High-grade gliomas such as glioblastoma are not always equal in children and adults. In pediatric patients, the tumor location, cell type, treatment and prognosis differ from that of adults, arising through distinctly different genomic and epigenomic drivers of disease. In both the pediatric and adult setting, there are currently no effective therapies to fight glioblastoma. Following surgery, frontline adjuvant therapies consisting of radiation and alkylating agents rely on DNA damage and requisite cellular responses to only temporarily reduce tumor burden. Emerging evidence suggest therapies targeting the DNA damage response (DDR)that is activated by DNA damaging chemotherapy and/or radiation may demonstrate improved efficacy in a frontline or recurrent setting. As we improve our understanding of the mechanisms underlying the DDR in brain tumors, identifying optimal strategies to override DNA repair with cell death is central to overcoming therapeutic resistance observed in childhood brain tumors. This review summarizes clinical challenges facing pediatric glioblastoma patients, and highlights opportunities to exploit DNA damage and replicative stress through the integration of conventional chemotherapy with targeted DDR inhibition.

• DNA damage response

• Replicative stress

• Pediatric brain cancer

• Glioblastoma

• High-grade glioma

• Targeted therapy

Stamatkin C, Saadatzadeh RM, Shih CS, Renbarger LJ, Cohen-Gadol AA, et al. (2017) Targeting the DNA Damage Response for Treatment of Pediatric Glioblastoma. JSM Brain Sci 2(1): 1009.

DDR: DNA Damage Response, TMZ: Temozolomide, GBM: Glioblastoma, HGG: High-Grade Glioma, EFS: Event-Free Survival, OS: Overall Survival, IR: Interventional Radiology

 Pediatric neoplasms are remarkably diverse in their cellular origins, developmental timing and clinical features. Malignant brain tumors such as glioblastoma (GBM) are the leading cause of cancer related mortality in children. GBM represents the most frequent and aggressive form of brain tumor in adults accounting for 16% of primary brain tumors [1]. Although brain malignancies are rare in children, they represent the most common solid pediatric tumor accounting for 20% of all childhood cancers [2,3]. The estimated yearly incidence of high-grade glioma (HGG) in children is 0.8 per 100,000 children, making it the most prevalent central nervous system (CNS) malignancy in this age group [1,4]. As with adult GBM, the current standard of care for pediatric GBM is a combination of surgical resection if possible, followed by radiotherapy and chemotherapy, usually consisting of concurrent adjuvant radiotherapy in combination with DNA alkylating chemotherapy [5-7]. It is now evident this approach is largely ineffective, having a 5-year survival after diagnosis of less than 5% [8]. In the face of such poor prognosis, new efforts have been led by The Cancer Genome Atlas (TCGA) network and others to delineate the molecular drivers of GBM with the goal of identifying more effective treatment targets and strategies [9]. Gene expression comparisons of HGG from adults and children indicate significant differences suggesting distinct origins and subsets [10,11]. Similar molecular genetic studies now identify unique expression signature subsets among pediatric cohorts which may better guide patient selection for future clinical trials [11-14]. The observed resistance to monotherapy and necessary urgency to move promising therapies into clinical evaluation has prompted many groups to explore combination regimens using rationally selected targeted drugs in conjunction with the DNA damaging frontline agents radiation and/or temozolomide (TMZ). Herein we summarize the current therapeutic approaches for treating pediatric GBM, with a special focus on those therapies targeting the DNA damage response.

