Although early studies suggested that and status could predict response to EGFR-targeted therapies [201, 202], outcome was not correlated with the presence of amplification, loss or other molecular alterations in subsequent studies, and molecular predictors for the efficacy of EGFR targeted therapies remain undetermined. review the most promising biological insights that have opened the way AG 957 for the development of targeted therapies in glioblastoma, and examine recent data from clinical trials evaluating targeted therapies and immunotherapies. We discuss challenges and opportunities for the development of these agents in glioblastoma. and promoter, and [10]. Table 1 Genomic alterations and example targeted therapies in glioblastoma and oncogenic variants in a single cell) [29, 30, 40], which overall results in heterogeneity in drug sensitivity within individual tumor cells [41] (Figure ?(Figure1).1). Open in a separate window Figure 1. Cellular heterogeneity of RTK aberrations in glioblastoma: implications for appropriate drug targeting (adapted from Francis et al. [30]). Dynamics of the glioblastoma genome may generate or select for subclonal populations of tumor cells that are highly resistant to treatment, overall suggesting that comprehensive characterization of tumor heterogeneity is a prerequisite for the success of pharmacological inhibition AG 957 of RTK alterations. Left, multiple amplifications of distinct RTK genes can be observed in non-overlapping subclonal populations from individual tumors, or within individual tumor cells. In other cases (right), tumor heterogeneity may exist as multiple alterations within a single RTK gene. Targeting growth factor receptors and their downstream signaling pathways Drugs directed against alterations that lead to constitutive activation of growth factor RTKs are the most common type of targeted therapy in all types of cancer with successful responses seen in many cancers. These drugs have also been of great interest in glioblastoma because direct alterations in RTKs and/or downstream MAPK/PI3K signaling pathways represent a hallmark of this tumor (Table ?(Table1)1) [10]. EGFR-targeted therapies amplification, rearrangement or point mutations are found in approximately half of glioblastomas and multiple aberrations in often co-exist within an individual tumor [10, 30, 42C44]. Nearly 20% of glioblastomas harbor deletion of exons 2C7 of amplification. Preclinical studies have demonstrated that EGFRvIII-driven tumors are only weakly sensitive to first generation EGFR tyrosine kinase inhibitors (TKI) erlotinib and gefitinb [45, 46]. Indeed, EGFRvIIIas most other SNVs found in glioblastomaalters the extracellular domain of EGFR in glioblastoma, while in contrast lung adenocarcinomas typically harbor direct activating mutations in the kinase domain [45]. Rindopepimut is an EGFRvIII peptide vaccine that demonstrated signs of activity in preclinical models of glioblastoma and early phase trials [16, 47, 48]. The recently completed randomized phase II study ReACT evaluated the association of rindopepimut plus bevacizumab in EGFRvIII-positive recurrent glioblastoma. Advantage to rindopepimut therapy was reported across multiple endpoints including 2-year OS rate and progression-free survival (PFS), although the trial failed to meet its primary endpoint [49] (Table ?(Table2).2). Preliminary analyses from the phase III randomized study of rindopepimut in newly diagnosed EGFRvIII-positive glioblastoma indicated that its benefit on OS will not reach statistical significance (23?months from diagnosis in both arms), resulting in the closure of the trial [50]. Subgroup analyses suggested that rindopepimut might have failed due to reduced amount of EGFRvIII antigen burden in patients that underwent gross total resection (2-year survival rate of 30% in patients with non-minimal residual disease versus 19% in patients with minimal residual disease), although these results will need confirmation after longer follow-up. Further development of rindopepimut is uncertain. Table 2 Recently reported trials of targeted therapies in recurrent glioblastoma = 64 (ona/beva), = 65 (beva/p)8.8 (ona/beva), 12.6 (beva/p)3.9 (ona/beva), 2.9 (beva/p)33.9% (ona/beva), 29% (beva/p)[97]Phase II, double-blind, randomizedBevacizumab + rindopepimut (beva/rindo) or bevacizumab + placebo (beva/p)VEGF (bevacizumab), EGFRvIII (rindopepimut)First or second recurrence, bevacizumab-na?ve, EGFRvIII- positive, = 7311.6 (beva/rindo), 9.3 (beva/p)NA28% (beva/rindo), 16% (beva/p)[49]Phase II, randomizedTemozolomide (TMZ) or afatinib (afa) or afatinib + temozolomide (afa/TMZ)EGFR (Afatinib)First recurrence, = 39 (TMZ), = 41 (afa),.As an illustration, novel MDM2 inhibitors have been reported to inhibit the growth of amplification status [117, 118]. responses have been documented in patients, to date no targeted therapy has been formally validated as effective in clinical trials. The lack of knowledge about relevant molecular drivers combined with a lack of highly bioactive and brain penetrant-targeted therapies remain significant challenges. In this article, we review the most promising biological insights that have opened the way for the development of targeted therapies in glioblastoma, and examine recent data from clinical trials evaluating targeted therapies and immunotherapies. We discuss challenges and opportunities for the development of these agents in glioblastoma. and promoter, and [10]. Table 1 Genomic alterations and example targeted therapies in glioblastoma and oncogenic variants in a single cell) [29, 30, 40], which overall results in heterogeneity in drug sensitivity within individual tumor cells [41] (Figure ?