Simultaneous inhibition of PI3K and PAK in preclinical models of neurofibromatosis type 2-related schwannomatosis.

Neurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.

Drug Repositioning for Refractory Benign Tumors of the Central Nervous System.

Drug repositioning (DR) is the process of identifying novel therapeutic potentials for already-approved drugs and discovering new therapies for untreated diseases. DR can play an important role in optimizing the pre-clinical process of developing novel drugs by saving time and cost compared with the process of de novo drug discovery. Although the number of publications related to DR has rapidly increased, most therapeutic approaches were reported for malignant tumors. Surgical resection represents the definitive treatment for benign tumors of the central nervous system (BTCNS). However, treatment options remain limited for surgery-, chemotherapy- and radiation-refractory BTCNS, as well as malignant tumors. Meningioma, pituitary neuroendocrine tumor (PitNET), and schwannoma are the most common BTCNS. The treatment strategy using DR may be applied for refractory BTCNS, such as Grade 2 meningiomas, neurofibromatosis type 2-related schwannomatosis, and PitNETs with cavernous sinus invasion. In the setting of BTCNS, stable disease can provide significant benefit to the patient. DR may provide a longer duration of survival without disease progression for patients with refractory BTCNS. This article reviews the utility of DR for refractory BTCNS.

Cotargeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells.

Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.

Metformin Reduces Tumor Growth in a Murine Flank Schwannoma Model.

HYPOTHESIS: Metformin and aspirin reduce vestibular schwannoma (VS) growth. BACKGROUND: There have been reported associations between patients with VS prescribed metformin and decreased tumor volumetric growth. Aspirin has also been associated with decreased VS growth in animal studies. METHODS: Rat schwannoma cell lines were grown and implanted into 50 athymic nude mice. Tumors were grown to 5 mm, and then mice were injected with either low- or high-dose metformin, aspirin, or saline daily. Tumors were measured until 14 days elapsed or mice demonstrated symptoms such as ulceration, inability to walk, or passed away. RESULTS: There were no significant differences in day 0 tumor sizes between the control and the treatment groups ( p = 0.73). In the low-dose, but not high-dose groups, day 7 volumes were significantly different for both metformin ( p = 0.04) and aspirin ( p = 0.02) compared with placebo. Mean tumor growth rates were 126.6 ± 65.6 mm 3 /day for saline compared with 73.7 ± 29.5 mm 3 /day for low-dose metformin ( p = 0.03) and 68.7 ± 34.8 mm 3 /day for low-dose aspirin ( p = 0.016). There were no significant differences in tumor sizes ( p = 0.59) or growth rates ( p = 0.75) between low-dose metformin and aspirin groups. Low-dose groups had treatment stopped at 14 days, with continued monitoring demonstrating significant increases in tumor growth off treatment for both aspirin ( p = 0.006) and metformin ( p = 0.048). CONCLUSIONS: Metformin treatment significantly reduced VS growth to a similar level as aspirin. Furthermore, when removing both metformin and aspirin treatment, tumor growth significantly increased.

Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma.

BACKGROUND: Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. METHODS: Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2-/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models. RESULTS: Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential. CONCLUSIONS: This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.

Regression of a spinal schwannoma after Pomalidomide.

A 77-year old female with a history of neurofibromatosis type 2 (NF2) was diagnosed with a spinal schwannoma that was managed conservatively over a decade. During this time, follow up imaging revealed this lesion had been growing and the patient had become symptomatic from it necessitating surgical decompression. However, the patient had been diagnosed with multiple myeloma and underwent treatment with Pomalidomide chemotherapy which delayed surgery for the spinal schwannoma. Further imaging of the spine revealed significant regression in the size of the spinal schwannoma. This phenomenon has not previously been reported and this report aims to explore the implications of Pomalidomide in patients with NF2 related spinal schwannomas.

Effect of Antibiotic Treatment on Attenuated Salmonella typhimurium VNP20009 Mediated Schwannoma Growth Control.