Pediatric GBM Background

Adult vs pediatric GBM: Both pediatric and adult HGGs are characterized by their highly aggressive clinical presentation that accounts for a significant degree of morbidity and mortality for those diagnosed with brain cancer. In contrast to pediatric brain tumors, the molecular landscape underlying adult malignancies has been extensively studied and well characterized to provide a detailed picture into the multifaceted genomic and epigenomic features of the disease. Only recently have HGG in children been given the meaningful attention needed to classify and compare the molecular hallmarks distinguishing adult and pediatric GBM. Disease presentation in adults generally occurs in two distinct forms; (1) primary GBM occurs de novo in older patients and frequently presents somatic gain-of-function mutations and amplifications in the gene for epidermal growth factor receptor (EGFR) [15]. (2) Secondary GBM are thought to arise from lowgrade astrocytomas in adult patients under the age of 40 and more frequently harbor mutations in TP53 and retinoblastoma (RB) [16]. Less is known regarding the molecular pathogenesis driving pediatric GBM. Recent progress deciphering the unique biological features of childhood brain tumors based upon copy number and (epi)genomic profiling efforts have reframed tumor classifications into more clinically informative molecular based subgroups [10,11,17,18]. Foremost of molecular identifiers differing between pediatric and adult GBM, are the recurrent somatic histone 3 mutations unique to childhood tumors [19,20]. Mutations in the histone H3 variants, H3.3 (H3F3A) and H3.2 (HIST1H3B, HIST1H3C) affect the chromatin remodeling pathway resulting from amino acid substitutions at critical residues on the histone tail (K27M, G34R/G34V) [21,22]. Interestingly, these are mutually exclusive mutations only identified in childhood glioblastomas and not found in adult disease [21]. These histone defects are thought to reprogram the epigenome and govern the oncogenic origins of specific childhood GBM tumor subsets. Studies into mutationally rich genomic landscape of adult and pediatric GBM using wholeexome sequencing have yielded a number of high frequency recurrent events common to both diseases, as well as many unique features of disease [23]. For example, mutations affecting TP53 (38%), RB (10%), and NF1 (25%) are equally common for both adult and pediatric forms of GBM [24-26] Whereas, PTEN and EGFR mutations are rare in children compared to adult GBM [27]. Although well characterized in adults as an overexpressed genomic driver of GBM, amplifications of PDGFRA are among the most frequent genomic events identified in children. A smaller molecularly defined subset occurring in about 10% of pediatric GBM is the BRAF V600E mutation [28,29]. These BRAF V600E variants are often found in high-grade GBM tumors also harboring CDKN2A/B deletions and appear to be mutually exclusive to PDGFRA amplifications [25,30]. There are no certain risk factors known for childhood brain tumors, however there are some associations such as radiation exposure, in particular if a child is previously treated with radiation for leukemia [31,32]. Individuals harboring familial or inherited genetic syndromes such as Tuberous sclerosis [33], Neurofibromatosis types 1 and 2 [34,35], Von Hippel-Lindau disease [36], Li-Fraumeni syndrome [37], Turcot syndrome [38], Rubinstein-Taybi syndrome [39], and Gorlin syndrome are at an increased risk for developing brain cancer [40,41].

Advances and opportunities in pediatric GBM management: In spite of the numerous prospective clinical trials tailored for children with HGG over the last 40 years, little improvement in patient outcomes has been gained. To date, the first and most effective treatment strategy for a child with newly diagnosed HGG is to perform a maximal safe surgical resection. Others have demonstrated there is a prognostic value relative to the amount of tumor resection, and that only with radical tumor resection (> 90%) can one significantly improve the progression free-survival (PFS) rates in children [42]. The first prospective randomized clinical trial for children with HGG(CCG-943) demonstrated significantly improved outcomes, increasing the 5-year PFS from 16% to 46% using adjuvant radiation therapy (RT) followed by pCV chemotherapy (prednisone, CCNU and vincristine) versus RT alone [43]. However, in subsequent years efforts to repeat such dramatic increases PFS have failed; under retrospective scrutiny others attribute discrepancies to the inclusion of large numbers of low-grade gliomas in the cohort that received chemotherapy [44]. Present-day trials using improved neuropathology standards have demonstrated a 3-year event-free survival (EFS) of approximately 10% and overall 3-yearsurvival (OS) rates of 20% [8,42]. In adults, administration of single-agent temozolomide (TMZ) alongside or after RT is shown to significantly extend EFS and OS with GBM relative to RT alone, however in children this treatment regimen was found not to improve outcome compared to previously established adjuvant chemotherapies [4,8]. Acknowledging the failure of current treatments for pediatric HGG brings into focus the need to improve conventional chemotherapeutic strategies. One approach is the rational incorporation of molecularly targeted agents into drug combinations with frontline agents to improve patient responses while maintaining acceptable normal tissue toxicity and quality of life. Overcoming the resistance to chemotherapeutic agents remains a major hurdle for clinicians in nearly all HGG patients young and old. The poor responses to TMZ in children and adults have been attributed to a number of factors such as suboptimal dosing [45], MGMT expression [46,47], deregulated oncogene/tumor suppressor signaling [48,49], P-gp expression [50], and the presence of cancer stem cells among others [51,52]. The promise of molecular targeted therapies directed at specific tumor alterations or resistance pathways hold potential for improving patient survival when used alone or in combination with frontline approaches. The genome wide characterization studies undertaken in adult GBM tumors have revealed the heterogeneity of this malignancy, while identifying a number of commonly occurring somatic mutations such as TP53, EGFR, PTEN, IDH1, NF1 [23,53-55]. An abundance of clinical trials in advanced adult GBM using inhibitors targeting growth factor receptor signaling such as EGFR (erlotinib, gefitinib, cetuximab, and imatinib) and angiogenesis (bevacizumab and cediranib) [56-61]. To date, targeted agents tested alone and in combination with frontline IR/TMZ or with other anticancer drugs have yet to improve patient survival when compared to standard of care in unselected adult GBM patients [62]. In children, there are a number of clinical trials specifically recruiting brain cancer patients encompassing a diverse range of clinical targets and novel therapeutic modalities (Table 1).

