N. Hanna,et al.  Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  H. Fine,et al.  Diffuse Glioma Heterogeneity and Its Therapeutic Implications. , 2021, Cancer discovery.

[20]  W. Yung,et al.  The promise of DNA damage response inhibitors for the treatment of glioblastoma , 2021, Neuro-oncology advances.

[21]  D. Tache,et al.  Updated Insights on EGFR Signaling Pathways in Glioma , 2021, International journal of molecular sciences.

[22]  A. Idbaih,et al.  Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives , 2020, Cancers.

[23]  T. Owonikoko,et al.  Benefits and limitations of real-world evidence: lessons from EGFR mutation-positive non-small-cell lung cancer. , 2020, Future oncology.

[24]  T. Snape,et al.  A therapeutic update on PARP inhibitors: implications in the treatment of glioma. , 2020, Drug discovery today.

[25]  B. Cornelissen,et al.  PARP Inhibitors in Cancer Diagnosis and Therapy , 2020, Clinical Cancer Research.

[26]  Yongsheng Gao,et al.  Targeted Therapy with Anlotinib for a Patient with an Oncogenic FGFR3-TACC3 Fusion and Recurrent Glioblastoma. , 2020, The oncologist.

[27]  Michael W Lee,et al.  Current methods in translational cancer research , 2020, Cancer and Metastasis Reviews.

[28]  D. Lacombe,et al.  Past, Current, and Future Cancer Clinical Research Collaborations: The Case of the European Organisation for Research and Treatment of Cancer , 2020, Clinical and translational science.

[29]  Susan M. Chang,et al.  Phase 0 and Window of Opportunity Clinical Trial Design in Neuro-Oncology: A RANO Review. , 2020, Neuro-oncology.

[30]  Voichita D. Marinescu,et al.  Whole-genome sequencing of glioblastoma reveals enrichment of non-coding constraint mutations in known and novel genes , 2020, Genome Biology.

[31]  J. Sarkaria,et al.  Baseline Requirements for Novel Agents Being Considered for Phase II/III Brain Cancer Efficacy Trials:Conclusions from the Adult Brain Tumor Consortium's First Workshop on CNS Drug Delivery. , 2020, Neuro-oncology.

[32]  Raymond Y Huang,et al.  Glioblastoma in Adults: A Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) Consensus Review on Current Management and Future Directions. , 2020, Neuro-oncology.

[33]  H. Engelhard,et al.  Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma , 2020, Molecular Neurobiology.

[34]  S. Park,et al.  Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline , 2020, JCO global oncology.

[35]  Susan M. Chang,et al.  Optimizing eligibility criteria and clinical trial conduct to enhance clinical trial participation for primary brain tumor patients. , 2020, Neuro-oncology.

[36]  Dane Dickson,et al.  The Master Observational Trial: A New Class of Master Protocol to Advance Precision Medicine , 2020, Cell.

[37]  Winnie S. Liang,et al.  Temporospatial genomic profiling in glioblastoma identifies commonly altered core pathways underlying tumor progression , 2020, Neuro-oncology advances.

[38]  J. Barnholtz-Sloan,et al.  Long-term trends in glioblastoma survival: implications for historical control groups in clinical trials. , 2019, Neuro-oncology practice.

[39]  R. Verhaak,et al.  Molecular Evolution of IDH Wild-Type Glioblastomas Treated With Standard of Care Affects Survival and Design of Precision Medicine Trials: A Report From the EORTC 1542 Study. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  Jeffrey H. Chuang,et al.  LONGITUDINAL MOLECULAR TRAJECTORIES OF DIFFUSE GLIOMA IN ADULTS , 2019, Nature.

[41]  G. Reifenberger,et al.  Molecular targeted therapy of glioblastoma. , 2019, Cancer treatment reviews.

[42]  I. Noorani.  Genetically Engineered Mouse Models of Gliomas: Technological Developments for Translational Discoveries , 2019, Cancers.

[43]  K. Debatin,et al.  Temozolomide and Other Alkylating Agents in Glioblastoma Therapy , 2019, Biomedicines.

[44]  Mariella G. Filbin,et al.  An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma , 2019, Cell.

[45]  Nader Sanai,et al.  A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma Patients Incorporating a Tumor Pharmacodynamic- and Pharmacokinetic-Guided Expansion Cohort , 2019, Clinical Cancer Research.

[46]  A. Matheu,et al.  Liquid Biopsy in Glioblastoma: Opportunities, Applications and Challenges , 2019, Cancers.

[47]  A. Drilon,et al.  Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors. , 2019, Journal of Clinical Oncology.

[48]  Ellie G. Siden,et al.  Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols , 2019, Trials.

[49]  W. Ma,et al.  Recent Advances in the Clinical Targeting of Hedgehog/GLI Signaling in Cancer , 2019, Cells.

[50]  P. Wen,et al.  Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A Bayesian Adaptive Platform Trial to Develop Precision Medicines for Patients With Glioblastoma , 2019, JCO precision oncology.