BACKGROUND/AIM: This study evaluated the effect of enrofloxacin antibiotic treatment on the ability of an attenuated Salmonella typhimurium (S. typhimurium) strain VNP20009 to control schwannoma growth in a preclinical mouse schwannoma tumor model. MATERIALS AND METHODS: The antitumor efficacy of VNP20009 intratumoral (i.t.) injection was assessed in a syngeneic mouse-NF2 schwannoma model, with and without subcutaneous (s.c.) injection of enrofloxacin beginning on day-1 or day-8 post-VNP20009 injection. S. typhimurium colonization was assessed in excised tumor samples following antibiotic treatment. RESULTS: I.t. injection of the VNP20009 significantly decreased the growth of schwannoma tumors in mice compared to PBS-treated controls. Treatment of mice with enrofloxacin on day-1 post-VNP20009 injection resulted in abrogation of VNP20009-mediated tumor growth control. In contrast, tumor growth in i.t. VNP20009-injected mice infused with enrofloxacin beginning on day 8 was significantly decreased compared to i.t. PBS-injected controls. Enrofloxacin significantly reduced the number of viable VNP20009 bacteria in excised tumor samples within one day of antibiotic infusion. Viable bacteria were either few or essentially eliminated at the end of the experiment in antibiotic-treated animals compared to VNP20009-only. CONCLUSION: Viable VNP20009 can persist for as long as 2.5 weeks following intratumoral injection of schwannoma, during which time tumor growth is retarded. Antibiotic treatment starting 1-day following i.t. VNP20009 abrogated bacterial tumor growth control, whereas initiation of antibiotics 8-days following i.t. VNP20009 was associated with control of tumor growth, albeit less than seen in animals unexposed to antibiotics.

Design of a randomized, placebo-controlled, phase 2 study evaluating the safety and efficacy of tanezumab for treatment of schwannomatosis-related pain.

BACKGROUND: Schwannomatosis (SWN) is a rare tumor suppressor syndrome that predisposes affected individuals to develop multiple schwannomas and, less often, meningiomas. The most common symptom is chronic, severe pain. No medications are broadly effective in treating SWN-associated pain. The clinical trial described in this manuscript is a phase 2, randomized, double-blind, placebo-controlled study investigating the safety and efficacy of tanezumab - a humanized monoclonal antibody that inhibits nerve growth factor - for treatment of SWN-related pain. As the first therapeutic trial for SWN-related pain, it also aims to evaluate trial endpoints, understand recruitment patterns, and improve clinical trial design in this rare disease. AIMS: The primary objective of this trial is to assess the analgesic efficacy of subcutaneous tanezumab 10 mg in subjects with SWN who continue pre-existing pain therapy (excluding non-steroidal anti-inflammatory drugs). The secondary objective is to assess safety in this population. Exploratory objectives include assessment of pain features, quality of life, and predictive biomarkers. METHODS: The study is comprised of four periods (pre-treatment, double-blind treatment, single-arm treatment, safety follow-up) across 10 months with a delayed-start trial design to allow all participants to receive tanezumab. Forty-six participants will be enrolled and randomized 1:1 to receive either tanezumab or placebo subcutaneously in the double-blind treatment period; all participants receive tanezumab during the single-arm treatment period. CONCLUSIONS: This study is the first therapeutic trial for SWN patients and targets a biological driver of SWN-related pain. It aims to establish a model for future pain studies in SWN and other rare diseases. CLINICAL TRIAL REGISTRATION: NCT04163419 on ClinicalTrials.gov.

Novel patient-derived xenograft and cell line models for therapeutic screening in NF2-associated schwannoma.

