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Improving outcomes for 1–associated brain tumors

Expert Rev. Anticancer Ther. Early online, 1–9 (2015)

Nicole M Brossier1 and Children and adults with neurofibromatosis type 1 (NF1) are predisposed to developing CNS David H Gutmann*2 tumors, including optic pathway (OPGs), gliomas (BSGs) and high-grade gliomas. Although current first-line treatments for low-grade gliomas (OPGs and BSGs) may 1Department of Pediatrics, St. Louis Children’s Hospital, St. Louis, MO, USA prevent further tumor growth, they rarely result in restoration of the associated visual or 2Department of , Washington neurological deficits. The availability of accurate small-animal models of NF1-associated brain University School of Medicine, tumors has established tractable experimental platforms for the discovery and evaluation of Box 8111, 660 South Euclid Avenue, promising therapeutic agents. On the basis of these preclinical studies, biologically targeted St. Louis, MO, USA *Author for correspondence: agents are now being evaluated in children with NF1-associated low-grade brain tumors. Tel.: +1 314 362 7379 Collectively, these models have also begun to reveal potential neuroprotective and risk Fax: +1 314 362 2388 assessment strategies for this -prone population. [email protected]

KEYWORDS: brainstem . cyclic AMP . genetically-engineered mice . microglia . mTOR . neurofibromatosis type 1 . optic pathway glioma . preclinical . RAS

Neurofibromatosis type 1 (NF1) is a common will exhibit axillary or inguinal freckling by tumor predisposition syndrome, affecting late childhood. Lisch nodules are observed in 1:2500 individuals worldwide. Although half of virtually all adults with NF1. Also included in For personal use only. children diagnosed with NF1 have an affected the NF1 diagnostic criteria are two characteris- parent with NF1, nearly 50% of all cases of tic tumors (optic pathway glio- NF1 arise in children without a family history mas [OPGs] in the CNS and of NF1, presumably as a result of de novo muta- in the peripheral nervous system). In addition, tion of the NF1 tumor suppressor . distinctive bony abnormalities (tibial Although NF1 transmission occurs in an auto- with or without pseudarthrosis and sphenoid somal dominant fashion with complete pene- wing dysplasia) and a positive family history of trance, the clinical manifestations of this NF1 are used to make the diagnosis of NF1. disorder can be quite variable, even among fam- Although not included as NF1 diagnostic cri- ilies with the same germline NF1 [1]. teria, collectively over 60% of children with This variable makes it challenging NF1 also have learning, attention and behav- to predict the clinical course and specific disease ioral delays. As such, these individuals fre- manifestations in a child with NF1. quently struggle in the classroom setting and The diagnosis of NF1 is established using often require additional educational resources. clinical criteria originally formulated by the Less commonly, children and adults with Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by St. Jude Children's Research Hospital on 02/10/15 National Institutes of Health Consensus NF1 may present with vascular abnormalities, Development Conference in 1987 [2]. Using including moya-moya disease and renal artery these criteria, children or adults harboring two stenosis [3]. or more of seven diagnostic features are given Most individuals with NF1 will manifest the diagnosis of NF1. Three of these seven neurofibromas (benign peripheral nerve sheath features – cafe-au-lait macules, skinfold freck- tumors) by adolescence or early adulthood. ling, and Lisch nodules (iris ) – Approximately one-third of young children will are pigmentary abnormalities. Although nearly have a more extensive type of , all children with NF1 will have more than five termed a plexiform neurofibroma. These cafe-au-lait macules by 2 years of age, most tumors can be associated with significant

informahealthcare.com 10.1586/14737140.2015.1009043 2015 Informa UK Ltd ISSN 1473-7140 1 Review Brossier & Gutmann