As for targeted agents, currently there are three EGFR inhibitors under clinical evaluation in pediatric gliomas, each differing with regard drug selectivity, patient inclusion or combination with chemotherapy/ IR. Interestingly, an ongoing trial testing the BRAF inhibitor dabrafinib in patients having recurrent BRAFV600E mutant tumors may lend unique insight into the efficacy of targeting this small molecularly defined pediatric subset [63]. The only other targeted agent currently being studied in pediatric gliomas is the PARP inhibitor, veliparib (ABT-888), which is described later in greater detail as an inhibitor targeting the DNA damage response. Nearly all trials are still early phase I/II which are evaluating the efficacy and safety of anti-cancer agents, most of which are combined with nonselective DNA damaging radiation therapy and DNA alkylating agents in recurrent HGGs. Therefore, it is critical to gain a detailed mechanistic understanding of chemotherapyinduced DNA damage response in pediatric HGG, which may help minimize resistance or stabilize disease progression.

DDR as a druggable multi-faceted target in pediatric brain cancer

DDR background: DNA is vulnerable to a variety of endogenous and exogenous factors that persist in our everyday lives such as chemical carcinogens, free radicals, ionizing radiation, and pharmaceuticals. In order to cope with the multitude of DNA damage events that occur daily, mammalian cells have evolved a variety of mechanisms to address such assaults that collectively are deemed the DNA damage response (DDR). Detection of DNA damage normally triggers cell-cycle arrest to coordinate DNA repair and replication, however bypassed lesions that remain unrepaired or poorly resolved damage may accumulate to impact genomic stability. The cumulative effect and signaling endpoints through the DDR ultimately determine the cell fate through possible induction of apoptosis, necrosis, autophagy, and senescence or as continued tumor proliferation (Figure 1).

Figure 1 DNA damage response pathway

As an anticancer target, understanding at a molecular level the DDR elements governing cell fate may inform how best to potentiate cell death pathways relative to DNA repair, in effect improving genotoxic therapies in pediatric brain cancers.

Alkylating agents such as TMZ act directly on DNA by forming cytotoxic DNA adducts, most important of which is the O6-methylguanine (O6-MeG) lesion. The response and repair enzyme O6-MeG-DNA methyltransferase (MGMT) resolves methylated damage, however unrepaired O6-MeG DNA induces replicative failure and mismatch repair (MMR) mediated doublestrand breaks (DSBs) that can trigger apoptosis, necrosis, and autophagy [64]. The threshold to survive TMZ or other forms of DNA damage can be seen as a proportional balance between the degree of DNA damage relative to the DNA repair capacity,proliferative rate, functional p53 status, expression levels of critical DDR proteins such as ATM, ATR and DNA-PK, mitogenic signaling and the molecular readiness of downstream cell death pathways [65,66]. In both adult and pediatric gliomas, the highly variable cellular balance between O6-MeG damage and functional MGMT is predictive of the relative cytotoxicity or resistance to TMZ treatment [47,67-69]. Exploiting the cell fate switch with genotoxic chemotherapy and/or targeted therapies based upon impairing the DDR in cancers may offer significant opportunities to improve therapeutic outcomes especially in selected patients having certain defects in DDR elements. Differing from normal cells, most cancer cells have one or more defective DDR pathways that reduce their resolution capacity and make them more reliant on remaining pathways to manage both internal and external DNA damage [70,71]. This is especially true for HGGs, where multiple alterations affecting DNA repair pathways have been identified to influence an aggressive phenotype associated with poor outcomes [72]. It is thought that 25% of recurrent mutations in cancer have established roles in DNA repair [73], many of which are associated with increased cancer incidence, such as in the germline BRCA1 gene mutations common to breast cancers. Selective targeting of such vulnerabilities can be viewed as a synthetic lethal approach to improve responses in the tumor cells while sparing normal cells [74,75]. One promising example of this approach can be seen in the use of poly (ADP-ribose) polymerase (PARP) inhibitors to induce cell death in BRCA-deficient tumors [76]. The major role of PARP1 is to repair single-strand DNA breaks and has been found to be upregulated in many tumor types, including pediatric GBM [77]. Gene knockout experiments of PARP-1 impair DNA repair capacity in response to radiation or conventional chemotherapeutic agents [78]. Encouraging preclinical evidence in pediatric HGG indicates PARP inhibitors are effective at sensitizing tumors to DNA damaging agents [79], a strategy which is currently being investigated in clinical trials for pediatric HGG testing veliparib in combination with IR/TMZ (Table 1). Veliparib is a potent and selective inhibitor of both PARP-1 and PARP-2, with respective Ki s of 5.2 and 2.9 nmol/L [80]. Early preclinical studies demonstrated veliparib potentiated the effects of DNA damaging agents TMZ, platinumbased agents, and cyclophosphamide in multiple tumor types and identified that veliparib was blood-brain barrier permeable (BBB) permeable [80,81]. Others expanded upon these preclinical studies to better tailor dose and schedule of veliparib/TMZ combinations, and identified genetic predictors of sensitivity in glioblastoma models such as MGMT and PTEN alterations [82- 85]. Further supporting this therapeutic strategy is the story of another PARP inhibitor lynparza (olaparib), which was recently granted fast-track FDA approval (2015) as a single-agent to treat advanced recurrent BRCA mutant ovarian cancers that have previously failed multiple rounds chemotherapy [86].

