Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines

Clarke, Michelle J.; Mulligan, Evan A.; Grogan, Patrick T.; Mladek, Ann C.; Carlson, Brett L.; Schroeder, Mark A.; Curtin, Nicola J.; Lou, Zhenkun; Decker, Paul A.; Wu, Wenting; Plummer, ER; Sarkaria, Jann N.

doi:10.1158/1535-7163.mct-08-0854

Cited by 86 publications

(83 citation statements)

References 25 publications

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“…MGMT, being a suicide enzyme depleted on activation, was minimally decreased in all xenografts after treatment, indicating that MGMT is active in MGMT + lines, although not sufficient to render resistance to therapy. These results are in contrast to recent studies on primary human glioma xenografts where MGMT + lines exhibited resistance to ABT-888+TMZ combination therapy (38). The underlying reasons for differential sensitivity to ABT-888+TMZ in MGMT + lines are not clear but may reflect tumor type-dependent responses.…”

Section: Discussioncontrasting

confidence: 99%

“…Thus, the enhancement of TMZ activity by ABT-888+TMZ was not surprising in TMZ-sensitive models. Interestingly, ABT-888+TMZ was significantly efficacious in most of the models examined, including those that were initially resistant or became resistant to TMZ, indicating that PARP inhibition can confer sensitivity to TMZ-refractory tumors perhaps through BER-mediated repair mechanisms (16,17,38). Therefore, TMZ response was not an absolute predictor of enhanced sensitivity to ABT-888+TMZ combination therapy.…”

Section: Discussionmentioning

confidence: 98%

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ABT-888 Confers BroadIn vivoActivity in Combination with Temozolomide in Diverse Tumors

Palma

Wang

Rodrı́guez

et al. 2009

Clinical Cancer Research

128

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Purpose: ABT-888, currently in phase 2 trials, is a potent oral poly(ADP-ribose) polymerase inhibitor that enhances the activity of multiple DNA-damaging agents, including temozolomide (TMZ). We investigated ABT-888+TMZ combination therapy in multiple xenograft models representing various human tumors having different responses to TMZ. Experimental Design: ABT-888+TMZ efficacy in xenograft tumors implanted in subcutaneous, orthotopic, and metastatic sites was assessed by tumor burden, expression of poly(ADP-ribose) polymer, and O 6 -methylguanine methyltransferase (MGMT). Results: Varying levels of ABT-888+TMZ sensitivity were evident across a broad histologic spectrum of models (55-100% tumor growth inhibition) in B-cell lymphoma, small cell lung carcinoma, non-small cell lung carcinoma, pancreatic, ovarian, breast, and prostate xenografts, including numerous regressions. Combination efficacy in otherwise TMZ nonresponsive tumors suggests that TMZ resistance may be overcome by poly(ADP-ribose) polymerase inhibition. Profound ABT-888+TMZ efficacy was seen in experimental metastases models that acquired resistance to TMZ. Moreover, TMZ resistance was overcome in crossover treatments, indicating that combination therapy may overcome acquired TMZ resistance. Neither tumor MGMT, mismatch repair, nor poly(ADP-ribose) polymer correlated with the degree of sensitivity to ABT-888+TMZ. Conclusions: Robust ABT-888+TMZ efficacy is observed across a spectrum of tumor types, including orthotopic and metastatic implantation. As many TMZ nonresponsive tumors proved sensitive to ABT-888+TMZ, this novel combination may broaden the clinical use of TMZ beyond melanoma and glioma. Although TMZ resistance may be influenced by MGMT, neither MGMT nor other mechanisms of TMZ resistance (mismatch repair) precluded sensitivity to ABT-888+TMZ. Underlying mechanisms of TMZ resistance in these models are not completely understood but likely involve mechanisms independent of MGMT. (Clin Cancer Res 2009;15(23):7277-90) ABT-888 is a new poly(ADP-ribose) polymerase (PARP) inhibitor with excellent potency (K I , 5.2 and 2.9 nmol/L, PARP-1/ PARP-2) and oral bioavailability (1). As shown previously, ABT-888 enhanced the activity of multiple DNA-damaging agents, including cisplatin, carboplatin, cyclophosphamide, irinotecan, radiation, and temozolomide (TMZ), in various xenograft and syngeneic preclinical models (2). In this study, we evaluated in detail the activity of TMZ and the ability of ABT-888 to enhance TMZ antitumor activity in multiple xenograft tumors implanted in subcutaneous, orthotopic, and metastatic sites.The PARP family of enzymes is characterized by the ability to ADP ribosylate protein substrates, implicated in many cellular processes (differentiation, gene regulation, protein degradation, replication, transcription, cell cycle progression, and methylation), and overall maintenance of genomic stability (3, 4). PARP is also critical for single-strand break repair by base excision repair (BER) that can lead to radioresi...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 98%

