DW-MRI as a Biomarker to Compare Therapeutic Outcomes in Radiotherapy Regimens Incorporating Temozolomide or Gemcitabine in Glioblastoma

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, United States of America.
PLoS ONE (Impact Factor: 3.23). 04/2012; 7(4):e35857. DOI: 10.1371/journal.pone.0035857
Source: PubMed


The effectiveness of the radiosensitizer gemcitabine (GEM) was evaluated in a mouse glioma along with the imaging biomarker diffusion-weighted magnetic resonance imaging (DW-MRI) for early detection of treatment effects. A genetically engineered murine GBM model [Ink4a-Arf(-/-) Pten(loxP/loxP)/Ntv-a RCAS/PDGF(+)/Cre(+)] was treated with gemcitabine (GEM), temozolomide (TMZ) +/- ionizing radiation (IR). Therapeutic efficacy was quantified by contrast-enhanced MRI and DW-MRI for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ and radiation showed a significant reduction in growth rates as early as three days post-treatment initiation. Both combination treatments (GEM/IR and TMZ/IR) resulted in improved survival over single therapies. Tumor diffusion values increased prior to detectable changes in tumor volume growth rates following administration of therapies. Concomitant GEM/IR and TMZ/IR was active and well tolerated in this GBM model and similarly prolonged median survival of tumor bearing mice. DW-MRI provided early changes to radiosensitization treatment warranting evaluation of this imaging biomarker in clinical trials.

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    • "Its diffuse and infiltrative nature makes complete resection impossible as tumour cells spread beyond the macroscopic margins [2] [3]. Numerous innovative treatments have been proposed, including photodynamic therapy [4] [5] [6], but the current standard treatment with maximal safe surgery and concomitant radiotherapy (RT) and temozolomide (TMZ) chemotherapy (CTx) can provide a median overall survival (OS) of 14–16 months [7] [8] [9] [10] [11] [12] [13]. Stupp et al. reported improved OS rates at 2 years (27.2% versus 10.9%) and 5 years (9.8% versus 1.9%) for those receiving concomitant TMZ and RT versus RT alone [11] [12]. "
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    ABSTRACT: Glioblastoma multiforme (GBM) is a malignant and incurable glial brain tumour. The current best treatment for GBM includes maximal safe surgical resection followed by concomitant radiotherapy and adjuvant temozolomide. Despite this, median survival is still only 14–16 months. Mechanisms that lead to chemo- and radio-resistance underpin treatment failure. Insights into the DNA repair mechanisms that permit resistance to chemoradiotherapy in GBM may help improve patient responses to currently available therapies.
    Journal of Clinical Neuroscience 11/2014; 22(1). DOI:10.1016/j.jocn.2014.09.003 · 1.38 Impact Factor
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    • "MRI is routinely employed to estimate tumor volume using anatomic images but also tumor-associated edema and tumor cellularity using the apparent diffusion coefficient (ADC) of water calculated using diffusion-weighted (DW) MRI sequences [7] [8] [9] [10]. Diffusion imaging has been successfully used to assess glioma response to different chemotherapies [9] [11] [12] as well as radiotherapy [12]. Taken together, these studies have shown that DW-MRI is a sensitive biomarker that is capable of detecting early cellular changes in treated tumors, which precede macroscopic volumetric response. "
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    ABSTRACT: Treatment of glioblastoma (GBM) remains challenging due in part to its histologic intratumoral heterogeneity that contributes to its overall poor treatment response. Our goal was to evaluate a voxel-based biomarker, the functional diffusion map (fDM), as an imaging biomarker to detect heterogeneity of tumor response in a radiation dose escalation protocol using a genetically engineered murine GBM model. Twenty-four genetically engineered murine GBM models [Ink4a-Arf(-/-)/Pten(loxp/loxp)/Ntv-a RCAS/PDGF(+)/Cre(+)] were randomized in four treatment groups (n = 6 per group) consisting of daily doses of 0, 1, 2, and 4 Gy delivered for 5 days. Contrast-enhanced T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scans were acquired for tumor delineation and quantification of apparent diffusion coefficient (ADC) maps, respectively. MRI experiments were performed daily for a week and every 2 days thereafter. For each animal, the area under the curve (AUC) of the percentage change of the ADC (AUCADC) and that of the increase in fDM values (AUCfDM+) were determined within the first 5 days following therapy initiation. Animal survival increased with increasing radiation dose. Treatment induced a dose-dependent increase in tumor ADC values. The strongest correlation between survival and ADC measurements was observed using the AUCfDM+ metric (R (2) = 0.88). This study showed that the efficacy of a voxel-based imaging biomarker (fDM) was able to detect spatially varying changes in tumors, which were determined to be a more sensitive predictor of overall response versus whole-volume tumor measurements (AUCADC). Finally, fDM provided for visualization of treatment-associated spatial heterogeneity within the tumor.
    Translational oncology 10/2013; 6(5):554-61. DOI:10.1593/tlo.13532 · 2.88 Impact Factor
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    • "Seven days later, each group of the mice was randomly divided into two groups to receive treatment with either DMSO or combination of TMZ (5 mg/kg, i.p.) followed by XRT, 2 Gy/kg with a 3 h lag time between treatments as suggested by Galban et al. 17. All treatments were administered once a week for a 5-week period. "
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    ABSTRACT: Metalloproteinases are membrane-bound proteins that play a role in the cellular responses to antiglioma therapy. Previously, it has been shown that treatment of glioma cells with temozolomide (TMZ) and radiation (XRT) induces the expression of metalloproteinase 14 (MMP14). To investigate the role of MMP14 in gliomagenesis, we used several chemical inhibitors which affect MMP14 expression. Of all the inhibitors tested, we found that Marimastat not only inhibits the expression of MMP14 in U87 and U251 glioma cells, but also induces cell cycle arrest. To determine the relationship between MMP14 inhibition and alteration of the cell cycle, we used an RNAi technique. Genetic knockdown of MMP14 in U87 and U251 glioma cells induced G2/M arrest and decreased proliferation. Mechanistically, we show that TMZ and XRT regulated expression of MMP14 in clinical samples and in vitro models through downregulation of microRNA374. In vivo genetic knockdown of MMP14 significantly decreased tumor growth of glioma xenografts and improved survival of glioma-bearing mice. Moreover, the combination of MMP14 silencing with TMZ and XRT significantly improved the survival of glioma-bearing mice compared to a single modality treatment group. Therefore, we show that the inhibition of MMP14 sensitizes tumor cells to TMZ and XRT and could be used as a future strategy for antiglioma therapy. Glioblastoma remains an incurable form of brain cancer. In this manuscript, we show that inhibition of MMP14 can potentiate the efficacy of current standard of care which includes chemo- and radiotherapy.
    Cancer Medicine 08/2013; 2(4):457-67. DOI:10.1002/cam4.104 · 2.50 Impact Factor
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