[51]  Sankha S. Basu,et al.  Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  C. Brennan,et al.  Tracking Tumor Evolution in Glioma through Liquid Biopsies of Cerebrospinal Fluid , 2018, Nature.

[53]  David T. W. Jones,et al.  N2M2 (NOA-20) phase I/II trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed non-MGMT hypermethylated glioblastoma. , 2018, Neuro-oncology.

[54]  C. Limatola,et al.  CXCL16/CXCR6 Axis Drives Microglia/Macrophages Phenotype in Physiological Conditions and Plays a Crucial Role in Glioma , 2018, Front. Immunol..

[55]  Lorenzo Trippa,et al.  The clinical trials landscape for glioblastoma: is it adequate to develop new treatments? , 2018, Neuro-oncology.

[56]  Juxiang Chen,et al.  Gene Fusion in Malignant Glioma: An Emerging Target for Next-Generation Personalized Treatment , 2018, Translational oncology.

[57]  Timothy Heffron.  Challenges of developing small-molecule kinase inhibitors for brain tumors and the need for emphasis on free drug levels. , 2018, Neuro-oncology.

[58]  Vivek Subbiah,et al.  Challenging Standard-of-Care Paradigms in the Precision Oncology Era. , 2018, Trends in cancer.

[59]  Martin Klein,et al.  Lomustine and Bevacizumab in Progressive Glioblastoma , 2017, The New England journal of medicine.

[60]  Brian M Alexander,et al.  Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE , 2017, Clinical Cancer Research.

[61]  G. Parmigiani,et al.  Leveraging molecular datasets for biomarker-based clinical trial design in glioblastoma , 2017, Neuro-oncology.

[62]  J. Moffat,et al.  Intratumoral heterogeneity: pathways to treatment resistance and relapse in human glioblastoma , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[63]  Susan M. Chang,et al.  Response Assessment in Neuro-Oncology Clinical Trials. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  V. Prasad,et al.  Drugs that lack single-agent activity: are they worth pursuing in combination? , 2017, Nature Reviews Clinical Oncology.

[65]  N. McGranahan,et al.  Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future , 2017, Cell.

[66]  M. Kattan,et al.  An independently validated nomogram for individualized estimation of survival among patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825. , 2016, Neuro-oncology.

[67]  K. Peck,et al.  Molecular and Clinical Effects of Notch Inhibition in Glioma Patients: A Phase 0/I Trial , 2016, Clinical Cancer Research.

[68]  Steven J. M. Jones,et al.  Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma , 2016, Cell.

[69]  A. Iavarone,et al.  Detection, Characterization, and Inhibition of FGFR–TACC Fusions in IDH Wild-type Glioma , 2015, Clinical Cancer Research.

[70]  R. Verhaak,et al.  The landscape and therapeutic relevance of cancer-associated transcript fusions , 2014, Oncogene.

[71]  K. Aldape,et al.  Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. , 2014, The Lancet. Oncology.

[72]  Shawn M. Gillespie,et al.  Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma , 2014, Science.

[73]  K. Hoang-Xuan,et al.  Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. , 2014, The New England journal of medicine.

[74]  K. Aldape,et al.  A randomized trial of bevacizumab for newly diagnosed glioblastoma. , 2014, The New England journal of medicine.

[75]  W. Wick,et al.  Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials , 2013, Neuro-oncology.

[76]  Reid C. Thompson,et al.  The relative value of postoperative versus preoperative Karnofsky Performance Scale scores as a predictor of survival after surgical resection of glioblastoma multiforme , 2014, Journal of Neuro-Oncology.

[77]  M. Lomax,et al.  Biological consequences of radiation-induced DNA damage: relevance to radiotherapy. , 2013, Clinical oncology (Royal College of Radiologists (Great Britain)).

[78]  S. Fricker.  Physiology and Pharmacology of Plerixafor , 2013, Transfusion Medicine and Hemotherapy.

[79]  D. Tseng,et al.  Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas , 2011, British Journal of Cancer.

[80]  S. Morrison,et al.  Heterogeneity in Cancer: Cancer Stem Cells versus Clonal Evolution , 2009, Cell.

[81]  R. Mirimanoff,et al.  Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. , 2009, The Lancet. Oncology.

[82]  E. D. de Vries,et al.  Prognostic versus predictive value of biomarkers in oncology. , 2008, European journal of cancer.

[83]  Larry Rubinstein,et al.  Phase 0 Clinical Trials: Conceptions and Misconceptions , 2008, Cancer journal.

[84]  Elizabeth Eisenhauer,et al.  Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. , 2008, The Lancet. Oncology.

[85]  Kumanan Wilson,et al.  Barriers to participation in clinical trials of cancer: a meta-analysis and systematic review of patient-reported factors. , 2006, The Lancet. Oncology.

[86]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[87]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[88]  Cynthia Hawkins,et al.  Identification of a cancer stem cell in human brain tumors. , 2003, Cancer research.