Inactivating mutations in NF1 underlie the prevalent familial cancer syndrome neurofibromatosis type 1 [1]. The NF1-encoded protein is a Ras GTPase-activating protein (RasGAP) [2]. Accordingly, Ras is aberrantly activated in NF1-deficient tumors; however, it is unknown which effector pathways critically function in tumor development. Here we provide in vivo evidence that TORC1/mTOR activity is essential for tumorigenesis. Specifically, we show that the mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated malignancies in a genetically engineered murine model. However, in these tumors rapamycin does not function via mechanisms generally assumed to mediate tumor suppression, including inhibition of HIF-1alpha and indirect suppression of AKT, but does suppress the mTOR target Cyclin D1 [3]. These results demonstrate that mTOR inhibitors may be an effective targeted therapy for this commonly untreatable malignancy. Moreover, they indicate that mTOR inhibitors do not suppress all tumor types via the same mechanism, suggesting that current biomarkers that rely on HIF-1alpha suppression may not be informative for all cancers. Finally, our results reveal important differences between the effects of mTOR inhibition on the microvasculature in genetically engineered versus xenograft models and indicate that the former may be required for effective preclinical screening with this class of inhibitors.

Objective:To determine the treatment outcome and prognostic factors in patients with adenoid cystic carcinoma of the skull base treated with proton beam radiation therapy.Design: Retrospective analysis.Setting: Massachusetts General Hospital, Massachusetts Eye and Ear Infirmary, and Harvard Medical School, Boston.Patients: From 1991 to 2002, 23 patients with newly diagnosed adenoid cystic carcinoma with skull base extension were treated with combined proton and photon radiotherapy. There was tumor involvement of the sphenoid sinus in 61% of patients (14), nasopharynx in 61% (14), clivus in 48% (11), and cavernous sinus in 74% (17). The extent of surgery was biopsy alone in 48% (11), partial resection in 39% (9), and gross total resection with positive margins in 13% (3). The median total dose to the primary site was 75.9 cobalt-gray equivalent. The median follow-up of all surviving patients was 64 months. Main Outcome Measures:Locoregional control and disease-free survival and overall survival rates.Results: Tumors recurred locally in 2 patients at 33 and 68 months, respectively. No patients developed neck recurrence. Eight patients had distant metastasis as the first site of recurrence. The local control rate at 5 years was 93%. The rate of freedom from distant metastasis at 5 years was 62%. The disease-free and overall survival rates at 5 years were 56% and 77%, respectively. In multivariate analysis, significant adverse factors predictive for overall survival were change in vision at presentation (P=.02) and involvement of sphenoid sinus and clivus (P=.01). Conclusions:High-dose conformal proton beam radiation therapy results in a very encouraging local control rate in patients with adenoid cystic carcinoma of the skull base. Changes in vision at presentation and tumor involvement of the sphenoid sinus and clivus are important prognostic factors.

Late relapse is common among adult patients with medulloblastomas, and long-term follow-up monitoring is important. Because of the high risk of systemic failure among the low-risk patients treated with radiotherapy alone, the role of chemotherapy for this group of patients needs to be further investigated. Complete resection, the absence of brainstem invasion, and an overall radiotherapy duration of less than 48 days are important prognostic factors.

Merlin, the product of the NF2 tumor suppressor gene, is closely related to the ERM (ezrin, radixin, moesin) proteins, which provide anchorage between membrane proteins and the underlying cortical cytoskeleton; all four proteins are members of the band 4.1 superfamily. Despite their similarity, the subcellular distributions and functional properties of merlin and the ERM proteins are largely distinct. Upon cell-cell contact merlin prevents internalization of and signaling from the epidermal growth factor receptor (EGFR) by sequestering it into an insoluble membrane compartment. Here we show that the extreme amino (N) terminus directs merlin biochemically to an insoluble membrane compartment and physically to the cortical actin network, with a marked concentration along cell-cell boundaries. This insoluble-membrane distribution is required for the growth-suppressing function of merlin and for the functional association of merlin with EGFR and other membrane receptors. Our data support a model whereby locally activated merlin sequesters membrane receptors such as EGFR at the cortical network, contributing to the long-held observation that the cortical actin cytoskeleton can control the lateral mobility of and signaling from certain membrane receptors.With the identification of the neurofibromatosis type 2 (NF2) tumor suppressor gene in 1993, it was immediately appreciated that the NF2-encoded protein, merlin, was a member of the band 4.1 superfamily of membrane-associated proteins and thus a novel type of tumor suppressor (40, 50). Although studies of NF2 in humans and mice suggest a broad role for NF2 loss in tumorigenesis and in tumor progression (9,12,19,31,32), the mechanism whereby merlin controls cell proliferation has only recently begun to be elucidated (reviewed in reference 33).Merlin is closely related to the ERM (ezrin, radixin, moesin) proteins, which are thought to organize specific membrane domains by providing regulated anchorage between the membrane and underlying cortical actin cytoskeleton (reviewed in references 4 and 33). All four proteins contain an amino (N)-terminal FERM (four-point one, ezrin, radixin, moesin) domain, which mediates membrane association, are regulated by conformation-dependent changes in localization, and share common interacting partners. Nevertheless, the ERM proteins cannot functionally compensate for merlin, which is required for embryonic development in mice, flies, and worms (10, 31; J. Gervais, J. Satterlee, and A. I. McClatchey, unpublished data); similarly, in contrast to merlin, the ERM proteins are not known to function as tumor suppressors and loss of ERM function in mammals, flies, and worms is not associated with altered proliferation. While the subcellular distributions of merlin and the ERM proteins can overlap, they are often distinct. For example, in cultured cells, merlin and the ERM proteins are often concentrated in dynamic membrane structures, such as lamellipodia, filopodia, and sites of cell-cell adhesion (8,14,17,25,43). However, in highly polarize...

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Patients with bilateral vestibular schwannomas associated with neurofibromatosis type 2 (NF2) experience significant morbidity such as complete hearing loss. We have recently shown that treatment with bevacizumab provided tumor stabilization and hearing recovery in a subset of NF2 patients with progressive disease. In the current study, we used two animal models to identify the mechanism of action of anti–vascular endothelial growth factor (VEGF) therapy in schwannomas. The human HEI193 and murine Nf2−/− cell lines were implanted between the pia and arachnoid meninges as well as in the sciatic nerve to mimic central and peripheral schwannomas. Mice were treated with bevacizumab (10 mg/kg/wk i.v.) or vandetanib (50 mg/kg/d orally) to block the VEGF pathway. Using intravital and confocal microscopy, together with whole-body imaging, we measured tumor growth delay, survival rate, as well as blood vessel structure and function at regular intervals. In both models, tumor vessel diameter, length/surface area density, and permeability were significantly reduced after treatment. After 2 weeks of treatment, necrosis in HEI193 tumors and apoptosis in Nf2−/− tumors were significantly increased, and the tumor growth rate decreased by an average of 50%. The survival of mice bearing intracranial schwannomas was extended by at least 50%. This study shows that anti-VEGF therapy normalizes the vasculature of schwannoma xenografts in nude mice and successfully controls the tumor growth, probably by reestablishing a natural balance between VEGF and semaphorin 3 signaling.

The incidence of late dysphagia is similar in IMRT and CRT, but the mechanism of dysphagia is different.

High-dose radiotherapy with proton beam resulted in excellent local control rates in patients with locally advanced sinonasal cancer, irrespective of the extent of surgery. Complete resection, however, was predictive of improved disease-free survival and decreased rate of distant metastasis.