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. 2016 Feb;18(2):82-9.
doi: 10.1016/j.neo.2015.11.014.

Evaluation of Concurrent Radiation, Temozolomide and ABT-888 Treatment Followed by Maintenance Therapy with Temozolomide and ABT-888 in a Genetically Engineered Glioblastoma Mouse Model

Benjamin Lemasson  1 , Hanxiao Wang  2 , Stefanie Galbán  3 , Yinghua Li  4 , Yuan Zhu  4 , Kevin A Heist  2 , Christina Tsein  5 , Thomas L Chenevert  2 , Alnawaz Rehemtulla  5 , Craig J Galbán  2 , Eric C Holland  6 , Brian D Ross  7
Affiliations

Evaluation of Concurrent Radiation, Temozolomide and ABT-888 Treatment Followed by Maintenance Therapy with Temozolomide and ABT-888 in a Genetically Engineered Glioblastoma Mouse Model

Benjamin Lemasson et al. Neoplasia. 2016 Feb.

Abstract

Despite the use of ionizing radiation (IR) and temozolomide (TMZ), outcome for glioblastoma (GBM) patients remains dismal. Poly (ADP-ribose) polymerase (PARP) is important in repair pathways for IR-induced DNA damage and TMZ-induced alkylation at N7-methylguanine and N3-methyldenine. However, optimized protocols for administration of PARP inhibitors have not been delineated. In this study, the PARP inhibitor ABT-888 was evaluated in combination with and compared to current standard-of-care in a genetically engineered mouse GBM model. Results demonstrated that concomitant TMZ/IR/ABT-888 with adjuvant TMZ/ABT-888 was more effective in inducing apoptosis and reducing proliferation with significant tumor growth delay and improved overall survival over concomitant TMZ/IR with adjuvant TMZ. Diffusion-weighted MRI, an early translatable response biomarker detected changes in tumors reflecting response at 1 day post TMZ/IR/ABT-888 treatment. This study provides strong scientific rationale for the development of an optimized dosing regimen for a PARP inhibitor with TMZ/IR for upfront treatment of GBM.

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Figures

Figure 1
Figure 1
Schematic diagram of treatment schedules. Evaluation of ABT-888, TMZ and IR as monotherapies or combination therapies in a glioblastoma mouse model. Tumor bearing animals were divided into 8 groups and treated with vehicle (1% DMSO in saline), ABT-888 (25 mg/kg per dose, 2 doses a day, 5 d/wk for 2 weeks), TMZ (50 mg/kg per day, 5 d/wk for 2 weeks), IR (1 Gy/day, 5 d/wk for 2 wk), TMZ/ABT-888 (2 weeks of TMZ/ABT-888 treatment), IR/ABT-888 (2 weeks of ABT-888/IR treatment), TMZ/IR (2 weeks of IR/TMZ treatment followed by 2 weeks of TMZ treatment), and TMZ/IR/ABT-888 (2 weeks of IR/TMZ treatment followed by 2 weeks of TMZ/ABT-888 treatment). MRI was used to monitor change in tumor volume every other day.
Figure 2
Figure 2
Evaluation of ABT-888, temozolomide (TMZ) and ionizing radiation (IR) as monotherapies or combination therapies in a glioblastoma mouse model. A, Percentage change of intracerebral tumor volumes for vehicle treated control, ABT-888, TMZ, IR, TMZ/ABT-888, IR/ABT-888, TMZ/IR, and TMZ/IR/ABT-888 groups assessed by MRI as a function of time. Note time-to-progression occurred at 20 versus 35 days for TMZ/IR and TMZ/IR/ABT-888 groups, respectively. The graph depicts mean ± SEM. Kaplan-Meier plots for each group are presented for progression-free survival (B) and overall survival (C).
Figure 3
Figure 3
Western blot evaluation of PARP activity and DNA damage in post-treatment tumor tissues. Western blotting using antibodies against PAR, a marker for PARP-1 activity, and pH2Ax, a marker for DNA double strand break. Tumor tissues were harvested from two animals in each group three days post treatment initiation.
Figure 4
Figure 4
Histopathological analysis of tumor tissue. A, Representative images showing tumor tissue morphology (H&E), apoptosis (Apoptag) and proliferation (Ki67) in tumor tissues from various groups. B, Percentage of apoptotic cells (Apoptag positive) and proliferative cells (Ki67 positive) in each group. The graph depicts mean ± SEM.
Figure 5
Figure 5
A, Representative T1-weighted and ADC images of various groups prior to treatment initiation and 2 days post treatment initiation. B, Percentage change of mean ADC values for each group. Data is plotted as mean ± SEM.
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References

    1. Bondy ML, Scheurer ME, Malmer B, Barnholtz-Sloan JS, Davis FG, Il'yasova D, Kruchko C, McCarthy BJ, Rajaraman P, Schwartzbaum JA. Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer. 2008;113:1953–1968. - PMC - PubMed
    1. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–466. - PubMed
    1. Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer. 2012;12:801–817. - PubMed
    1. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12:587–598. - PubMed
    1. Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays. 2004;26:882–893. - PubMed

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