Therapeutic Application of PARP Inhibitors in Neuro-Oncology

TRECAN 00419 No. of Pages 13

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Review

Therapeutic Application of PARP Inhibitors in Neuro-Oncology Jianfang Ning1,* and Hiroaki Wakimoto2,* In response to a variety of cellular stresses, poly(ADP-ribose) polymerase 1 (PARP1) has vital roles in orchestrating DNA damage repair and preserving genomic integrity. Clinical activity of PARP inhibitors (PARPis) in BRCA1/2 mutant cancers validated the concept of synthetic lethality between PARP inhibition and deleterious BRCA1/2 mutations, leading to clinical approval of several PARPis. Preclinical and clinical studies aiming to broaden the therapeutic application of PARPis identified sensitivity biomarkers and rationale combination strategies that can target BRCA wild-type and homologous recombination (HR) DNA repair-proficient cancers, including central nervous system (CNS) malignancies. In this review, we summarize recent progress in PARPi therapy in brain tumors, and discuss current opportunities for, and challenges to, the use of PARPis in neuro-oncology.

Highlights Clinical activity of single-agent PARPis has been confirmed in cancers with deficient HR, validating the concept of synthetic lethality and leading to US Food and Drug Administration (FDA) approval. Expanding the use of PARPis to cancers without known HR defects (BRCAness), including many brain tumors, remains a significant challenge and an active research topic. Recent preclinical research has identified novel biomarkers of, and approaches to therapeutically induce, BRCAness, paving ways toward rational PARPi combinations applicable to CNS tumors.

Multifaceted Roles of PARP1 PARP1 is the best-studied member of the PARP family, which comprises 17 enzymes with a common catalytic ADP-ribosyltransferase (ART) motif [1–3]. Abundant in the nucleus, PARP1 catalyzes PARylation, a reaction that uses NAD+ to attach negatively charged poly(ADP-ribose) polymers (PAR) to various target proteins [4]. PARylation is a major post-translational modification and regulates many aspects of human cell biology [5]. PARP1 is a sensor of DNA damage, recruiter of repair proteins, and a signal transducer in a variety of DNA repair and replication processes. Early studies focused on the primary roles of PARP1 in single-strand break repair (SSBR) and base excision repair (BER) [6,7], by detecting SSB damage and recruiting the scaffolding factor XRCC1 to DNA strand breaks [8]. Now, accumulating evidence implicates the multifaceted roles of PARP1 in regulating other DNA damage response pathways, such as nucleotide excision repair (NER) [9], DNA mismatch repair (MMR) [10], double-strand break (DSB) repair, including classical nonhomologous end-joining (cNHEJ) [11], alternative nonhomologous end-joining (aNHEJ) [12], and HR [13,14]. PARP1 is also activated in response to replication stress and cooperates with BRCA2 to stabilize replication forks [15]. PARP1 has four critical domains: an N terminal DNA-binding domain, a caspase-cleaved domain, an automodification domain, and a C-terminal catalytic domain. The PARP1-mediated catalytic process involves the DNA-binding, automodification, and catalytic domains [16]. The DNAbinding domain comprises two zinc finger motifs, which are capable of recognizing and binding to a variety of damaged DNA structures, including SSBs and DSBs [17]. Following DNA binding, the PARP catalytic domain becomes activated, leading to the formation and addition of PAR to acceptor proteins, including PARP1 itself [18,19]. After PARP1 senses and responds to DNA damage sites, a burst of PAR synthesis initiates the DNA damage response (DDR). Automodification by negatively charged PAR polymers is responsible for releasing PARP1 from the DNA and facilitates the recruitment of downstream repair proteins. PARP1 dissociation from DNA consequently suppresses its enzymatic function [20]. Some of the functions of PARP1 in DDR are shared by PARP2. Trends in Cancer, Month 2019, Vol. xx, No. xx

PARPis induce immunological consequences that widen combination therapy partners to immune modulators. Ongoing PARPi clinical trials in neurooncology will inform feasibility and early efficacy signs of newer potent PARPi and new combination strategies.

1

Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA 2 Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

*Correspondence: [email protected] (J. Ning) and [email protected] (H. Wakimoto).

https://doi.org/10.1016/j.trecan.2019.12.004 © 2019 Elsevier Inc. All rights reserved.

