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Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma.

ABSTRACT: BACKGROUND:The O 6 -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM. METHODS:The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination with RT was tested on a panel of patient derived cell lines (PDCLs) and patient-derived xenografts (PDX) models generated from GBM patients with MGMT unmethylated tumors. RESULTS:The combination of veliparib and RT inhibited colony formation in the majority of PDCLs tested. The PDCL, RN1 showed significantly reduced levels of the homologous repair protein, Mre11 and a heightened response to PARP inhibition measured by increased apoptosis and decreased colony formation. The oral administration of veliparib (12.5 mg/kg, twice daily for 5 days in a 28-day treatment cycle) in combination with whole brain RT (4 Gy) induced apoptosis (Tunel staining) and decreased cell proliferation (Ki67 staining) in a PDX of MGMT unmethylated GBM. Significantly longer survival times of the PDX treated with the combination treatment were recorded compared to RT only or veliparib only. CONCLUSIONS:Our results demonstrate preclinical efficacy of targeting PARP at multiple levels and provide a new approach for the treatment of MGMT unmethylated GBM.

SUBMITTER: Jue TR

PROVIDER: S-EPMC5356284 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma.

Jue Toni Rose TR Nozue Kyoko K Lester Ashleigh J AJ Joshi Swapna S Schroder Lisette B W LB Whittaker Shane P SP Nixdorf Sheri S Rapkins Robert W RW Khasraw Mustafa M McDonald Kerrie L KL

Journal of translational medicine 20170317 1

<h4>Background</h4>The O <sup>6</sup> -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM.<h4>Methods</h4>The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable in ...[more]

PMID: 28314386

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Project description:Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Resistance to TMZ is correlated with expression of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT), which is highly expressed in a majority of GBM tumors. Dianhydrogalactitol (VAL-083) is a first-in-class bi-functional DNA-targeting agent that exhibited activity against GBM in NCI-sponsored clinical trials both as a single agent and in combination with radiotherapy. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue. We have demonstrated that VAL-083 targets N7-Guanine and rapidly induces interstrand DNA cross-links, leading to DNA double-strand breaks, S/G2 cell-cycle arrest and cell death in GBM cell lines and GBM cancer stem cells (CSCs) in vitro. This unique N7-guanine targeting mechanism not only circumvents MGMT-mediated chemo-resistance but also maintains cytotoxic activity in cancer cells deficient in mismatch repair (MMR). These data suggest VAL-083 may offer a superior chemotherapeutic alternative in the treatment of MGMT-unmethylated or MMR deficient GBM. Here, we provide an update of ongoing clinical trials with VAL-083 in MGMT-unmethylated GBM: i) a single-arm, biomarker-driven, Phase II study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab improves survival compared to historical lomustine control (clinicaltrials.gov identifier: NCT02717962); ii) a single-arm, biomarker-driven, Phase II study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients (clinicaltrials.gov identifier: NCT03050736). The results of these studies may support a new treatment paradigm in for the treatment of MGMT-unmethylated GBM.

Project description:BACKGROUND:Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed. METHODS:The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by ?H2AX immunostaining and promoter methylation of DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments-approved methylation-specific polymerase chain reaction. RESULTS:The combination of TMZ/veliparib statistically significantly extended survival of GBM models (P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT-hypermethylated lines (average extension in median survival = 87 days, range = 20-150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter-hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter-hypermethylated lines. CONCLUSION:Veliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM.

Project description:Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) and maintenance TMZ. Almost all GBM patients experience recurrent/progressive disease, and median survival after recurrence is 3–9 months. Effective therapies for recurrent GBM (rGBM) are lacking, representing a significant unmet medical need. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with a poor prognosis. Second-line treatment with the anti-angiogenic agent bevacizumab (BEV) has not improved survival, and 5-year survival is less than 3%. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083s cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells, and in vivo GBM models. We completed a 3 + 3 dose-escalation trial of VAL-083 in TMZ- and BEV-refractory rGBM. 40mg/m2/day given on days 1,2,3 of a 21-day cycle was generally well-tolerated, and this dose was selected for further clinical evaluation in Phase 2 trials. The trial described here is an ongoing single-arm, biomarker-driven Phase 2 trial in MGMT-unmethylated BEV-naïve adult rGBM. In this trial, 48 patients will receive VAL-083 40mg/m2/day on days 1,2,3 of a 21-day cycle. Tumor response will be assessed by MRI approximately every 42 days, per RANO criteria. The primary objective of this study is to determine if VAL-083 improves median overall survival (mOS) for MGMT-unmethylated rGBM patients compared to a historical mOS of 7.1 months for such patients treated with lomustine (EORTC26101). Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life (QOL) evaluation using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962.

Dataset Information

Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma.

Publications

Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma.

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