Treatment of schwannomas in patients with neurofibromatosis type 2 (NF2) is extremely unsatisfactory, and innovative therapeutic approaches are urgently needed. However, the lack of clinically relevant NF2-associated schwannoma models has severely hampered drug discovery in this rare disease. Here we report the first establishment and characterization of patient-derived xenograft (PDX) and cell line models of NF2-associated schwannoma, which recapitulates the morphological and histopathological features of patient tumors, retain patient NF2 mutations, and maintain gene expression profiles resembling patient tumor profiles with the preservation of multiple key signaling pathways commonly dysregulated in human schwannomas. Using gene expression profiling, we identified elevated PI3K/AKT/mTOR networks in human NF2-associated vestibular schwannomas. Using high-throughput screening of 157 inhibitors targeting the PI3K/AKT/mTOR pathways in vitro, we identified a dozen inhibitors (such as BEZ235, LY2090314, and AZD8055) with significant growth-suppressive effects. Interestingly, we observed that three cell lines displayed differential therapeutic responses to PI3K/AKT/mTOR inhibitors. Furthermore, we demonstrated that two orally bioavailable inhibitors, AZD8055 and PQR309, suppressed NF2-associated schwannoma growth both in vitro and in vivo. In conclusion, our novel patient-derived models of NF2-associated schwannoma closely mimic the phenotypes and genotypes of patient tumors, making them reliable preclinical tools for testing novel personalized therapies. © 2022 The Pathological Society of Great Britain and Ireland.

Sustained response to bevacizumab in a patient with mosaic neurofibromatosis type 2 carrying the NF2:c.784C>T p.(Arg262*) variant.

Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by the growth of schwannomas, especially bilateral vestibular schwannomas (VS), meningiomas, and ependymomas. The anti-VEGF antibody bevacizumab has shown efficacy for VS in some NF2 patients. However, there is limited data on the effect of bevacizumab on non-vestibular tumors, and on the correlation between therapy response and genotype. Here, we report on a 33-year-old patient with bilateral VS, 14 additional intracranial or spinal schwannomas, and a meningioma treated with bevacizumab, off-label in the European Union, for 2 years. The genotype of the patient was determined by mutational analysis of NF2, SMARCB1, and LZTR1 on DNA of multiple tissues. Additionally, we performed volumetric measurements of quantifiable non-vestibular tumors (n = 8) on MRI scans from 5 pre-therapeutic and 2 therapeutic years, and pure-tone audiometry of the non-deaf ear. A heterozygous NM_000268.3(NF2):c.784C>T p.(Arg262*) variant was identified in DNA from 3 schwannomas, but not in leukocyte or oral mucosa DNA, and no rare SMARCB1/LZTR1 variants were detected, establishing the diagnosis of definite NF2 mosaicism. While schwannomas had progressed with a mean annual growth rate of 38% pre-therapeutically, volume stabilization or reduction of all schwannomas along with improvement of pain and neurological deficits, including hearing impairment, were observed under 24 months of bevacizumab. In summary, this is the first report of a sustained response to bevacizumab in a patient shown to carry the frequent mosaic NF2:c.784C>T p.(Arg262*) variant. Our results may be of particular relevance to guide treatment decisions in mosaic NF2 patients harboring this variant.

18F-FDG PET/CT imaging for aggressive melanotic schwannoma of the L3 spinal root: A case report.

RATIONALE: Melanotic schwannoma (MS) is an unusual variant of a nerve sheath neoplasm that accounts for less than 1% of all primary peripheral nerve sheath tumors. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has unique value in detecting malignant MS lesions. To date, only 4 cases of MS with hepatic metastasis have been reported. Herein, we report the fifth case, which is the first reported patient with MS of Asian ethnicity with hepatic metastasis. PATIENT CONCERNS: A 29-year-old woman with a 1-day history of backache was admitted to our hospital. PET/CT showed a paravertebral heterogeneous soft tissue mass along the spinal nerve at the L2-L3 level with strong FDG uptake, and a nodule with increased FDG uptake in the lateral lobe of the left liver. DIAGNOSIS: A puncture biopsy of the L3 bony destruction and surrounding soft tissue mass was performed. The final diagnosis was spinal MS with hepatic metastasis. INTERVENTIONS: The patient underwent 6 courses of systemic chemotherapy. OUTCOMES: The patient did not receive further treatment for half a year after the end of chemotherapy and recovered well. LESSONS: Unlike conventional schwannomas, which are completely benign, MS has an unpredictable prognosis. It is thought to have low malignant potential, and the malignant type tends to metastasize. FDG PET/CT has a unique and important value in the differential diagnosis of benign and malignant lesions, in detecting occult metastases, monitoring the treatment response, and assessing the prognosis of MS.