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It has become widely accepted that PARP1 and other PARP members participate in several other cellular processes [14,21], such as gene transcription, telomere maintenance, chromatin remodeling, immune responses, angiogenesis and aging, inflammation, and programmed cell death. PARP participates in several forms of cell death, including necrotic and apoptotic cell death programs [22]. Small-molecule inhibitors that selectively target PARP1 and PARP2 have been extensively studied as therapeutics for several disease conditions, most notably cancer [23,24]. PARPis have become part of the standard of care for certain cancer types, such as ovarian cancer. Although a PARPi has not yet been approved clinically in the field of neuro-oncology, recent preclinical and clinical investigations have advanced our understanding of molecular mechanisms underlying PARPi and its potential utility for the management of brain tumors. In this review, we summarize cutting-edge knowledge in PARPi therapy and dissect challenges to the preclinical and clinical development of PARPis, with a particular focus on their utilities in treating neurooncological malignancies.

PARPis in BRCA-Mutant or HR-Deficient Cancers PARP1/2 is essential in the repair of SSBs. When PARP1/2 is absent or inhibited, SSBs accumulate and are converted into DSBs when they are encountered by replication forks. DSBs are the most toxic DNA lesions in cells, and are repaired by HR, which accurately repairs DSBs, or by other DSB repair mechanisms, which are error prone. When HR is not available, erroneous DNA repair of DSBs leads to genomic instability and cell death. This is the original concept of synthetic lethality of PARP inhibition and HR deficiency that was first demonstrated preclinically in cancers harboring mutant BRCA1 and BRCA2 that encode key effector molecules in HR [25,26]. Subsequently, PARPis have been rapidly developed via clinical testing for ovarian and breast cancers with germline BRCA1/2 mutations and cancers defective in other HR genes. Currently, there are six orally available clinical PARPis that all potently inhibit the catalytic function of PARP1 and PARP2 via outcompeting with NAD+ to bind PARP1/2 [24]. Olaparib, rucaparib, niraparib, and talazoparib are approved by the US Food and Drug Administration (FDA) with a primary indication for BRCA-mutated ovarian and breast cancers [24]. In addition to catalytic inhibition, most PARPis have the ability to trap PARP on DNA, preventing auto-PARylation and PARP1 release from the site of damage [27,28]. The potency of PARPis to trap PARP1 widely differs; talazoparib is the most potent and veliparib the least potent PARP trapper [27], and these properties appear to be attributable to size and rigidity differences of PARPis [28]. Trapped PARP1 on DNA forms a PARP1–DNA complex and blocks replication fork processing, creating a lesion that requires HR repair to prevent fork collapse and DSB formation [28]. This trapped PARP-induced toxicity is now considered the major mechanism of PARPi-mediated killing of HR-defective cancer cells [23,28]. PARPis with higher trapping capability exhibit potent killing of HR-deficient cells. However, recent reports suggest an association between the high PARPtrapping potency of PARPis and an increased risk of normal tissue toxicities, such as bone marrow suppression [24,29,30]. PARPis are also effective in cancers with mutations in other HR proteins, such as ATM [31–33] and PALB2 [34], expanding the application of PARPis.

PARPi and the Blood–Brain Barrier The blood–brain (tumor) barrier (BBB) impedes the penetration of drugs into brain tumors. Rucaparib and talazoparib are subject to the efflux pumps (ATP-binding cassette transporters) at the BBB, restricting drug delivery. Accordingly, rucaparib and talazoparib were not effective in sensitizing TMZ in mouse brain tumor models [35,36]. By contrast, niraparib crossed the BBB and achieved sustained brain exposure [37]. This favorable pharmacokinetic property enabled niraparib to mediate greater inhibition of tumor growth in the brain compared with olaparib, 2

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which is a substrate of P-glycoprotein (ABCB1, MDR1) [37,38]. However, reports showed olaparib penetration and activity in malignant brain tumor glioblastoma (GBM) in the brain (described later). These studies suggest that being the substrate of drug efflux transporters may not predict the inability of PARPis to penetrate tumors in the brain. Thus, pharmacokinetics and pharmacodynamics studies for individual agent are probably both useful and necessary.