A B C D

Figure 1. Anatomic localization of NF1-OPGs. (A) 6-year-old girl with an asymptomatic right ; (B) 6-year-old girl with asymptomatic bilateral optic nerve gliomas; (C) 10-year-old boy with a symptomatic bilateral optic nerve/chiasm glioma and (D) 6-year-old girl with a symptomatic optic radiation glioma. Arrows denote the tumors. NF1: Neurofibromatosis type 1; OPG: Optic pathway gliomas.

morbidity, including bone erosion, airway compression and in the context of NF1 tend to occur in younger children and impingement on local structures. Moreover, individuals with generally follow a more indolent course than their non-NF1 NF1 carry a 10% lifetime risk of developing a malignant periph- counterparts [5,6]. Despite their slow growth rate, however, low- eral , a highly metastatic that exhibits a grade CNS tumors in individuals with NF1 can cause vision poor response to currently available chemotherapeutic and radio- loss, and other neurologic deficits [7]. High- therapy regimens. Individuals with NF1 are also prone to the grade gliomas (HGGs: anaplastic and glioblasto- development of other , including rhabdomyosarcoma, mas) occur less frequently than low-grade gliomas (LGGs) in juvenile myelomonocytic , pheochromocytomas and individuals with NF1, but their incidence is increased at least gastrointestinal stromal tumors. 10-fold relative to the general population [8–10]. Similarly, non- Although OPGs are the most common brain tumor arising gliomatous CNS tumors, such as , in people with NF1, affected individuals are similarly predis- and , are usually not encountered in people posed to develop other CNS tumors, including brainstem glio- with NF1. For personal use only. mas (BSGs) and, far less commonly, malignant gliomas (). These tumors can result in significant morbidity Optic pathway gliomas and mortality depending on their location and clinical progres- OPGs are the most common CNS tumor seen in individuals sion. Moreover, children with NF1 frequently manifest with NF1. OPGs account for approximately 3–5% of all pedi- T2-hyperintense abnormalities (previously referred to as atric brain tumors, but as many as 70% of these arise in chil- unidentified bright objects or UBOs) within the optic pathway, dren with NF1 [11]. In the context of NF1, gliomas can arise in brainstem, and basal ganglia. Although these radio- any region along the optic pathway, ranging from the retro- logical findings are of unclear clinical significance, their appear- orbital optic nerve to the optic radiations (FIGURE 1). Although ance in regions where gliomas also develop may raise the not routinely biopsied or surgically removed, the vast majority suspicion for a brain tumor. These T2 hyperintensities have no of the tumors for which is available have been iden- associated mass effect and lack contrast enhancement, and tified as WHO grade I gliomas (pilocytic astrocytomas [PAs]). importantly, decrease in size and number over time [4]. These low-grade glial rarely, if ever, transform into Although current therapies for NF1-associated CNS tumors higher grade (e.g., glioblastoma). Instead, clinical may halt further tumor growth, they often fail to reverse the progression of these tumors is related to decline in visual func- associated visual or neurological deficits. For this reason, there tion or radiologic evidence of continued tumor growth.

Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by St. Jude Children's Research Hospital on 02/10/15 has been significant interest in the identification and evaluation Despite a shared pathologic classification, NF1-OPGs are of new therapeutic strategies that inhibit tumor progression and distinct from their sporadic counterparts. First, the histologic improve neurological outcomes. In this review, we describe the architecture of PAs in the setting of NF1 appears to result current clinical management of NF1-associated gliomas and from circumferential growth of transformed within discuss promising experimental therapeutic options and their the perineurial space to create a fusiform enlargement of the potential impact on the future management of children with affected nerve segment. In contrast, sporadic OPGs typically these brain tumors. demonstrate an intraneural pattern of growth with obliteration of the subarachnoid space due to fusion of the pia to the arach- CNS tumors in NF1 noid and [12]. Second, bilateral optic nerve involve- Although histologically similar to their sporadic counterparts, ment occurs almost exclusively in children with NF1, whereas NF1-associated gliomas have several distinct features. Gliomas chiasmatic and post-chiasmal tumors are more commonly