Novel response to neoadjuvant anti-PD1 therapy for a patient with retrocaval melanotic schwannoma.

Melanotic schwannoma is a rare nerve sheath tumor composed of melanin-producing Schwann cells with the potential for metastasis. These tumors can be associated with familial tumor syndromes and can cause significant symptoms related to nerve compression and mass effect. Due to the rarity of these lesions, they can be initially misidentified as melanocytomas, pigmented dermatofibrosarcoma protuberans, neurofibromas or malignant melanomas. Surgical excision is the mainstay of treatment with limited benefit from adjuvant systemic chemotherapy or radiation. Modern treatments with immune checkpoint blockade have demonstrated significant improvements in progression-free and overall survival for a variety of cancer histologies; however, anti-PD1 therapy has yet to be evaluated in patients with melanotic schwannoma. This report demonstrates a significant improvement in symptomatology and tumor stability with neoadjuvant anti-PD1 therapy for a retrocaval melanotic schwannoma initially masquerading as malignant melanoma. This report demonstrates the potential benefit of a novel therapeutic option for patients with melanotic schwannoma.

Structural Origin and Surgical Complications of Peripheral Schwannomas.

BACKGROUND/AIM: In this study, we investigated the locations and surgical complications of schwannomas. PATIENTS AND METHODS: Data of 130 patients with schwannomas were retrospectively reviewed. Pre- and post-operative neurological symptoms, tumor locations, and nerves of origin (sensory, motor, or mixed) were reviewed. RESULTS: Before surgery, 69 patients had Tinel-like signs, 56 patients had pain, 32 patients had numbness, four patients had motor deficits. After surgery, 20 patients had developed a new neurological deficit; 11 patients had motor deficits, ten patients had sensory deficits, and one patient had both motor and sensory deficits. Most schwannomas occurred in mixed nerves, including the median nerve in 17 patients and tibial nerve in 13 patients. CONCLUSION: The most common site of schwannoma was the median nerve. Although the nerve of origin of the schwannoma could be identified in only 26.0% of cases, the data suggest that schwannomas occur in both sensory and motor nerves.

Available Therapies for Patients with Neurofibromatosis-Related Nervous System Tumors.

OPINION STATEMENT: Though the majority of nervous system tumors are sporadic, several clinically relevant genetic syndromes are associated with a predisposition to tumors of the central and peripheral nervous system including neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis (SWN). These represent prototypical tumor suppressor syndromes where loss of a tumor suppressor gene-protein impairs the cell's ability to regulate cell proliferation. While clinical manifestations vary widely for each of these syndromes, tumors arising in the peripheral nerve sheath are a unifying feature. Clinical clues should prompt the clinician to recognize the underlying genetic syndrome and screen for associated tumors including, among others, plexiform neurofibromas and gliomas in NF1 and vestibular schwannomas, meningiomas, and spinal ependymomas in NF2. Improvements in mechanistic understanding of how the genetic mutations that underlie these syndromes contribute to tumor formation have led to new advances in targeted therapies. MEK inhibitors have shown promise for treating progressive plexiform neurofibromas in NF1. Bevacizumab has been shown to improve hearing and treat vestibular schwannomas in NF2. This article reviews the currently available data on management of tumors associated with these three syndromes.

PD-1/PD-L1 negative schwannoma mimicking obstructive bronchial malignancy: A case report.