Combination of PARPis with Temozolomide The DNA damage-inducing treatments radiotherapy (RT) and the alkylating agent temozolomide (TMZ) are part of the standard clinical care for GBM [39], the most malignant primary brain tumor in adults. The vital functions of PARP in the repair of damaged DNA provide a rationale for combining PARPi with TMZ and RT. Along with O6methyl-guanine, TMZ generates methyl adducts at N3-adenine and N7-guanine. These N-alkyl lesions are normally rapidly repaired by BER [40], in which PARP1 has a role. Veliparib enhanced TMZ cytotoxicity and DNA damage signaling in both TMZ-sensitive and resistant GBM models in vitro [41]. However, combined TMZ/veliparib, compared with TMZ alone, significantly delayed tumor growth and enhanced DNA damage signaling and γH2AX levels in TMZ-sensitive GBM xenografts, but not in TMZ-resistant models. This is because concentrations of veliparib and TMZ required to sensitize TMZ-resistant cancer cells cannot be achieved in vivo using a tolerable dosing regimen [41]. Similar results were shown in patient-derived orthotopic GBM xenografts (PDX) with hypermethylated and unmethylated MGMT promoter status, demonstrating a combination benefit of TMZ/veliparib only in MGMThypermethylated tumors [42]. By contrast, combination therapy of TMZ/veliparib increased survival in orthotopic PDX models derived from MGMT methylated as well as unmethylated or recurrent malignant gliomas that were resistant to TMZ alone, supporting the ability of veliparib to restore TMZ chemosensitivity in vivo [43]. Furthermore, veliparib and olaparib exhibited the ability to restore sensitivity to TMZ in mismatch repair-deficient (MSH6-inactivated), TMZ-resistant GBM cells in vitro and in vivo [44]. Rucaparib also augmented TMZ chemosensitivity in pediatric malignant brain tumor medulloblastoma in vitro and in subcutaneous xenograft models [45]. A comparison of veliparib and olaparib examined the impact of PARP trapping on the efficacy of PARPi potentiation of TMZ [46]. When combined with TMZ, olaparib induced greater levels of PARP1–DNA complexes (a marker of PARP trapping) and GBM cell death compared with veliparib. Thus, this study demonstrated a critical role of PARP trapping in PARPi/TMZ combination efficacy. Overall, preclinical studies have demonstrated the potential of PARPi to sensitize GBM cells to the cytotoxic effects of TMZ. However, research is necessary to define tumor molecular biomarkers of response to define patients who will most likely benefit from PARPi when combined with TMZ. Furthermore, chemosensitization activity of newer PARPis with potent PARP trapping capability needs to be determined.

Combination of PARPis with Radiation A body of literature offers evidence that PARPi enhances radiation therapy in gliomas. PARPi E7016 inhibited DNA repair and increased radiosensitivity in GBM cells in vitro and in a subcutaneous tumor model in vivo [47]. Combining veliparib with radiation yielded enhanced cell killing in four GBM cell lines, two with high and two with undetectable levels of MGMT expression, showing radiosensitization effects irrespective of the MGMT status of the cells [48]. Radio- and chemosensitization were further enhanced when veliparib was combined with both X-ray and TMZ [48]. Talazoparib sensitized radioresistant GBM stem cells (GSCs) to conventional low linear energy transfer irradiation as well as to carbon ion beam high linear energy transfer particle Trends in Cancer, Month 2019, Vol. xx, No. xx

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therapy in vitro [49]. GBM-initiating cells (GICs) exhibited a reliance on PARP, with decreased viability induced upon PARPi treatment. Olaparib sensitized GICs to radiation and inhibited growth, self-renewal, and DNA damage repair [50]. In vivo treatment with PARPi and RT attenuated the radiation-induced enrichment of GICs and inhibited the growth of subcutaneous tumors [50]. Elevated DDR driven by replication stress in GSCs was targeted by the combined use of an ATR inhibitor (ATRi) and PARPi to reverse radiation resistance [51]. These preclinical studies collectively support the potential of a PARPi/radiation combination to eradicate GSCs, providing a rationale for clinical testing of the strategy.