Due to its protective role and the frequency of mutations affecting the p53 gene in human malignancies, exploiting the cytotoxic effects of DNA damage and replicative stress based upon functional p53 status is the mechanistic underpinning of many therapies [74,87]. Depending on the degree and type of damage, p53 plays a central role in direct cell-cycle arrest triggering either pro-survival or pro-apoptotic genes. The effect of sustained p53 activation via Mdm2 antagonists that block p53- Mdm2 interactions and Mdm2-mediated ubiquitination of p53 have been evaluated in preclinical GBM models. Efficacy of Mdm2 antagonists as a single-agent [88], (or in combination with TMZ have been reported [89]. In the context of p53 loss, cells become reliant on CHK1 to activate replicative checkpoints, therefore the in presence of DNA damage, blockade of CHK1 leads to mitotic failure and cell death [90]. A number of preclinical studies indicate targeting the checkpoint kinases CHK1/2 and WEE1 sensitize tumors to a variety of DNA damaging agents, some of which are currently being investigated in early phase clinical trials [65,91,92]. Similar interest in using combinations of DNA damaging chemotherapy with inhibitors that functionally impair elements key to the DDR by targeting the DNA repair machinery, cell-cycle effectors, or at the level of ATM/ATR or CHK1/CHK2 axis (Table 2).

Furthermore, it is likely that targeting multiple elements of DDR may be required for some resistant tumor types. For example, targeting ATM and/or ATR kinases in some cancers, including pediatric GBM models, sensitized cells to DNA damaging agents, and killing effects could be further potentiated by blocking DDR pathway redundancies mediated by baseexcision repair pathway [93].

Another exploitable hallmark of cancer cells under DDR control is the inescapable presence of replicative stress, which at a basic level is distinguishable from most normal differentiated cells in that they rarely need to replicate DNA for cell proliferation. A number of internal and external origins of replicative stress are known and have proven to be valuable therapeutic tools when perturbed, such is the case with nucleoside analogs, ribonucleotide reductases (gemcitabine), and thymidylate synthetase (5-FU) which lead to insufficient nucleotide pools, slower DNA synthesis and increased replicative stress [94]. The dysregulated activity of oncogene or tumor suppressor signaling further promote replicative stress, as most function to drive the cell cycle progression through the G1-S transition. Genetic alterations at G1-S cell-cycle checkpoints such as those affecting pRB, p53, CDKN2A, amplification of Cyclins D1 and Cyclin E, can elicit replicative stress by early S-phase entry and are among most common mutated genes in cancer [95,96]. Alkylating agents and platinum based drugs act by directly modifying DNA, leading to inter- and intra-strand base crosslinking. The DNA lesions form a barrier leading to the arrest polymerases during DNA replication or transcription. A major inducer of replicative stress result from radiation and chemotherapy induced DNA adducts and the generation of ROS which oxidize and damage nucleotides which underlies mismatch mutations [97]. Associated DNA strand breaks and secondary structures resulting from certain chemotherapies such as platinum agents or topoisomerase inhibitors are known to induce replicative stress by limiting the progression of both DNA and RNA polymerases [98,99].

The cellular responses to DNA damage and replicative stress are unique to a given tumor and represent promising therapeutic targets to combat pediatric GBM while avoiding toxicity to normal tissues. With the significant advances in sequencing technologies, we can better identify and understand the (epi) genetic alterations that initiate and drive GBM progression, and appreciate the differences between adult and pediatric disease. This information will allow for improved understanding and a personalized approach to actionable abnormalities specific to a given tumor. Furthermore, molecular information in conjunction with functional genomics will be useful to guide chemotherapy and targeted DDR inhibitors, such as the improved responses to TMZ in patient tumors harboring MGMT promoter methylation, the increased sensitivity to CHK1/2 inhibitors inp53 mutant cancers, and PARP sensitivity in BRCA1 deficient cancers. As the early phase clinical trial results come in, it is apparent that drug combinations consisting of DDR inhibitors and DNA damaging agents appear poised to supplant the current single-agent therapies in the future.

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