Schwannomas are homogeneous tumors of schwann cells and occur at peripheral and cranial nerves on the upper limbs, the head and neck area. Rarely, a bronchial schwannoma may appear in the lung and be misdiagnosed as lung neoplasms. Here, we report a 56-year old woman with a 5.8 × 7.0 × 2.8 cm lesion in her right upper lobe bronchus. The lesion had a maximum standardized uptake value (SUVmax ) of 8.5 by 18-fluorodeoxyglucose positron emission tomography (FDG-PET). Bronchoscopy showed a mass obstructing the bronchus that bled easily. Despite repeated biopsies, a lung malignancy could not be excluded, and surgical resection was subsequently performed. Pathological examination demonstrated a primary bronchial schwannoma that was positive for molecular markers S-100 and SOX-10, negative for immune checkpoint marker PD-1/PD-L1 but also demonstrated certain uncommon pathological features. This case highlights the heterogeneity of bronchial masses and the diagnostic challenge for differentiating benign and malignant tumors in the thorax. KEY POINTS: Rare bronchial schwannoma mimics lung malignancy and poses a diagnostic challenge. This case of bronchial schwannoma, unlike peripheral schwannoma, lacks PD-L1. Pathological features indicate autonomic nerve origin for pulmonary schwannomas.

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas.

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.

False localizing sign caused by schwannoma in cervical spinal canal at C1-2 level: A case report.

RATIONALE: False localizing sign means that the lesion, which is the cause of the symptom, is remote or distant from the anatomical site predicted by neurological examination. This concept contradicts the classical clinicoanatomical correlation paradigm underlying neurological examinations. PATIENT CONCERNS: A 54-year-old man consulted for the right sciatica-like leg pain that had aggravated 1 year ago. Radiological examinations revealed degenerative spondylolisthesis with instability and right-sided recess stenosis at the L4-5 level. After initial improvement following 3 transforaminal epidural steroid injections with gabapentin and antidepressant medication, there was a recurrence of the symptoms a year later, along with wasting of the right leg for several months. Physical examination revealed difficulty in heel-walking and a weakness of extension of the right big toe; tendon reflexes were normal. Lumbar spine radiographs revealed no new findings. The initial course of treatment was repeated, but was ineffective. DIAGNOSES: Further cervicothoracic spine evaluations revealed a right-sided intradural-extramedullary mass and myelopathy at the C1-2 level. INTERVENTIONS: The cervical mass was surgically resected and identified histopathologically as a schwannoma. OUTCOMES: Immediately after surgery, sciatica-like pain and weakness of right leg were completely resolved. LESSONS: It is difficult to make an accurate diagnosis if there are symptoms caused by false localizing sign. Additionally, it is even more difficult to diagnose false localizing sign accurately when there is a co-existing lumbar lesion that can cause the similar symptoms.

Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2.

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype.

Tumor expression of survivin, p53, cyclin D1, osteopontin and fibronectin in predicting the response to neo-adjuvant chemotherapy in children with advanced malignant peripheral nerve sheath tumor.

PURPOSE: Selected cell-cycle regulators and extracellular matrix proteins were found to play roles in malignant peripheral nerve sheath tumor (MPNST) biology. We aimed to analyze whether initial tumor tissue expressions of survivin, p53, cyclin D1, osteopontin (OPN) and fibronectin (FN) correlate with the response to neo-adjuvant CHT (naCHT) in children with advanced inoperable MPNST. METHODS: The study included 26 children with MPNST (M/F 14/12, median age 130 months) treated in Polish centers of pediatric oncology between 1992 and 2013. Tissue expression of markers was studied immunohistochemically in the manually performed tissue microarrays and assessed semi-quantitatively as low and high, based on the rate of positive cells and staining intensity. RESULTS: Good response to naCHT was noted in 47.6%, while poor-in 52.4% of patients. The response to naCHT was influenced negatively by the presence of neurofibromatosis NF1 and high initial tumor tissue expression of OPN, survivin, p53 and cyclin D1. Patients with high tumor expression of either OPN, survivin or p53 and those with simultaneous high expression of ≥ 3 of the markers, responded significantly worse to naCHT, than patients, in whom expression of ≤ 2 markers were detected at diagnosis. Nearly, 85% of patients expressing ≥ 3 markers, responded poor to CHT; while 87.5% of children, expressing ≤ 2 markers, were good responders. CONCLUSION: The initial tumor tissue expression of OPN, survivin, p53 and cyclin D1 may serve as markers to predict response to naCHT in pediatric advanced MPNST. Future studies in more numerous group of patients are needed to confirm these preliminary results.