Recent Advances in Biomarker and Combination Approaches Many cancer types, including nearly all malignancies of the CNS, are not characterized by HR defects. Two major goals when developing broader applications for PARPi are to: (i) identify biomarkers that predict cancer response to PARPi alone or in combination therapies; and (ii) develop ways to induce defective HR in cancer cells that confer responsiveness to PARPi. The cellular state with defective HR without mutations in BRCA1/2 genes is called BRCAness, and recent research has suggested a variety of approaches to generate BRCAness. Mutant IDH1/2 Induces BRCAness and PARPi Sensitivity Mutations of the two isocitrate dehydrogenase genes (IDH1 and IDH2) at IDH1 R132 and IDH2 R172 confer neomorphic activity of the corresponding enzymes and the overproduction of oncometabolite (R)-2HG (hydroxyglutarate) [52]. IDH1/2 mutant gliomas are a major subset of diffuse glioma that are characterized by natural history and clinical features that are distinct from IDH-wild-type gliomas [53]. The major effects of 2HG on tumorigenesis have been ascribed to its inhibition of α-ketoglutarate-dependent dioxygenases [54]. IDH1/2 mutant cells are deficient in DNA DSB repair compared with IDH wild-type cells [55]. This phenotype observed in IDH mutant cells was due to a deficiency in HR that was caused directly by high levels of 2HG, because exogenous supplementation of 2HG to IDH wild-type cells induced HR defects. Mechanistically, 2HG inhibition of α-ketoglutarate-dependent dioxygenases, KDM4A and KDM4B (lysine demethylase 4A and 4B), led to reduced HR activity. This chemically induced BRCAness rendered cells with IDH1 R132H sensitive to olaparib and talazoparib. Specific inhibitors of mutant IDH reversed the DSB repair phenotype and PARPi sensitivity in IDH1 mutant cells. Patient-derived cultures of IDH-mutant glioma cells exhibited increased DSBs, decreased HR and better response to talazoparib compared with their IDH-wild-type counterparts. In vivo, olaparib demonstrated activity in two IDH-mutant flank cancer xenografts (HT1080 and IDH1engineered HCT116). Although orthotopic glioma models were not tested in this study, this preclinical evidence provided the scientific basis for multiple ongoing clinical trials of PARPi and PARPi combinations that specifically target gliomas with IDH1/2 mutations (described later). Myc-CDK18-ATR Axis as a New Biomarker and Target in PARPi Therapy The Myc family of transcription factors are potent oncogenic drivers implicated in the maintenance of GSCs [56] and the pathogenesis of subsets of medulloblastoma [57]. Recent work demonstrated that MYC or MYCN amplification in patient-derived GSCs generated sensitivity to PARPi [58]. Myc potently repressed transcription of CDK18, a poorly characterized cyclin-dependent kinase [58]. In response to PARPi, CDK18 interacted with ATR and regulated ATR-Rad9/ATR-ETAA1 interactions to facilitate ATR activation, thereby promoting HR and PARPi resistance [58]. Previously, CDK18 was shown to promote replication stress signaling [59], highlighting the role of CDK18 in HR. Thus, amplification of MYC or MYCN and CDK18 expression has emerged as potential biomarkers of PARPi sensitivity (or BRCAness) and insensitivity, respectively. However, the significance of MYC/MYCN and CDK18 may be context dependent and their clinical relevance still needs to be determined. 4

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ATR inhibitors reversed PARPi resistance in non-Myc GSCs and augmented PARPi sensitivity in Myc-driven GSCs in vitro. The combination of the ATRi VE822 with olaparib extended the survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity, without causing noticeable general toxicity [58]. Furthermore, combination therapy induced robust DNA damage (γH2AX) and cell death (cleaved PARP) in tumors, providing evidence that both agents penetrated tumors in mouse brains. ATR orchestrates the DNA replication stress response and mediates HR [60], and is a promising therapeutic target in DNA damage-inducing therapies. Indeed, an ATRi was shown to sensitize cancer cells to PARPi in additional models, including BRCA-mutant ovarian cancer and breast cancer [61–63]. Currently, multiple clinical trials testing the combination of PARPi with ATR inhibitors are underway for cancers outside the arena of neuro-oncology. Combination of PARPi with Oncolytic Virus Oncolytic viruses are a class of antitumor agents with unique mechanisms of action: cancerselective replication and killing, followed by induction of antitumor immune responses [64,65]. Oncolytic herpes simplex virus (oHSV) has been approved for advanced melanoma [66], and multiple clinical trials are active for malignant gliomas [67]. Human GSCs are differentially sensitive to PARPi despite uniform inhibition of PARP activity [68]. Genetically engineered oHSV, G47Δ and MG18L, sensitized GSCs to PARPi, irrespective of their PARPi sensitivity. Mechanistically, this was through oHSV-mediated selective proteasomal degradation of the key HR protein Rad51 [68]. The oHSV-induced BRCAness in GSCs enabled synthetic lethal-like interaction with PARPi that increased DNA damage, apoptosis, and cell death in vitro and in vivo. Combined treatment of MG18L and olaparib greatly extended median survival compared with either agent alone in mice bearing PARPi-sensitive or -resistant GSC-derived intracranial tumors [68]. Thus, the unique property of oHSV to impair DDR selectively in cancer cells offers opportunities to combine oHSV with a variety of DNA damage inducers [69]. In a model of anaplastic thyroid carcinoma, oncolytic adenovirus infection induced PARP activation, and PARP inhibition increased viral replication and oncolytic activity in vitro and in vivo [70]. Anti-Angiogenic Agent Cediranib Induces BRCAness Cediranib (AZD2171) is an oral pan-VEGF receptor tyrosine kinase inhibitor and a potent antiangiogenic agent. In combination with the standard-of-care chemoradiation, cediranib benefited a subset of patients with newly diagnosed GBM by increasing blood perfusion and improving tumor oxygenation [71]. A randomized Phase II trial with cediranib and olaparib versus olaparib alone in patients with relapsed platinum-sensitive ovarian cancer was a landmark study probing a combination approach utilizing PARPi and antiangiogenic agents [72,73]. This study, which enrolled 90 patients, showed a significant increase in progression-free survival (PFS; 16.5 vs 8.2 months) in the combination arm compared with the olaparib-alone arm. Subset analyses revealed that the benefit of cediranib was primarily observed in patients whose germline BRCA1/2 status was wild-type or unknown. In this subpopulation of patients, and not in the population with BRCA1/2 mutation, the combination of cediranib and olaparib significantly increased overall survival (OS). Cediranib conferred sensitivity to olaparib by downregulating key HR genes, BRCA1/2 and RAD51, and functionally suppressing HR [74]. Cediranib-induced suppression of HR was due to its inhibition of PDGFRβ, not VEGFR2. Cediranib was able to activate protein phosphatase 2A (PP2A), leading to E2F4/p130-mediated repression of the expression of BRCA1/2 and RAD51. However, HR suppression by cediranib may be context dependent and may not be extrapolated to multiple tumor types. Nevertheless, these clinical and preclinical studies performed in other cancer types provide mechanistic insights into a trial that is testing the same cediranib– olaparib combination therapy for patients with recurrent GBM (described later).