ABT-888 Confers BroadIn vivoActivity in Combination with Temozolomide in Diverse Tumors

Palma

Wang

Rodrı́guez

et al. 2009

Clinical Cancer Research

128

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“…Despite being an attractive therapeutic target, PARP inhibitors have achieved mixed results in biologic and clinical studies (28,30,31,47). We demonstrated that while all the PARP inhibitors tested effectively inhibited PARP activity, not all were able to reduce pHGA and DIPG tumor cell growth.…”

Section: Discussionmentioning

confidence: 86%

“…This led us to hypothesize that PARP inhibition could potentially be used as a monotherapy or to enhance the therapeutic index of ionizing radiation (IR) in pHGA and DIPG. Veliparib, olaparib, and niraparib are three orally available PARP inhibitors which have all entered phase III clinical trials for adult cancer, demonstrating good tolerability in phase II studies (25)(26)(27)(28)(29)(30)(31). However, there is a lack of knowledge regarding the efficacy of these PARP inhibitors in pediatric brain tumors.…”

Section: Introductionmentioning

confidence: 99%

Poly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma

Chornenkyy

Agnihotri

et al. 2015

Molecular Cancer Therapeutics

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Pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas (DIPG) are devastating malignancies for which no effective therapies exist. We investigated the therapeutic potential of PARP1 inhibition in preclinical models of pHGA and DIPG. PARP1 levels were characterized in pHGA and DIPG patient samples and tumor-derived cell lines. The effects of PARP inhibitors veliparib, olaparib, and niraparib as monotherapy or as radiosensitizers on cell viability, DNA damage, and PARP1 activity were evaluated in a panel of pHGA and DIPG cell lines. Survival benefit of niraparib was examined in an orthotopic xenograft model of pHGA. About 85% of pHGAs and 76% of DIPG tissue microarray samples expressed PARP1. Six of 8 primary cell lines highly expressed PARP1. Interestingly, across multiple cell lines, some PARP1 protein expression was required for response to PARP inhibition; however, there was no correlation between protein level or PARP1 activity and sensitivity to PARP inhibitors. Niraparib was the most effective at reducing cell viability and proliferation (MTT and Ki67). Niraparib induced DNA damage (gH2AX foci) and induced growth arrest. Pretreatment of pHGA cells with a sublethal dose of niraparib (1 mmol/L) before 2 Gy of ionizing radiation (IR) decreased the rate of DNA damage repair, colony growth, and relative cell number. Niraparib (50 mg/kg) inhibited PARP1 activity in vivo and extended survival of mice with orthotopic pHGA xenografts, when administered before IR (20 Gy, fractionated), relative to control mice (40 vs. 25 days). Our data provide in vitro and in vivo evidence that niraparib may be an effective radiosensitizer for pHGA and DIPG.

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“…On the other hand, cancer-type specific responses cannot be ruled out as it has been suggested that only MGMT À leukemia and glioblastoma multiforme cells would respond to temozolomide combined with the PARPi veliparib (40,43,44). It is nevertheless important to consider that variables such as differences in PARPi action, bioavailability, or the application of particular treatment regimes need to be taken into account to correlate in vitro and in vivo efficacy of temozolomide and PARPi combinations as well as clinical efficacy (31,(42)(43)(44)(45). Indeed, to synergize with temozolomide, both drugs work through catalytic PARP inhibition and trapping PARP-DNA complexes.…”

Section: /Mgmtmentioning

confidence: 99%

MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

Erice

Smith

White

et al. 2015

Molecular Cancer Therapeutics

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Melanoma and other solid cancers are frequently resistant to chemotherapies based on DNA alkylating agents such as dacarbazine and temozolomide. As a consequence, clinical responses are generally poor. Such resistance is partly due to the ability of cancer cells to use a variety of DNA repair enzymes to maintain cell viability. Particularly, the expression of MGMT has been linked to temozolomide resistance, but cotargeting MGMT has proven difficult due to dose-limiting toxicities. Here, we show that the MGMT-mediated resistance of cancer cells is profoundly dependent on the DNA repair enzyme PARP. Both in vitro and in vivo, we observe that MGMT-positive cancer cells strongly respond to the combination of temozolomide and PARP inhibitors (PARPi), whereas MGMT-deficient cells do not. In melanoma cells, temozolomide induced an antiproliferative senescent response, which was greatly enhanced by PARPi in MGMTpositive cells. In summary, we provide compelling evidence to suggest that the stratification of patients with cancer upon the MGMT status would enhance the success of combination treatments using temozolomide and PARPi.

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Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines

Cited by 86 publications

References 25 publications

ABT-888 Confers BroadIn vivoActivity in Combination with Temozolomide in Diverse Tumors

ABT-888 Confers BroadIn vivoActivity in Combination with Temozolomide in Diverse Tumors

Poly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma

MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

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