Faculty Bibliography

Vestibular schwannomas (VS) arising sporadically or in patients with neurofibromatosis type 2 (NF2) consistently lack expression of Merlin, a tumor suppressor. Conventional treatment options include surgery and radiotherapy but there is no validated medical option. Recent evidence suggests that Merlin deficiency may result in abnormal activation of receptor tyrosine kinases (RTKs) and downstream signaling, promoting tumor growth. Although small-molecule RTK inhibitors are widely available for clinical use, no such therapy has been validated in patients with VS. To screen for RTK activation, surgical VS specimens from patients with and without NF2 were analyzed by phospho-RTK profiling arrays. Downstream signaling pathway activation was analyzed by phospho-MAPK arrays. Activated RTKs and downstream kinases were validated immunohistochemically in corresponding formalin-fixed, paraffin-embedded tissues. Phospho-RTK arrays and immunohistochemistry showed consistent overexpression and activation of EGFR family receptors and evidence of ERK1/2 downstream signaling was observed in all samples analyzed (n = 11). Based on the findings, the small-molecule EGFR/ErbB2 kinase inhibitor lapatinib was selected for evaluation of target inhibition and treatment efficacy in our in vitro human schwannoma model. EGFR/ErbB2 targeted therapy with lapatinib inhibited ErbB2 phosphorylation and survivin upregulation, as well as downstream ERK1/2 and AKT activation, resulting in decreased proliferation. We conclude that EGFR family receptor activation is a consistent feature of both sporadic and NF2-related VS. Molecular targeted therapy with lapatinib downregulates survivin and has antiproliferative activity in a preclinical VS model. Based on these findings, a clinical trial with lapatinib for the treatment of VS is currently underway

Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human ependymoma, a form of neural tumour that arises throughout the central nervous system (CNS). Subgroup-specific alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. To select cellular compartments most likely to give rise to subgroups of ependymoma, we matched the transcriptomes of human tumours to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a and b). The transcriptome of human supratentorial ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf(-/-) NSCs. Notably, activation of Ephb2 signalling in these, but not other, NSCs generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human supratentorial tumour. Further, comparative analysis of matched mouse and human tumours revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup-specific driver mutations with cellular compartments to model and interrogate cancer subgroups.

OBJECTIVES/HYPOTHESIS:: Medulloblastoma is the most common pediatric malignant tumor of the central nervous system in children. Treatment includes surgical excision, external beam radiation, and multiagent chemotherapy. Otologic sequelae are common and may result from radiation and/or chemotherapy. Profound sensorineural hearing loss (SNHL) is a known complication of neuro-oncologic treatment and may render these patients eligible for cochlear implantation (CI). Issues of CI in this population, including diagnosis, treatment of preoperative middle ear disease, operative and postoperative course, performance data, and long-term tumor surveillance are highlighted and reviewed. STUDY DESIGN:: Retrospective chart review. METHODS:: Three patients treated for pediatric medulloblastoma with surgical resection, postoperative hyperfractioned craniospinal radiotherapy, and multiagent adjuvant chemotherapy who underwent cochlear implantation were identified. Details of neuro-oncologic treatment and associated otologic complications are presented and analyzed. Primary outcome assessment includes treatment of middle ear pathology, perioperative cochlear implant course, and postimplantation performance data. RESULTS:: Each patient required surgical treatment of chronic ear disease 4 to 16 years after chemoradiation. All progressed to profound SNHL and were implanted 8 to 17 years post-neuro-oncologic treatment. There were no intraoperative complications, and full insertion of the cochlear implant electrode array was achieved in each patient. One patient developed postoperative wound dehiscence requiring operative closure. Postimplantation performance data support significant benefit in all patients. CONCLUSIONS:: Patients treated for pediatric medulloblastoma develop otologic sequelae, including profound SNHL, and may require cochlear implantation. Successful management of middle ear and mastoid pathology involves consideration of potential future cochlear implantation. Postoperative performance data supports cochlear implantation in this population. Laryngoscope, 2009

INTRODUCTION: ACNS 0122 aimed to improve event-free survival (EFS) and OS (overall survival) for intracranial NGGCT, by increasing response rate (complete [CR] and partial [PR]) with neoadjuvant carboplatin/VP-16, alternating with ifosfamide/VP-16, followed by craniospinal irradiation (CSI) plus involved field boost. In patients not obtaining CR/PR by neuro-imaging and tumor marker response after neoadjuvant chemotherapy, second-look surgery was recommended. Patients with persistent radiographic disease or positive markers underwent myeloablative chemotherapy (thiotepa/VP-16) prior to CSI. OBJECTIVES: 1) To determine response rate following three cycles of neoadjuvant chemotherapy; 2) to determine EFS and OS; and 3) To determine whether additional CR can be achieved with high-dose thiotepa/VP-16 for patients not achieving CR/PR. RESULTS: 104 patients enrolled from 1/04-7/08. Median age was 12 (range 3-23) years. 76% were male,. No toxic deaths occurred. Among 84 evaluable patients, response rate was reported as 70% (33 CR, 26 PR). With central imaging review (58/84 patients reviewed to date) response rate was 90%. Nineteen patients underwent second-look surgery, 2 secondary to progression; reviewed pathology in 11 was malignant teratoma or mature teratoma (8), fibrosis (1), and NGGCT (2). Median follow-up for patients without events is 1.9 years (range 0.06-4.9). Fifteen patients have experienced recurrence or progression to date with 6 subsequent deaths. Two-year EFS and OS are 84.4%+/-4% and 93% +/-3%, respectively. Further stratification of responses will be presented. CONCLUSION: Neoadjuvant chemotherapy for NGGCT demonstrates a very high response rate and when administered before CSI may increase survival