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Combination of PARPi with Immunotherapy Research has begun to elucidate the immunological consequences of PARPi-induced DNA damage [75]. PARPis upregulate the expression of PD-L1 in breast cancer cells and xenografts via PARPi-mediated inactivation of GSK-3α/β (S9/21 phosphorylation) and PD-L1 stabilization [76]. Olaparib-induced PD-L1 upregulation suppressed anticancer T cell immunity, and blockade of PD-L1 potentiated the activity of olaparib in a murine breast cancer model [76]. Talazoparib induced accumulation of cytosolic DNA fragments that in turn activated the DNA-sensing cGASSTING signaling pathway, leading to upregulation of PD-L1 and secretion of the chemokines Ccl5 and Cxcl10 [77]. This response triggered by PARPi was not limited to cancer cells with BRCA mutations. Immune checkpoint blockade targeting the PD-L1/PD-1 pathway enhanced the therapeutic effects of talazoparib in murine cancer models in a T cell-dependent manner [77]. Similarly, targeting DDR with PARPi or CHK1 inhibitor was shown to activate the STING/IRF3 innate immune pathway and cytotoxic T cells in small cell lung cancer [78] and Brca1-deficient ovarian cancer [79]. This immunomodulatory function of PARPi was effectively combined with blockade of the PD-L1/PD-1 axis in animal models, offering a new combinational opportunity for targeting cancer that does not respond to immune checkpoint blockade alone [78,79]. In ERCC1-deficient nonsmall cell lung cancer, PARPi triggered activation of cGAS/STING and downstream type 1 IFN signaling, and potentiated IFNγ-induced PD-L1 expression [80]. Thus, evidence is accumulating that PARPis are immunomodulators in cancer, and new combination approaches with immune checkpoint inhibitors are emerging. However, the significance of these findings in neuro-oncology remains to be validated.

Mechanisms of Response and Resistance to PARPi Expression of SLFN11 has been reported to be associated with response to chemotherapeutics and PARPi [81]. SLFN11 is recruited to replication forks in response to replication stress and blocks replication [63]. Inactivation of SLFN11 confers resistance to PARPi in cells with intact HR since ATR-mediated replication pause allows for fork repair and replication restart [24]. Due to reliance on ATR upon PARPi treatment, the resistance to PARPis by SLFN11 inactivation was overcome by ATR inhibition [81]. Recently, PARPi was shown to accelerate, rather than stall, fork progression, providing new insights into the replication stress mechanism caused by PARPi [82]. Mutations in ARID1A have been frequently identified in human cancers [83]. In neuro-oncology, alterations in ARID1A have been reported in high-grade meningioma [84]. ARID1A is a component of the SWI/SNF chromatin-remodeling complex, which is involved in DNA processes such as replication, transcription, and DNA repair. ARID1A deficiency impaired DSB-induced ATR activation and signaling, and sensitized cells to PARPis [85]. A drug screen combining PARPi with 20 epigenetic modulators identified a synergistic interaction between olaparib and the BET bromodomain inhibitors, JQ1, I-BET762, and OTX015, in HRproficient cancer cells [86]. Inhibition or depletion of BET proteins repressed transcription of BRCA1 and RAD51, inhibiting HR. In vivo, treatment with the BET inhibitor JQ1 sensitized HR-proficient breast and ovarian cancer xenografts to olaparib [86].

Combination of PARPis with Topoisomerase 1 Inhibitors Unlike TMZ, topoisomerase 1 inhibitors (Top1is) are not approved for the treatment of primary brain tumors. Top1is, such as camptothecin and irinotecan, reversibly trap Top1 in covalent complexes on DNA and generate lesions repaired by processes that require PARP1 [87,88]. Phase II clinical studies are underway investigating the combination of Top1i and PARPi in solid cancers [89]. However, clinical use of camptothecin and its derivatives is hampered by their poor stability 6

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and bioavailability in patients. Newer generations of Top1is are being designed with improved pharmacokinetics properties and, thus, may have potential utility in neuro-oncology [90], particularly in conjunction with PARPi [91].