doi: 10.1586/14737140.2015.1009043 Expert Rev. Anticancer Ther. Improving outcomes for NF1-associated brain tumors Review

observed in sporadic OPG cases [13]. Third, progressive disease Only one-third of children with initially symptomatic is more commonly observed in sporadic OPGs, whereas NF1-OPGs will demonstrate clinical or radiographic progression NF1-associated tumors typically exhibit a more indolent clini- after the diagnosis of their tumor. This phenomenon is even cal course. In this regard, there are rare reports of spontaneous rarer in asymptomatic NF1-associated OPG, where the reported regression of symptomatic NF1-OPGs [14]. Finally, unlike rates of progression range from 0–10% [6,20,27]. Although it is NF1-OPGs, sporadic OPGs do not harbor in the not clear what factors dictate clinical progression, recent studies NF1 [15]. Molecular analyses of these have revealed that optic tract/radiation involvement, optic nerve sporadic PA tumors have instead revealed multiple chromo- pallor, age <2 years [7] and female sex [28] are associated with somal alterations that each result in the production of fusion worse visual outcome in children with NF1-OPGs. transcripts containing the kinase domain of the BRAF signaling Worsening visual acuity with or without radiologic evidence molecule [16–18]. of tumor expansion is the most common indication for initiat- In some case series, OPGs have been reported to represent ing therapy. The finding of a two-line decrement in visual acu- 60–75% of the primary brain tumors encountered in children ity is sufficient to warrant treatment, typically with a vincristine with NF1 [6]. OPG prevalence has been estimated at 15–20% and regimen shown to be efficacious in pediatric in individuals with NF1 [5,19], and diagnosis typically occurs LGGs [29]. There is a limited role for in the manage- prior to 7 years of age [5]. In this regard, the peak age of OPG ment of these tumors; surgical intervention is usually reserved detection occurs between 3 and 5 years of age. Of those diag- for the treatment of intraorbital tumors in a blind or nearly nosed in late childhood and adulthood, many are asymptom- blind eye or for the of large tumors to relieve hydro- atic [6,20]. Given the low incidence of clinical progression (e.g., cephalus [11]. Radiotherapy, while formerly a mainstay of treat- visual decline) in asymptomatic individuals [20] and the indo- ment for low-grade glial neoplasms, is not used in the context lent nature of these lesions, routine MRI imaging is not recom- of NF1 due to significantly increased risks of secondary neo- mended for asymptomatic individuals [19–21]. Instead, annual plasms [30] and radiotherapy-associated vasculopathy [31]. ophthalmologic examinations performed by an experienced Although may successfully prevent further pediatric neuro-ophthalmologist are recommended for all chil- tumor growth as visualized by brain MRI, its impact on visual dren with NF1 from 1 year to at least 12 years of age [7,21,22]. acuity is less clear. In recent studies, as many as 30% of chil- This detailed examination should include age-appropriate meas- dren with demonstrable tumor shrinkage following chemother- ures of visual acuity, assessments and funduscopic apy continued to experience further deterioration of their visual inspections [21]. Current recommendations entail annual eye acuity. Conversely, nearly 25% of individuals with progressive examinations from 1 to 12 years of age using Teller acuity disease following chemotherapy had improvement in their For personal use only. cards for infants and young preverbal children, HOTV or Lea visual acuity [22]. For these reasons, it is recommended that cards for young children, and Snellen charts for older individu- visual acuity, rather than radiographic response, be the primary als [23]. Other alternatives, such as visual evoked responses, are endpoint in clinical trials evaluating new therapeutic agents for not commonly used. When abnormal visual acuity is detected, NF1-associated OPG [7,22]. MRI is performed to identify a potential OPG followed ini- tially by quarterly MRI and ophthalmological assessments. Brainstem gliomas A 2-line decrement in visual acuity is commonly used to initi- BSGs account for approximately half of all extra-optic gliomas ate treatment [22]. Future modalities, including optical coher- in individuals with NF1 and comprise 10–15% of all CNS ence tomography, may prove useful in monitoring visual tumors in this tumor predisposition syndrome [6]. In the con- dysfunction [24]. text of NF1, BSGs are usually diagnosed during childhood, Decreased visual acuity is the most common presentation of with the average age of detection between 8 and 9 years [32,33]. a symptomatic OPG in children with NF1. Visual field deficits Similar to NF1-OPGs, these tumors tend to be more indolent and color vision loss often accompany visual acuity loss, but than their sporadic counterparts. Although the majority of spo- rarely exist in isolation [25]. Proptosis is usually associated with radic childhood BSGs are high-grade diffuse infiltrative pontine prechiasmatic tumors and is more often encountered in youn- gliomas [34] and carry a dismal prognosis [35], NF1-associated

Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by St. Jude Children's Research Hospital on 02/10/15 ger children; however, this feature does not always correlate BSGs tend to arise within the medulla [32,33] and are most com- with decreased visual acuity [20]. The clinical identification of monly WHO grade I or II astrocytomas [32,33,36]. precocious puberty should warrant neuroimaging to exclude Unlike NF1-OPGs, NF1-BSGs are often symptomatic, and hypothalamic tumor infiltration [26]. Although less common, is the most commonly reported symptom. Other clin- precocious puberty has also been reported in children without ical abnormalities include gross motor incoordination, , an obvious OPG as well as in individuals whose tumor does , cranial neuropathies, , dysphagia and not appear to directly involve the [20,27]. Other [32,33]. Moderate-to-severe is also symptoms, such as an afferent pupillary defect, , stra- more common in NF1-BSGs compared to NF1-OPGs and bismus and optic disc swelling are variably reported and do not often requires placement of a ventriculoperitoneal shunt. correlate well with visual acuity findings. Increased intracranial Despite the higher incidence of symptomatic presentation, pressure is a rare presenting symptom in NF1-associated OPG. fewer than one-third of NF1-BSGs will exhibit further growth

informahealthcare.com doi: 10.1586/14737140.2015.1009043 Review Brossier & Gutmann

