The last decade has witnessed major progress in understanding the biology behind the clinical and histologic differences seen in medulloblastoma. Results of several transcriptional profiling studies from various cooperative groups have demonstrated that medulloblastoma consists of at least four different biological subgroups with divergent clinical and biological presentations and behaviour. The 4 groups, Wnt (Group 1), Sonic Hedgehog (SHH; Group 2), Group 3 and Group 4, differ in their demographics, histology, DNA copy-number aberrations and clinical outcome [8]. The identification of these molecular subgroups has triggered great interest in the identification of targeted therapies for each specific subgroup. So far, these studies have identified the SHH and Wnt pathways as potential molecular targets in medulloblastoma. The molecular pathogenesis of groups 3 and 4 medulloblastoma is still poorly understood and efforts are ongoing to develop accurate mouse models.

So far, most efforts to support translational developments have focused on the development and evaluation of SHH inhibitors. Tumours in the SHH group are associated with mutations in genes PTCH, SMO or SUFU. Aberrant activation of the SHH signalling pathway causes increased cell proliferation and is linked to the development of several types of cancer, in particular medulloblastoma, where activating or inactivating mutations in genes that regulate the SHH pathway have been identified in approximately 30 % of tumours. From early murine work, treatment of medulloblastoma in Ptc1(±) p53(−/−) mice with the SMO inhibitor HHAntag showed promising results. Following a high-throughput development cell-based screen for novel compounds capable of blocking SHH-activated gene transcription, several compounds were identified with potent activity. GDC-0449 (Vismodegib, Genentech) was the first-in-class small-molecule antagonist of the SHH receptor tested in medulloblastoma patients [9]. Another compound, LDE225 (Erismodegib, Novartis), was subsequently tested in clinical trials. Both drugs have shown activity in recurrent paediatric and adult medulloblastoma. A phase II trial of GDC-0449 is ongoing in children with recurrent or refractory medulloblastomas with evidence of activation of the Hedgehog signalling pathway. Likewise, a phase III trial of LDE225 has also recently opened for patients with SHH-pathway-activated medulloblastoma. The primary objective of the latter study is to compare the efficacy of LDE225 versus temozolomide in patients who have relapsed after prior standard-of-care therapy, including craniospinal radiotherapy with no prior temozolomide. This trial will also have two non-randomised, uncontrolled arms, one for paediatric patients aged less than 6 years who have not received radiotherapy as part of their initial treatment and one for adult and paediatric patients who have received prior craniospinal radiation with temozolomide as part of their primary therapy.

Despite multiple clinical trials of chemotherapy schedules (before and/or during and/or after radiation; low dose metronomic; intensive or high-dose chemotherapy with autologous stem cell rescue) and radiation techniques (hypo-, normo- or hyperfractionation), the outcome of this tumour is still devastating and no improvement in survival has been achieved over the last three decades. Post-mortem tissue collection was initiated in Canada, the USA and the Netherlands to address the lack of tumour material for research and to allow identification of new targets. These studies have shown a distinct genetic and methylation profile of DIPG as compared with other paediatric and adult high-grade gliomas. At the gene expression level, DIPG are mainly characterised by frequent amplification of the PDGF receptor, PDGFR. Other amplifications have been described involving the hepatocyte growth factor receptor MET, IGF receptor 1 (IGF1R), EGF receptors (EGFR, ERBB4 and EGFRv3), poly-ADP-ribose polymerase (PARP), VEGFA and associated downstream pathways including the PI3KAkt-phosphomammalian target of rapamycin (mTOR). In this context, several trials of small-molecule inhibitors have been conducted in recent years (reviewed in [2]).

Because of the role of PDGF in gliomagenesis and the frequent overexpression of PDGFR alpha in paediatric anaplastic astrocytoma, imatinib was the first agent incorporated into DIPG trials. A phase I/II study conducted by the Pediatric Brain Tumor Consortium enrolled 35 patients [2]. In this trial, the initial design was to administer imatinib in conjunction with radiation therapy. However, because of concerns regarding the incidence of intra-tumoural haemorrhage during irradiation, the protocol was amended to exclude patients with evidence of haemorrhage on MRI scan prior to irradiation, and imatinib treatment was started two weeks after completion of radiotherapy, provided that there was no evidence of intralesional blood on the post-irradiation MRI scan. This trial reported a 1-year event-free and overall survival rate of 24.3 % and 45.5 %, respectively, a result similar to that observed in previous DIPG studies of radiation with or without chemotherapy. This dampened enthusiasm for the development of further studies.

Although gene amplification of EGFR is uncommon in DIPG, overexpression of EGFR is nevertheless often detected. Two trials of EGFR inhibitors were conducted: one using gefitinib during and after radiation, and a trial of erlotinib that mandated histological confirmation of malignant brainstem gliomas [13, 14]. Both studies reported mild and reversible toxicity. Event-free and overall survival in these trials were consistent with the results of previous studies. However, intriguingly, anecdotal cases of long-term survivors were reported. For instance in the gefitinib study, three patients out of 43 cases remained progression free with 36 months of follow-up.

In addition to EGFR directed tyrosine kinase inhibitors, monoclonal antibodies that block EGFR have also been used in clinical trials. Bode et al. reported in 2006 the results of a phase II study of nimotuzumab, a monoclonal antibody that binds to and inhibits EGFR [36]. At the end of a 6-week induction period, one partial response and nine cases of stable disease were observed out of 21 DIPG patients. At the end of the consolidation phase (week 21), the trial reported three partial responses. Unfortunately, the promising results of this experience were not confirmed in a subsequent study of nimotuzumab combined with radiation in newly diagnosed DIPG patients [15].

With respect to other agents, the PBTC conducted a phase I followed by a phase II trial of tipifarnib, a farnesyl transferase inhibitor that had shown promising anti-neoplastic activity in a preclinical model with the ability to reverse radiation resistance in human glioma cells. In the initial phase I study, 17 DIPG patients were enrolled and no unexpected toxicity was observed; in particular there was no observation of intra-tumoural haemorrhage [2]. The subsequent phase II study enrolled 40 eligible DIPG patients and reported a median progression-free survival of 6.8 months and a median overall survival of 8.3 months [34]. Similarly, Broniscer reported the results of a phase I study of vandetanib administered during and after radiotherapy [35]. This small-molecule inhibitor of VEGFR2 and EGFR had shown activity against high-grade glioma cell lines and an orthotopic xenograft. Twenty-one DIPG patients were enrolled in this study that reported survival rates similar to other trials (Table 20.2).