Clinical Trials with PARPi in Neuro-Oncology Given the preclinical evidence that PARPi-mediated sensitization to genotoxic therapies, such as chemotherapy and RT, the first clinical investigations of PARPi in neuro-oncology used PARPi with TMZ and/or RT. A Phase I trial studied the tolerability of veliparib (ABT-888) in combination with the standard-ofcare TMZ and RT for newly diagnosed GBM. The study found that oral dosing of veliparib at 10 mg twice daily with concurrent RT/TMZ was not tolerable in patients with GBM as a result of hematological toxicity (NCT00770471i) [92]. A randomized Phase I/II study tested veliparib in combination with TMZ in recurrent TMZ-resistant GBM (NCT01026493ii) [93]. Grade 3/4 myelosuppression was observed in 20% overall and the median PFS was ~2 months. A Phase II trial is currently studying the combination therapy of veliparib, RT, and TMZ in newly diagnosed malignant gliomas without H3 K27M or BRAF V600 mutations (NCT03581292iii) (Table 1). Another Phase II study in Australia is investigating veliparib in conjunction with chemoradiotherapy in patients with newly diagnosed GBMs with unmethylated MGMT promoters. By contrast, a randomized Phase II/III study is listed as active (not recruiting) in which newly diagnosed GBMs selected with MGMT promoter hypermethylation are treated with TMZ combined with veliparib or placebo (NCT02152982iv). PARPi has also been clinically tested in pediatric neuro-oncology. A Phase I trial of concurrent veliparib and TMZ was conducted in children with recurrent brain tumors [94]. Myelosuppression was found to be dose limiting, and the recommended Phase II doses (veliparib 25 mg/m2 twice daily and TMZ 135 mg/m2/day) were tolerated. Although no objective response was observed, four of 29 evaluable patients had stable disease lasting over 6 months. This trial set the stage for the Phase I/II trial that is evaluating the combination of veliparib, TMZ, and RT in children with newly diagnosed brainstem gliomas (NCT01514201v). A Phase II clinical trial assessed veliparib in combination with whole-brain RT for patients with brain metastases from non-small cell lung cancer [95]. This randomized study found no significant differences in OS, intracranial response rate, and time to clinical or radiographic progression between RT and placebo versus RT with veliparib either 50 mg or 200 mg twice daily. However, the combination therapy did not increase adverse events. In the UK, a Phase I dose escalation study of olaparib was conducted studying olaparib in combination with TMZ in patients with relapsed GBM (OPARATIC) [96]. Tumor pharmacokinetics of orally bioavailable olaparib was investigated by tumor resection following four doses. Olaparib penetration of tumors was demonstrated, with a mean concentration of 588 nM and 500 nM at the tumor core and margin specimens, respectively. Olaparib (150 mg daily on days 1–3 weekly) was tolerated when combined with TMZ 75 mg/m2 daily. Interim analysis of this trial reported that 39% of evaluable patients remained progression-free at 6 months. This result led to clinical studies in newly diagnosed GBM testing olaparib in combination with RT for patients unsuitable for radical chemoradiation (Phase I/II, PARADIGM) and olaparib in combination with RT or RT plus TMZ based on stratification of patients by MGMT status (Phase I, PARADIGM-2) [97]. In France, a current Phase I/IIa study aims to determine the recommended dose of olaparib combined with the standard Stupp protocol (RT and TMZ) (Phase I), and OS (Phase II) (OLA-TMZ-RTE-01, NCT03212742vi). Trends in Cancer, Month 2019, Vol. xx, No. xx

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Table 1. Current PARPi Clinical Trials for CNS Tumorsa

a

Phase (trial)

PARPi

Other treatments

Target

Country

Status

Trial number

Notes

I (OPARATIC)

Olaparib

TMZ

Relapsed GBM

UK

Completed

NCT01390571

Pharmacokinetics data

I/IIa (OLA-TMZ-RTE-01)

Olaparib

Rad and TMZ

Unresectable HGG

France

Recruiting

NCT03212742

I/II (PARADIGM)

Olaparib

Rad

Newly Dx GBM

UK

Completed

2014-001216-19

Patients unsuitable for radical chemoradiation

I (PARADIGM-2)

Olaparib

Rad, or Rad and TMZ

Newly Dx GBM

UK

Active

2016-000865-22

Treatment stratified by MGMT status

II

Olaparib

No

Advanced glioma and solid tumors with IDH mutations

USA

Recruiting

NCT03212274

II

Olaparib

No

Recurrent IDH mutant glioma

France

Recruiting

NCT03561870

II (Pediatric MATCH trial)

