Personalized therapy based on the genetic characterization of a given patient's tumor offers great potential in cancer treatment. These therapies that target the molecular drivers of cancers offer high efficacy and more palatable side effect profiles compared to standard chemotherapies. Successes include imatinib which treats chronic myeloid leukemia with its characteristic translocations causing the fusion protein BCR-ABL and gefitinib for non small cell lung cancers with point mutations in the intracellular kinase domain of EGFR3, 4, 39, 51
. Activating mutations and amplifications are easier to block, than it is to reinstall the activity of disrupting mutations and deletions.
In GBM, developing targeted therapies is complicated: we need to (1) identify true driver mutations and alterations while steering clear of the hundreds of non-driver "passenger" mutations that result from massive genomic instability of GBM; (2) effectively deliver drug to the tumor despite the blood-brain barrier; and (3) completely perfuse the heterogeneous tumor with high enough drug levels to affect the target. Additionally, successful targeted therapies for GBM might be particularly challenging to develop because of co-activation of multiple, independent, signaling cascades that might require hitting multiple targets in order to effectively kill the tumor20, 52
. Targeting multiple pathways with multiple agents in this way makes clinical trial design more difficult and trials take longer, since the dose limiting toxicities of each drug must be demonstrated, and there might be synergistic effects between toxicities from multiple targeted agents combined. The field is further muddled by clinical trials that do not require evidence of given pathway activation as an inclusion criterion for study entry for the given targeted therapy. Such trials fail to account for the fact that GBM is a heterogeneous disease in which targeted therapies will have minimal effects when the target is not the driver for the treated patient's tumor. While such data can still be used to study dose limiting toxicity, it is not helpful in extrapolating the potential utility of the drug. The last limitation to interpreting results of targeted therapies is the failure to select agents that truly cause cell death -- and not just senescence or decreased cell proliferation -- in their targeted cells in vitro. Although cell death might not be required for the utility of targeted agents when used in combination with other drugs, it should be a distinguishing feature of drugs that are moved to high priority for further clinical testing. On a practical level, assessing successful target shut down in brain tumor patients is complicated: in order to select the appropriate patients, tissue is required. However, to assess successful target shut down requires more tissue after a given time of treatment. This therefore requires a minimum of two brain surgeries. While the first surgery might only require a relatively low risk biopsy for tissue, sample bias as a result of intratumoral heterogeneity is further complicating when it comes to improving treatment of GBM. The success of targeted therapies depends on patient selection, either by histological and staining criteria that define the susceptible pathway targeted, or tumor signatures that accurately predict response. For example, one study sponsored by North Central Cancer Treatment Group and NCI is collecting protein expression, immunohistochemistry staining, and gene expression data on patients to identify the best candidates for successful EGFR inhibition.
Of the 579 GBM clinical trials in the US and Europe presently listed on http://www.clinicaltrials.org
, a number aim to bring targeted therapies to GBM. Although far from an exhaustive, this list serves as an example of the depth of what is being tried, such as various targeted agents at different levels of action from the cell membrane down to cyclin dependent kinases.
Since EGFR and other RTK pathways are aberrant at the genomic level of a high fraction of tumors, these offer suitable targets for GBM therapies. Early trials of RTK-targeting were hampered by inadequate drug levels in the tumor or not assessing the tumor after treatment for target activity53, 54
. Erlotinib, which blocks internal tyrosine kinase activation of EGFR, cetuximab and nimotuxumab, which block ligand binding to EGFR, have been or are in trial55–57
. These might be a hopeful strategy for EGFR
-amplified tumors, but not necessarily tumors with constitutively activated EGFRvIII. Gefitinib, which effectively blocks EGFR with intracellular point mutations in lung adenocarcinoma, is under study although GBM is different from lung cancer in that the GBM EGFR mutations are typically extracellular and therefore the promise of gefitinib for GBM is less clear. PF00299804 is an irreversible pan ERBB family inhibitor that has shown efficacy in non small cell lung cancer models and is being tried in GBM given its EGFR inhibition58
. Other RTKs are being targeted as well, for example, XL184 which targets MET in addition to VEGFR2, also known as KDR, and MEDI-575, an antibody that targets the platelet-derived growth factor-receptor PDGFRα59
. Sunitinib targets PDGFRβ as well as KDR60, 61
. Tyrosine kinases are the targets in a trial with E7050 in combination with E7080 in addition to KDR61, 62
. A trial of pazopanib, which blocks PDGFR, FLT1 (VEGFR1), KDR, (VEGFR2), FLT4 (VEGFR3), and c-KIT, did not prolong progression free survival in patients with recurrent GBM63
genes are not found to be frequently mutated in GBM, tipifarnib is a RAS farnesyltransferase inhibitor that is under investigation, after it failed to gain approval for several other cancers64
. Lonafarnib is a farnesyltransferase that inhibits post-translational modification of H-RAS, but not N-RAS or K-RAS65
Downstream of RTK and RAS signaling, there are multiple agents that target the PI3K pathway such as pan PI3K inhibitor BKM12066
. Multiple studies include sirolimus or rapamycin, which target mTOR67
. There is an ongoing trial that includes nelfinavir, a protease inhibitor used in the treatment of HIV that also interferes with Akt activity68
. Sorafenib is a RAF inhibitor that also targets PDGFR as well as VEGFR69
. An example of targeting the cell cycle alterations found in GBM genomes is the CDK4/CDK6 inhibitor PD0332991; patients must have activated Rb in order to be enrolled70
. There are agents in trial that affect less commonly aberrant pathways in GBM, like an attempt to target TGFB2 with an antisense oligonucleotide, AP1200971
. Lastly, a large number of trials have been focusing on targeting members of pathways that enable vascularization, like VEGF receptors. While in studies there might be improvements in imaging characteristics (decreased gadolinium enhancement on MRI) and the ability for patients to decrease their steroid dose (less brain edema with VEGF-targeting agents), so far, there has been minimal benefit in survival72
. VEGFR status on the tumor cells is typically not used to decide whether a patient receives these agents and it possible that some subclasses of patients will be found to do better, such as those that express the angiogenesis marker. Interestingly, the Mesenchymal expression subtype signature contains several angiogenesis markers. An ongoing study of bevacizumab and temozolomide in older patients with newly diagnosed GBM, sponsored by UCLA and Genentech, is collecting tumor microarray data. Such studies are then able to ask questions like whether the Mesenchymal subclass signature predicts response to bevacizumab.