Brain Trauma Oncology Table 2: Selected Novel Therapies
Type Therapy Surgical
Convection-enhanced delivery (e.g. cintredekin besudotox, anti-TGF-β, antisense AP 12009, PRX321 (IL-4 linked to Pseudomonas exotoxin)
Overcoming Dose-dense TMZ resistance to TMZ Novel
MGMT inhibitors (e.g. O6-benzylguanine, lomeguatrib) PARP inhibitors (e.g. BSI-201, ABT-888) e.g. ANG1005, RTA744
chemotherapies Anti-angiogenic Anti-αvβ5 integrins (e.g. cilengitide) therapy
Targeted
Anti-hepatocyte growth factor (e.g. AMG-102) Anti-VEGF (e.g. bevacizumab, aflibercept [VEGF-Trap]) Anti-VEGFR (e.g. cediranib, vandetinib, pazopanib sorafenib, sunitinib, XL184, CT-322, IMC-1121B) Others (e.g. thalidomide) Akt (e.g. perifosine, MK2206)
molecular Bcl2 (AT101) therapy
EGFR inhibitors (e.g erlotinib, gefitinib, lapatinib, BIBW 29992, PF00299804, nimotuzumab, cetuximab) FTI inhibitors (e.g. tipifarnib and lornafarnib) HDAC inhibitors (e.g. vorinostat, depsipeptide, LBH589) HSP90 inhibitors (e.g. 17AAG, IPI504) Insulin-like growth factor receptor (OSI906) Met (e.g. XL184)
mTOR inhibitors (e.g. everolimus, sirolimus, temsirolimus, AP23573)
PI3K inhibitors (XL765) PKCβ (e.g. enzastaurin)
PDGFR inhibitors (e.g. dasatinib, imatinib, tandutinib, IMC3G3 (Mab against PDGFR-alpha) Proteosome (e.g bortezomib) Raf (e.g. sorafenib)
Src (e.g dasatinib, bosutinib [SK606]) TGF-β (e.g. AP12009) Combination therapies: Erlotinib + temsirolimus Gefitinib + everolimus Gefitinib + sirolimus
Sorafenib + temsirolimus, erlotinib or tipifarnib Pazopanib + lapatinib Bortezomib + vorinostat Vandetinib + sirolimus Cediranib + cilengitide
Immunotherapy Dendritic cell and EGFRvIII peptide vaccines, monoclonal antibodies (e.g 74I-anti-tenascin antibody) (CDX110)
Gene therapy Delta-24-RGD-4C Cerepro
Therapy Notch inhibitors (MRK0752, R4929097)
directed against Sonic hedgehog inhibitor (GDC-4409) stem cells Miscellaneous
74I-TM-601
EGFR = epidermal growth factor receptor; FTI = farnesylytransferase; HDAC = histone deacetylase; HSP90 = heat shock protein 90; MGMT = methylguanine-DNA-methyl transferase; mTOR = mammalian target of rapamycin; PARP = poly (ADP-ribose) polymerase; PDGFR = platelet-derived growth-factor inhibitor; PI3K = phosphatidylinositol 3-kinase; PKC = protein kinase C; RT = radiotherapy; TMZ = temozolomide; TGF= transforming growth factor; TMZ = temozolomide; VEGFR = vascular endothelial growth factor receptor.
difficult treatment targets because they transition slowly through the cell cycle, express high levels of drug-export proteins and may not express oncoproteins that are targeted by newer chemotherapeutic drugs.112
As a result, there is significant interest in molecular therapies affecting stem-cell pathways, such as notch (e.g. MRK0752 and
54
R4929097), sonic hedgehog (e.g. GDC4409)111,112,114 factors 1 and 2α.113
Overcoming Resistance to Targeted Molecular Therapy
Monotherapy with most targeted molecular agents (except for anti-VEGFR agents) has shown modest activity at best. These results are not surprising when one considers that most HGG have co-activation of multiple tyrosine kinases87
and highly redundant
signalling pathways. Approaches now under evaluation in clinical trials include the combination of a targeted agent with radiotherapy and chemotherapy, the combination of several targeted agents and agents that hit multiple relevant targets at once.10,20,115,116
For example,
the EGFR inhibitor erlotinib has been studied in combination with mTOR inhibitors, such as sirolimus117
and temsirolimus.118 Although
preliminary results from these erlotinib combination studies suggest only modest efficacy due to poor tolerability,118,119
other combinations
may be better tolerated and are in clinical trials. There is also continued interest in clinical trial designs that incorporate tissue specimens to identify biomarkers to predict tumour response to target inhibition.120,121
and hypoxia-inducible
This may allow identification of patients who are
more likely to respond to specific therapies. Advances in molecular profiling of tumour tissue may lead to more selective use of targeted molecular agents and tailoring of therapy to individual patients. A recent study demonstrated that GBM can be subdivided by genomic profiling into four subtypes, each of which demonstrates unique molecular alterations.122
A prominent mechanism of resistance to targeted molecular therapy is inadequate drug delivery across the blood–brain barrier. Increasingly, trials of novel targeted agents include a surgical component to evaluate the ability of the drug to reach therapeutic concentrations in the tumour and inhibit the putative target. Patients with recurrent HGG were administered the agent prior to planned surgery and the tumour is obtained for drug concentration and evidence of pathway inhibition.123
If drug concentration and target
inhibition in the tumour is poor, further evaluation of that agent in HGG is probably not warranted.120
Other Therapeutic Modalities
A large number of therapeutic modalities are being explored for HGG. Examples include inhibitors of the ubiquitin-proteosome system such as bortezomib,124–126 gene therapy,130
heat-shock protein inhibitors,127,128 synthetic chlorotoxins (TM-601),131
cytokines,129 chemotherapeutic
agents with enhanced ability to penetrate into tumour tissue and convection-enhanced delivery (CED) of drugs and toxins.132 Intracavitary TM-601, the synthetic version of a chlorotoxin found in the venom of the giant yellow Israeli scorpion, is under evaluation in a phase II study. Agents administered directly into HGG via CED that have been studied in phase III clinical trials include interleukin-13 (IL-13), Pseudomonas aeruginosa exotoxin and transferrin-C diphtheriae toxin. Unfortunately, both trials were terminated for futility after interim analysis.133
By contrast, studies of trabedersen
Transfer of ‘suicidal’ genes via viral vectors such as herpes simple virus thymidine kinase gene (HSV-tk) has demonstrated only limited survival benefit in several clinical trials for recurrent GBM.134
(AP1007), a phosphorothioate antisense oligonucleotide against transforming growth factor β2, appears to have activity in recurrent AG and is being evaluated in a phase III study. Therapy involves the insertion or modification of genes in a patient’s cell to treat a disease.134
EUROPEAN NEUROLOGICAL REVIEW
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