Olaparib

No

Relapsed/refractory advanced solid tumors with defects in DDR genes

USA

Recruiting

NCT03233204

II (Pediatric MATCH screening)

Olaparib

No

Relapsed/refractory advanced solid tumors

USA

Recruiting

NCT03155620

II

Olaparib

durvalumab

IDH-mutated solid tumors

Canada

Not yet recruiting

NCT03991832

II

Olaparib

cediranib

Recurrent GBM

USA

Active, not recruiting

NCT02974621

I/II

Veliparib

Rad and TMZ

Newly Dx DIPG

USA

Completed

NCT01514201

II

Veliparib

Rad and TMZ

Newly Dx malignant glioma without H3 K27M or BRAFV600 mutations

USA

Recruiting

NCT03581292

I

Veliparib

TMZ

Recurrent/refractory CNS pediatric tumors

USA

Completed

NCT00994071

II (VERTU)

Veliparib

Rad and TMZ

Newly Dx GBM with unmethylated MGMT promoter

Australia

Active

ACTRN12615000407594

II/III

Veliparib

TMZ

Newly Dx GBM with MGMT promoter hypermethylation

USA

Active, not recruiting

NCT02152982

I/II

Talazoparib

TMZ

Refractory or recurrent pediatric malignancies

USA

Completed

NCT02116777

I/II

Pamiparib

TMZ

Recurrent gliomas with IDH1/2 mutations

USA

Not yet recruiting

NCT03914742

I

Pamiparib

TMZ

IDH1/2-mutant grade I-IV gliomas

USA

Recruiting

NCT03749187

I/II

Pamiparib

Rad and/or TMZ

Newly Dx or recurrent GBM

USA

Active, not recruiting

NCT03150862

Abbreviations: DIPG, diffuse intrinsic pontine glioma; Dx, diagnosed; MGMT, O6 methylguanine methyltransferase; Rad, radiation therapy.

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Compared with bevacizumab

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A newer generation of PARPis are also under clinical investigation, including talazoparib and BGB290 (pamiparib). Based on the report that IDH-mutant gliomas are sensitive to PARPi [55], multiple trials are investigating PARPis (olaparib or pamiparib) for gliomas with IDH1 or IDH2 mutations. Pediatric patients are also an active target of PARPi therapy in neuro-oncology. These tumors include newly diagnosed diffuse intrinsic pontine glioma and recurrent/refractory CNS tumors [94]. Preclinical studies demonstrating PARPi-mediated upregulation of PD-L1 levels on tumor cells [76] provided a rationale for combining PARPi with immune checkpoint blockade. Recently, this new combination approach entered clinical investigations. For ovarian and triple-negative breast cancers, combination of the anti-PD-L1 antibody durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) was tolerable and active, yielding an 83% (ten out of 12) disease control rate [98,99]. The same combination regimen had acceptable toxicity and demonstrated activity against metastatic prostate cancer with DNA damage repair mutations [100]. A Phase II trial of a combination therapy of olaparib and durvalumab in IDH-mutated solid tumors was recently posted and is expected to start recruiting patients (NCT03991832vii). Cediranib, a multityrosine kinase inhibitor with antiangiogenic properties, has been shown to inhibit HR and confer sensitivity to PARPi [74]. A Phase II study aims to test the combination of cediranib and olaparib, compared with bevacizumab, in patients with recurrent GBM (NCT02974621viii).

Concluding Remarks Clinical activity of single-agent PARPis has been confirmed in cancers with deficient HR, validating the concept of synthetic lethality and leading to FDA approval. Currently, indication of PARPis is limited to ovarian and BRCA mutant breast cancers. Expanding the use of PARPis to cancers without known HR defects (BRCAness), including many brain tumors, remains a significant challenge and an active research topic (see Outstanding Questions).

Outstanding Questions What will be the utility of PARPis for tumors in the CNS that are typically proficient with HR DNA repair? How can we overcome limitations associated with poor drug penetration into brain tumors and dose-limiting toxicities that have been often encountered in early clinical trials testing PARPi combination therapies? Will newer PARPis with potent PARP1trapping capability show increased efficacy and safety over veliparib? Will the different biomarkers predicting PARPi sensitivity that have been preclinically identified be validated in clinical trials and become useful to stratify patients in the future? Will therapeutic induction of BRCAness sensitize tumors to PARPis and enable combination strategies that are safe and efficacious? Will PARPis alter the immune microenvironment of neuro-oncology tumors and provide novel opportunities to combine them with immune modulators?

