Table 1.
Current molecularly targeted molecular therapies under development and in ongoing clinical trials for central nervous system (CNS) tumors, highlighting attempts at theranostics and local delivery in the clinical setting.
| Agent | Mechanisms | Clinical Trials | Theranostics/Local Delivery |
|---|---|---|---|
| Angiogenesis Inhibitors | |||
| VEGF mAbs Bevacizumab | Inhibits vascular endothelial growth factor A (VEGF-A) [135] | No effect on OS in recurrent GBM [135,136,137,138] | 111In-bevacizumab SPECT in melanoma, RCC and CRC [139,140,141]; 89Zr-bevacizumab PET in primary BC [142,143]; Intra-arterial delivery of bevacizumab [37] |
| Epigenetic Therapies | |||
| HDAC inhibitors Panobinostat Vorinostat | Restore histone acetylation in histone mutated gliomas (GBM [144,145], medulloblastoma [146,147] and DIPG [148,149,150,151]) | Single agents in GBM [152] and DIPG [NCT02717455]; Combined agents [153]; Radiosensitizers [154] | - |
| Growth Factor Signaling | |||
| EGFR mAbs Cetuximab ABT-414 | Block EGFR signaling via binding extracellular domain. ABT-414 is an antibody-drug conjugate targeting EGFR/EGFRvIII | Cetuximab + temozolomide + XRT [155,156]; ABT-414: Phase II [NCT02573324] | 123I cetuximab crosses BBB, accumulates in NSCLC brain metastases [157]; Cetuximab SSIACI + mannitol BBBD [158] |
| EGFR TKIs Erlotinib Gefitinib | Block intracellular tyrosine kinase activity of EGFR | Limited single agent effect in Phase II studies; toxicities leading to early termination [159,160,161,162,163] | - |
| PI3K/mTOR inhibitors Everolimus Tacrolimus Sirolimus | Blockade of PI3K/mTOR growth signaling pathways | Everolimus + TMZ + XRT shows PET-visualized antiproliferative effects in GBM [164]; Everolimus in DIPG [NCT02233049] | - |
| PDGF/PDGFR Dasatinib Vandetanib | Targets PDGFR signaling; PDGFRA amplifications common in both adult and pediatric high-grade gliomas [165] | Dasatinib in DIPG [NCT02233049, NCT01644773]; Vandetanib in GBM shows no change in OS [166] | - |
| Immunotherapy/Vaccines | |||
| Vaccines Rindopepimut SL-701 | Vaccines establish immune response to either mutant EGFRvIIII antigen (rindopepimut) [167] or IL-13Ra2, survivin, and Epha2 (SL-701); additional personalized tumor lysate vaccines are under development | Rindopepimut + GM-CSF in newly diagnosed GBM patient prolongs PFS and OS with minimal toxicity [168]; Phase III discontinued [NCT01480479]; SL-701 in Phase I/II for GBM [NCT02078648]; BTIC/Imiquimod in DIPG [NCT01400672] | - |
| Checkpoint Inhibitors Ipilimumab Nivolumab | mAbs which target either CTLA-4 (ipilimumab) or PD-1 (nivolumab) enhancing immune system antitumoral response [169] | Phase III: Nivolumab + ipilimumab in recurrent GBM [NCT02017717]; Nivolumab in new GBM [NCT02617589] | - |
| Cell-based Therapies CAR-T | Chimeric antigen receptor transduced peripheral blood lymphocytes initiate cell-mediated cytotoxicity of target cells (i.e. against EGFRvIII) [170] | Phase I/II: GBM [NCT01454596] | - |
| Other | |||
| 124I-8H9 | MAb 8H9 recognizes B7-H3, extracellular antigen [83] | Phase I: DIPG [NCT01502917] | Agent delivered via CED |
HDAC: histone deacetylase; EGFR: epidermal growth factor recepton; XRT: radiotherapy; NSCLC: non-small cell lung cancer; SSIACI: superselective intraarterial cerebral infusion; TKI: tyrosine kinase inhibitor; TMZ: temozolomide; PI3K: phosphoinositide 3-kinase; mTOR: mechanistic target of rapamycin; PDGFR: platelet-derived growth factor receptor; OS: overall survival; IL-13Ra2: interleukin-13 receptor subunit alpha-2; Epha2: Ephrin type-A receptor 2.