(Figure1).1). Open in a separate window Figure 1. Cellular heterogeneity of RTK aberrations in glioblastoma: implications for appropriate drug targeting (adapted from Francis et al. [30]). Dynamics of the glioblastoma genome may generate or select for subclonal populations of tumor cells that are highly resistant to treatment, overall suggesting that comprehensive characterization of tumor heterogeneity is a prerequisite for the success of pharmacological inhibition of RTK alterations. Left, multiple amplifications of distinct RTK genes can be observed in non-overlapping subclonal populations from individual tumors, or within individual tumor cells. In other cases (right), tumor heterogeneity may exist as multiple alterations within a single RTK gene. Targeting growth factor receptors and their downstream signaling pathways Drugs directed against alterations that lead to constitutive activation of growth factor RTKs are the most common type of targeted therapy in all types of cancer with successful responses seen in many cancers. These drugs have also been of great interest in glioblastoma because direct alterations in RTKs and/or downstream MAPK/PI3K signaling pathways represent a hallmark of this tumor (Table ?(Table1)1) [10]. EGFR-targeted therapies amplification, rearrangement or point mutations are found in approximately half of glioblastomas and multiple aberrations in often co-exist within an individual tumor [10, 30, 42C44]. Nearly 20% of glioblastomas harbor deletion of exons 2C7 of amplification. Preclinical studies have demonstrated that EGFRvIII-driven tumors are only weakly delicate to first era EGFR tyrosine kinase inhibitors (TKI) erlotinib and gefitinb [45, 46]. Certainly, EGFRvIIIas almost every other SNVs within glioblastomaalters the extracellular domains of EGFR in glioblastoma, while on the other hand lung adenocarcinomas typically harbor immediate activating mutations in the kinase domains [45]. Rindopepimut can be an EGFRvIII peptide vaccine that showed signals of activity in preclinical types of glioblastoma and early stage studies [16, 47, 48]. The lately completed randomized stage II research ReACT examined the association of rindopepimut plus bevacizumab in EGFRvIII-positive repeated glioblastoma. Benefit to rindopepimut therapy was reported across multiple endpoints including 2-calendar year OS price and progression-free success (PFS), however the trial didn’t meet Mouse monoclonal to GAPDH its principal endpoint [49] (Desk ?(Desk2).2). Primary analyses in the stage III randomized research of rindopepimut in recently diagnosed EGFRvIII-positive glioblastoma indicated that its advantage on OS won’t reach statistical significance (23?a few months from medical diagnosis in both hands), leading to the closure from the trial [50]. Subgroup analyses recommended that rindopepimut may have failed because of reduction of EGFRvIII antigen AG 957 burden in sufferers that underwent gross total resection (2-calendar year survival price of 30% in sufferers with non-minimal residual disease versus 19% in sufferers with reduced residual disease), although these outcomes will need verification after much longer follow-up. Further advancement of rindopepimut is normally uncertain. Desk 2 Lately reported studies of targeted therapies in repeated glioblastoma = 64 (ona/beva), = 65 (beva/p)8.8 (ona/beva), 12.6 (beva/p)3.9 (ona/beva), 2.9 (beva/p)33.9% (ona/beva), 29% (beva/p)[97]Phase II, double-blind, randomizedBevacizumab + rindopepimut (beva/rindo) or bevacizumab + placebo (beva/p)VEGF (bevacizumab), EGFRvIII (rindopepimut)First or second recurrence, bevacizumab-na?ve, EGFRvIII- positive, = 7311.6 (beva/rindo), 9.3 (beva/p)NA28% (beva/rindo), 16% (beva/p)[49]Stage II, randomizedTemozolomide (TMZ) or afatinib (afa) or afatinib + temozolomide (afa/TMZ)EGFR (Afatinib)Initial recurrence, = 39 (TMZ), = 41 (afa), = 39 (afa/TMZ)10.6 (TMZ) 9.8 (afa) 8 (afa/TMZ) 1.9 (TMZ) 1 (afa) 1.5 (afa/TMZ) 23% (TMZ) 3% (afa) 10% (afa/TMZ) [62]Phase I, single-agentABT-414EGFR, EGFRvIIIAny recurrence, = 609.0NA28.3%[52]Stage II, single-agentPX-866PI3KFirst recurrence, = 33NANA17%[101]Stage II, single-armBuparlisib + bevacizumabPI3K (buparlisib), VEGF (bevacizumab)Initial recurrence, = 6810.85.3NA[102]Stage II, single-armErlotinib.