Despite the mechanistic foundation supporting the combination of DNA-damaging chemotherapy and PARPis to achieve lethal DNA damage, so far we have not seen objective benefit in early neuro-oncology trials exploring this strategy. Combined chemotherapy with PARPi often results in dose-limiting toxicity, typically myelosuppression, requiring dose reductions to continue investigation. Drug penetration into tumors in the brain represents another, related issue because some PARPis may not achieve therapeutic concentrations in the tumor due to efflux pump activity at the BBB. Thus, demonstration of olaparib penetration to both tumor cores and edges by the OPARATIC trial is a meaningful advance [96]. Clinical studies of TMZ combination with the newer and more potent PARPis, talazoparib and pamiparib, are underway and trial results are awaited. Selection of PARPis and optimization of treatment doses and schedules is a process that takes time but is necessary to identify activity and biomarkers of response (see Outstanding Questions). Recent preclinical research has identified novel biomarkers of BRCAness and approaches to therapeutically induce BRCAness. Such findings are guiding rational PARPi combinations applicable to CNS tumors (Figure 1). Potential BRCAness biomarkers relevant to neurooncology include mutant IDH1 and Myc (see Outstanding Questions). IDH1/2 mutant glioma is a major subset of gliomas, and single-agent olaparib and pamiparib TMZ combinations are currently being tested in this molecularly defined patient population. Preclinically, induction of a BRCAness phenotype has been achieved in several ways, including small-molecule targeted agents (e.g., cediranib, ATR inhibitors, and BET inhibitors) and anticancer viruses (oHSV) (see Outstanding Questions). The olaparib–cediranib combination trial for relapsed ovarian cancer is encouraging since the clinical benefit does not appear to depend on BRCA mutation in tumors [72,73]. As with the case with combinations of PARPi and DNA-damaging agents, Trends in Cancer, Month 2019, Vol. xx, No. xx

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Figure 1. Therapeutic Use of Poly(ADP-Ribose) Polymerase Inhibitors (PARPis) in Neuro-Oncology. (A) Conventional PARPi combinations involve DNA-damaging treatments that are part of current standard of care for glioblastoma. (B) Mutations of BRCA1/2 as well as other homologous recombination (HR) genes (such as ataxia telangiectasia mutated; ATM) are rare in neuro-oncology. Mutant isocitrate dehydrogenase (IDH)1/2 that overproduces 2HG and amplification of Myc genes induce inhibition of HR, sensitizing cells to PARPi. (C) Molecular-targeting agents, such as ataxia telangiectasia and Rad3-related protein inhibitors (ATRi), bromodomain and extra-terminal motif inhibitors (BETi), and cediranib, as well as oncolytic herpes simplex virus (HSV), can inhibit HR via different mechanisms, inducing BRCAness and PARPi sensitivity. (D) PARPi induces upregulation of programmed cell death protein ligand 1 (PD-L1) and secretion of cytokines and chemokines, altering the tumor microenvironment. Abbreviations: cGAS, cyclic GMP-AMP synthase; DSB, double-strand break; IFN, interferon; MGMT, O6 methylguanine methyltransferase; PDGFR, plateletderived growth factor receptor; STING, stimulator of interferon genes.

combining PARPi with molecular-targeted agents is expected to be associated with increased adverse events, likely necessitating dose optimization. By contrast, oHSV can be given directly to the tumor and is engineered to be capable of selective replication in neoplastic cells. This unique property of oHSV may allow the toxicity issues often problematic in PARPi combination therapies to be overcome and for the full-dose PARPi to be administered for maximize efficacy and retain safety. Finally, research has begun to reveal that PARPis induce immunological consequences that are characterized by innate immune cGAS/STNG signaling and upregulation of the immune checkpoint PD-L1. The presence and significance of these phenomena in neuro-oncological malignancies needs to be investigated (see Outstanding Questions). However, it is possible

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that PARPi-induced immune modulation is not limited to particular cancer types or molecularly defined cancers, but rather universal. A better understanding of the immunological aspects of PARP inhibition in brain tumors should provide an opportunity to widen combination therapy partners to immune modulators, such as immune checkpoint inhibitors or oncolytic viruses. Such an approach may open avenues towards overcoming the clinical barrier to apply PARPi to HR-proficient and immunologically cold primary brain tumors. Resources i

https://clinicaltrials.gov/ct2/show/NCT00770471

ii

https://clinicaltrials.gov/ct2/show/NCT01026493

iii

https://clinicaltrials.gov/ct2/show/NCT03581292

iv

https://clinicaltrials.gov/ct2/show/NCT02152982

v

https://clinicaltrials.gov/ct2/show/NCT01514201

vi

https://clinicaltrials.gov/ct2/show/NCT03212742

vii

https://clinicaltrials.gov/ct2/show/NCT03991832

viii

https://clinicaltrials.gov/ct2/show/NCT02974621

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