on MRI after the initial diagnosis, and even fewer will demon- Glioma formation in NF1 strate symptomatic progression. For this reason, observation is Similar to other autosomal dominant tumor predisposition syn- recommended for asymptomatic children with NF1-BSGs. dromes, children with NF1 are born with one non-functional Similar to NF1-OPGs, treatment is generally reserved for those (germline NF1 gene mutation) and one functional copy of the with progressive or worsening symptoms because radiologic NF1 gene. Gliomas develop following somatic (acquired) inac- evidence of tumor expansion does not reliably correlate with tivation of the remaining functional NF1 allele in astroglial worsening clinical status. Vincristine and carboplatin are the progenitor cells, rendering both copies of the NF1 gene non- first-line treatment for NF1-BSGs [29]. Given the challenging functional [46]. Pathologic examination also reveals NF1-hetero- anatomic localization of these tumors, partial surgical resection zygous stromal cells (microglia and endothelial cells) admixed is usually reserved for tumor debulking in severely symptomatic with the NF1-null neoplastic astrocytes in these tumors, and or rapidly progressive cases. communication between these cell types through elaboration of paracrine signaling factors is essential for tumor formation Pediatric gliomas arising in atypical locations and growth. Gliomas have also been reported in locations other than the With the cloning of the NF1 gene in 1990 and the identifi- optic pathway and brainstem in children with NF1, including cation of its protein product, neurofibromin, a more complete the cortex [6,9,36], cerebellum [6,36,37] and basal ganglia [6]. understanding of the mechanism(s) of tumorigenesis has Together, these represent approximately 10–15% of all CNS emerged. Examination of the predicted protein sequence of tumors in NF1 [6], with an onset typically in late adolescence neurofibromin revealed a small domain with significant homol- or adulthood [9]. Pathological examination of these tumors has ogy to yeast IRA-1 and IRA-2, two proteins known to function revealed both LGGs (WHO grades I & II) and HGGs (WHO as negative regulators of RAS activity. In mammals, RAS func- gades III & IV) [9,36], such that a significant proportion of tions as a proto-; when locked into its activated form tumors arising in older children or in atypical locations are by point mutations or by neurofibromin loss, its unregulated higher grade malignancies. As such, the presence of these activation promotes cell growth and tumor formation. These unusual features may be an indication for surgical [38]. pro-oncogenic properties are dependent upon the ability of the RAS proteins to activate downstream signaling cascades, includ- High-grade gliomas ing the RAF/MEK/ERK pathway and the AKT/mammalian Although HGGs can arise de novo in adults with NF1 [9], target of rapamycin (mTOR) pathway. Thus, neurofibromin- others arise as secondary tumors in those individuals who deficient cells demonstrate RAS hyperactivation as well as received for benign tumors during child- increased activation of the RAF/MEK/ERK and AKT/mTOR For personal use only. hood [39]. In fact, nearly 50% of people with NF1 who signaling cascades (FIGURE 2). Neurofibromin loss in astrocytes has received childhood cranial radiation developed secondary also been shown to result in lower intracellular levels of the tumors, including HGGs and malignant peripheral nerve growth-inhibitory cyclic AMP (cAMP) molecule [47]. Recent sheath tumors [30]. Treatment of both primary and secondary studies have revealed that neurofibromin regulation of cAMP HGGs typically involves surgical resection and radiotherapy may also be RAS dependent because RAS activation of the combined with the use of a variety of different chemotherapeu- atypical protein kinase C-zeta has been shown to inhibit the tic agents (paclitaxel, , lenalidomide, , activity of adenylate cyclase in neurofibromin-deficient irinotecan, Cytoxan and etoposide) [10]. Similar to their spo- [48]. radic counterparts, the overall prognosis is poor. As predicted, loss of neurofibromin function results in increased RAS activity and increased cell growth in astro- Future therapies for NF1-associated brain tumors cytes [46]. Moreover, human NF1-associated gliomas and With the development of small-animal models of NF1-associ- Nf1-deficient mouse astrocytes and optic gliomas [46,49,50] dis- ated brain tumors coupled with a growing understanding of play increased levels of ERK, AKT and mTOR activation. Acti- the function of the NF1 protein (neurofibromin), new therapies vation of these signaling cascades following neurofibromin loss for NF1-brain tumors are currently being explored. Because may cooperate with decreased cAMP levels to promote tumori-

Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by St. Jude Children's Research Hospital on 02/10/15 research into NF1-associated HGGs has until now largely genesis. In this manner, reduced cAMP generation promotes focused on basic mechanisms of disease rather than novel treat- glial cell survival [51], whereas RAS activation increases glial cell ment strategies [40–45], we will focus our discussion on future proliferation [52]. therapies for NF1-associated LGG. Due to the discordance between radiologic and functional out- Targeting neoplastic cells in LGGs comes in NF1-LGG, an international effort is currently under- Because targeting RAS activation directly has proved challeng- way to standardize the criteria used to determine therapeutic ing for NF1-associated tumors, the majority of preclinical and response to new investigational agents. The Response Evaluation clinical studies in NF1-gliomas have focused on inhibiting the in Neurofibromatosis and collaborative initia- function (activation) of the signaling intermediates downstream tive currently recommends that visual acuity should be a primary of RAS. Because MEK inhibitors have been shown to decrease endpoint in studies assessing response of NF1-OPGs [22]. the growth of other NF1-associated tumors (mouse plexiform

doi: 10.1586/14737140.2015.1009043 Expert Rev. Anticancer Ther. Improving outcomes for NF1-associated brain tumors Review

neurofibromas) in preclinical investigations [53], there has been Neurofibromin significant interest in determining whether these agents can be used to treat gliomas in children with NF1. In addition, there is compelling evidence that sporadic PAs, especially those har- boring BRAF fusion events, may be driven by RAF/MEK Inactive RAS -GDP Active RAS -GTP hyperactivation [17,54]. Interestingly, BRAF/MEK activation in cerebellar progenitor cells is sufficient for ectopic glioma-like formation, which reflects ERK activation of mTOR signal- ing [55]. Moreover, emerging evidence using Nf1 genetically- engineered mice strains that develop optic gliomas has also ζ revealed that neurofibromin loss leads to MEK-driven mTOR PKC PI3K activation and increased tumor proliferation [56]. RAF Although MEK inhibitor studies have not been completed in children with NF1-associated LGG, a high rate of early progres- AC AKT sion was reported in a recent Phase I clinical trial in which chil- MEK dren with progressive NF1- and sporadic-LGGs were treated with the upstream B-RAF inhibitor sorafenib [57]. The early ter- cAMP mTOR mination of this drug therapy trial for increased tumor growth ERK likely reflects the paradoxical activation of ERK seen with RAF inhibitors [58,59]. To circumvent this undesired ERK activation, Cell survival the MEK inhibitor selumetinib is now being evaluated in Cell growth human clinical trials for both sporadic and NF1-glioma [60]. Although recent evidence suggests that MEK may increase Figure 2. Neurofibromin regulates RAS and cAMP mTOR activation directly in NF1-OPGs, mTOR activity is also signaling. Neurofibromin stimulates the hydrolysis of active regulated by PI-3-Kinase/AKT signaling. As such, recent pre- RAS-GTP to generate inactive RAS-GDP. As such, complete NF1 gene inactivation in the tumor cells results in increased RAS clinical studies have demonstrated that PI-3-Kinase/AKT inhibi- activity. To propagate its growth-promoting signal, RAS binds to tion attenuates mouse Nf1 optic glioma growth [56]. The and activates RAF, which sequentially leads to MEK and convergence of MEK and AKT on mTOR-mediated glioma mitogen-activated protein kinase (ERK) hyperactivation. In growth control supports the idea that Nf1 murine optic glioma addition, RAS can activate PI3K and AKT, resulting in increased

For personal use only. mammalian target of rapamycin activity. Finally, RAS activation proliferation is mTOR dependent [50]. In this regard, inhibition following neurofibromin loss suppresses cAMP generation by of mTOR function with rapamycin analogs inhibits optic gli- inhibiting adenylate cyclase through the atypical protein kinase oma growth in Nf1 genetically-engineered mice [61]. On the C zeta in neurons [48]. basis of these preclinical studies, we found that the mTOR cAMP: Cyclic AMP. inhibitor everolimus (RAD001) is currently in Phase II trials for NF1-glioma [62]. mTOR inhibitors are also being evaluated in conjunction with EGF receptor inhibitors for NF1-gliomas [63] maintenance derives from experiments in which microglia func- based on preliminary feasibility studies demonstrating stabiliza- tion was genetically or pharmacologically silenced. Inhibition of tion of disease in a subset of individuals with progressive microglial function through either pharmacologic or genetic NF1-glioma [64]. mechanisms attenuated Nf1 mouse optic glioma growth [51,66–68]. Moreover, blocking microglia migration was similarly Targeting non-cancerous cells in LGG critical for optic glioma formation because mice harboring a Pathological examination of NF1-associated PAs reveals that mutation in a gene important for microglia movement exhibit 35–50% of the cells in the tumor are non-neoplastic stromal delayed optic glioma development [69]. Taken together, these cells, including immune system-like cells (microglia). Our data suggest that therapies aimed at blocking microglia function

Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by St. Jude Children's Research Hospital on 02/10/15 understanding of the importance of stromal cells in optic gli- may represent adjuvant approaches to reducing NF1-associated oma formation and growth largely derives from experiments OPG growth. performed in Nf1 genetically-engineered mice. In these studies, Although microglial-targeted therapies have not yet reached loss of Nf1 gene expression in astroglial progenitor cells is clinical trials in individuals with NF1, other methods of target- required, but not sufficient, to induce optic glioma develop- ing the microenvironment are currently under clinical investiga- ment. Optic gliomas only arise in mice in which a germline tion. For example, the anti-VEGF receptor agent bevacizumab Nf1 gene mutation is coupled with complete Nf1 gene inactiva- has recently been studied in pediatric LGGs because anti- tion in astroglial cells [65]. The requirement for a germline Nf1 VEGF receptor overexpression has been reported in these gene mutation argues that stromal cells are necessary for tumors [70]. An objective response was observed in the majority tumorigenesis (FIGURE 3). Additional evidence supporting a critical of children with multiple recurrent LGGs treated with a com- role for non-neoplastic microglia in mediating optic glioma bination of bevacizumab and irinotecan, including all three

informahealthcare.com doi: 10.1586/14737140.2015.1009043 Review Brossier & Gutmann

Growth NF1 gene may be at increased risk for glioma formation [75,76]. factors However, the value of this genotype–phenotype correlation for Microglia risk assessment and counseling remains to be determined. Addi- tional risk factors for glioma may also derive from subtle geno- mic polymorphisms. On the basis of studies in which the NF1+/– genomic background of the mouse was shown to dramatically influence glioma formation [40,41], two genomic loci have been linked to resistance. The Scram1 locus on the dis- NF1–/– tal portion of mouse 5 is associated with reduced Neoplastic glial cells spinal astrocytoma development [77], whereas the Arml1 locus NF1+/– on the distal portion of mouse chromosome 12 may confer male-specific resistance to astrocytoma formation [78]. The Growth translation of these findings to human risk stratification is cur- Endothelial cells factors rently in their infancy, but may one day lead to the identifica- tion of genomic predictors of glioma development. À À Figure 3. Stromal contribution to NF1-OPG. NF1 / astrocytic Another potential risk factor is the sex (gender) of the indi- cells within NF1-OPGs require paracrine signaling factors made vidual. Examination of two independent cohorts revealed that by NF1+/À microglia [51] or endothelial cells to support tumor maintenance and growth. girls with optic nerve gliomas were 5–10 times more likely to NF1: Neurofibromatosis type 1; OPG: Optic pathway gliomas. experience visual decline relative to their male counter- parts [28,79,80]. Similarly, only female Nf1 mutant mice with optic gliomas had decreased visual acuity. This sexually dimor- children with NF1 [71,72]. Although this regimen was relatively phic difference resulted from differences in cAMP levels in well tolerated, nearly all children progressed following the com- female versus male Nf1 mutant RGCs, leading to greater RGC pletion of bevacizumab therapy [72]. In addition, early phase death secondary to optic glioma in females [28]. Studies are cur- studies of the antiangiogenic agent lenalidomide have revealed rently underway to define the molecular basis for these sex- good tolerability and promising objective responses in children based differences in RGC function and visual outcome. with LGGs [73]. Additional studies may combine stroma- directed therapies with biologically targeted or standard Expert commentary . Since the identification of the NF1 tumor suppressor gene in For personal use only. 1990, the combination of clinical research and basic laboratory Improving vision in LGGs investigation has resulted in a greater appreciation for the fac- Studies in mouse models of NF1-associated optic glioma have tors that underlie glioma formation in children with NF1. demonstrated that visual decline results from the effect of the After detailed dissection of the mechanisms responsible for neu- tumor on axonal integrity. In these mice, the optic nerve axons rofibromin growth regulation in the brain, new therapeutic tar- begin to swell and degenerate, culminating in the death of their gets have emerged as promising anticancer therapies for cell bodies within the retina (retinal ganglion cells [RGCs]) [74]. NF1-glioma. Excitingly, some of these biologically based treat- These neurons in Nf1 mutant mice with optic glioma harbor ments have entered human clinical trials for these tumors. In one mutant (non-functional) copy of the Nf1 gene, similar to addition, small animal models of NF1-glioma have provided a children with NF1-OPG. Reduced neurofibromin expression in tractable experimental platform for the preclinical evaluation of RGCs leads to increased cell death within the retinal ganglion promising agents. These mouse models have provided valuable cell layer, a phenomenon linked to reduced levels of cAMP in insights into the role of the tumor microenvironment and these neurofibromin-deficient cells. Correction of these levels genetic background in the genesis and maintenance of these with agents that increase cAMP (e.g., forskolin and rolipram) common CNS tumors. Further mechanistic studies will likely rescue RGC death in vitro. Importantly, Nf1 mutant mice with lead to better risk assessment tools, enabling clinicians to iden-

Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by St. Jude Children's Research Hospital on 02/10/15 optic gliomas treated with rolipram exhibited a near-complete tify those children most likely to develop OPGs requiring treat- correction of RGC death in vivo [74]. These exciting findings ment and optimizing therapies for these tumors. suggest that future treatments aimed at promoting RGC sur- vival may improve visual outcomes in children with Five-year view NF1-OPG. With the establishment of the NF Clinical Trials Consor- tium [81] and the availability of preclinical mouse models, it is Risk assessment in LGGs now possible to envision a future in which newly identified Initial attempts at predicting risk in individuals with drugs are rapidly evaluated in mice and quickly brought to NF1 focused on the germline NF1 gene mutation. Early geno- clinical trial. The combination of improved risk assessment type–phenotype correlations have suggested that individuals methods and effective therapies is likely to facilitate a more effi- with germline truncating mutations in the first third of the cient use of medical resources and lead to better clinical

doi: 10.1586/14737140.2015.1009043 Expert Rev. Anticancer Ther. Improving outcomes for NF1-associated brain tumors Review

outcomes. In addition, because anticancer therapies are melded better clinical outcomes for individuals with NF1-associated with treatments that target growth-promoting cells in the gliomas. tumor microenvironment (microglia and endothelial cells), it is possible that better tumor control will result. Similarly, with Financial & competing interests disclosure additional research into the mechanisms responsible for RGC The authors have no relevant affiliations or financial involvement with death and visual dysfunction, complementary treatments that any organization or entity with a financial interest in or financial conflict promote retinal survival may serve to improve visual with the subject matter or materials discussed in the manuscript. This acuity in children with NF1-OPG. Taken together, the future includes employment, consultancies, honoraria, stock ownership or options, management of NF1-glioma might integrate risk assessment expert testimony, grants or patents received or pending, or royalties. strategies with targeted treatments that focus on the tumor No writing assistance was utilized in the production of this cells, non-neoplastic stroma cells, and dying RGCs to affect manuscript.

Key issues

. Individuals with neurofibromatosis type 1 (NF1) are predisposed to developing optic pathway gliomas (OPGs), brainstem gliomas and, less commonly, malignant gliomas. . Symptomatic progression, rather than radiographic progression, should be the basis for initiating therapy in NF1-OPGs and NF1-brainstem gliomas. . Risk factors for vision loss from NF1-OPG include post-chiasmatic involvement, age <2 years and female sex. . Current therapies are ineffective at restoring NF1-OPG-induced vision loss. . Clinical trials with mTOR and MEK inhibitors are underway for NF1-low-grade gliomas. . Optic glioma growth in mice is reduced following suppression of tumor-associated microglial function. . Stroma-directed therapies may represent adjuvant approaches for treating NF1-associated optic glioma. . Reduced cyclic AMP levels in retinal ganglion cells (RGCs) forms the molecular basis for increased neuronal death from Nf1 optic glioma. . Girls with NF1-OPG are more likely to experience visual decline and require treatment. . Female mice with Nf1 optic glioma exhibit reduced RGC survival and visual acuity. . Future therapies aimed at rescuing RGCs from dying secondary to NF1-OPG may improve vision. For personal use only.

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