Studies investigating dynamic susceptibility contrast magnetic resonance imaging-determined relative cerebral blood volume (rCBV) maps as a metric of treatment response assessment have generated ...conflicting results. We evaluated the potential of various analytical techniques to predict survival of patients with glioma treated with chemoradiation. rCBV maps were acquired in patients with high-grade gliomas at 0, 1, and 3 weeks into chemoradiation therapy. Various analytical techniques were applied to the same cohort of serial rCBV data for early assessment of survival. Three different methodologies were investigated: 1) percentage change of whole tumor statistics (i.e., mean, median, and percentiles), 2) physiological segmentation (low rCBV, medium rCBV, or high rCBV), and 3) a voxel-based approach, parametric response mapping (PRM). All analyses were performed using the same tumor contours, which were determined using contrast-enhanced T1-weighted and fluid attenuated inversion recovery images. The predictive potential of each response metric was assessed at 1-year and overall survival. PRM was the only analytical approach found to generate a response metric significantly predictive of patient 1-year survival. Time of acquisition and contour volume were not found to alter the sensitivity of the PRM approach for predicting overall survival. We have demonstrated the importance of the analytical approach in early response assessment using serial rCBV maps. The PRM analysis shows promise as a unified early and robust imaging biomarker of treatment response in patients diagnosed with high-grade gliomas.
The purpose of this paper is to compare two methods for quantifying metabolite concentrations using the one-pulse experiment for a sample undergoing chemical exchange and subject to an intervention ...or other temporal variation. The methods, LATR-C (Long Acquisition TR (interpulse delay); Corrected for partial saturation) and LATR-NC (Long Acquisition TR; Not Corrected), are compared in terms of signal-to-noise ratio, SNR, per unit time and quantitation errors. Parameters relevant to the isolated perfused rat heart are used as a specific application, although the results are general. We assume throughout that spin–lattice relaxation times,
T
1, do not change. For a given flip angle,
θ, TR’s are calculated which result in maximal SNR per unit time under 10%, 5%, and 1% constraints on quantitation errors. Additional simulations were performed to demonstrate explicitly the dependence of the quantitation errors on TR for a fixed
θ. We find (i) if the allowed error is large, and when both metabolite concentrations and rate constants vary, LATR-C permits use of shorter TR, and hence yields greater SNR per unit time, than LATR-NC; (ii) for small allowed error, the two methods give similar TR’s and SNR per unit time, so that the simpler LATR-NC experiment may be preferred; (iii) large values of
θ result in similar constrained TR’s and hence SNR per unit time for the two methods; (iv) the ratio of concentrations of metabolites with similar
T
1 exhibit similar errors for the two methods.
PURPOSE:
The inherent treatment resistance of glioblastoma (GBM) can involve multiple mechanisms including checkpoint kinase (Chk1/2)-mediated increased DNA repair capability, which can attenuate the ...effects of genotoxic chemotherapies and radiation. The goal of this study was to evaluate diffusion-weighted magnetic resonance imaging (DW-MRI) as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM.
EXPERIMENTAL DESIGN:
We evaluated a specific small molecule inhibitor of Chk1/2, AZD7762, in combination with radiation using
in vitro
human cell lines and
in vivo
using a genetically engineered GBM mouse model. DW-MRI and T1-contrast MRI were used to follow treatment effects on intracranial tumor cellularity and growth rates, respectively.
RESULTS:
AZD7762 inhibited clonal proliferation in a panel of GBM cell lines and increased radiosensitivity in p53-mutated GBM cell lines to a greater extent compared to p53 wild-type cells.
In vivo
efficacy of AZD7762 demonstrated a dose-dependent inhibitory effect on GBM tumor growth rate and a reduction in tumor cellularity based on DW-MRI scans along with enhancement of radiation efficacy.
CONCLUSION:
DW-MRI was found to be a useful imaging biomarker for the detection of radiosensitization through inhibition of checkpoint kinases. Chk1/2 inhibition resulted in antiproliferative activity, prevention of DNA damage-induced repair, and radiosensitization in preclinical GBM tumor models, both
in vitro
and
in vivo
. The effects were found to be maximal in p53-mutated GBM cells. These results provide the rationale for integration of DW-MRI in clinical translation of Chk1/2 inhibition with radiation for the treatment of GBM.
Imaging biomarkers capable of early quantification of tumor response to therapy would provide an opportunity to individualize patient care. Image registration of longitudinal scans provides a method ...of detecting treatment associated changes within heterogeneous tumors by monitoring alterations in the quantitative value of individual voxels over time, which is unattainable by traditional volumetric-based histogram methods. The concepts involved in the use of image registration for tracking and quantifying breast cancer treatment response using parametric response mapping (PRM), a voxel-based analysis of diffusion-weighted magnetic resonance imaging (DW-MRI) scans, are presented. Application of PRM to breast tumor response detection is described, wherein robust registration solutions for tracking small changes in water diffusivity in breast tumors during therapy are required. Methodologies that employ simulations are presented for measuring expected statistical accuracy of PRM for response assessment. Test-retest clinical scans are used to yield estimates of system noise to indicate significant changes in voxel-based changes in water diffusivity. Overall, registration-based PRM image analysis provides significant opportunities for voxel-based image analysis to provide the required accuracy for early assessment of response to treatment in breast cancer patients receiving neoadjuvant chemotherapy.
We demonstrate that rapamycin can induce regression of
adenomatous polyposis coli
(
Apc
) mutation-dependent colonic adenomas in genetically engineered mice (
CPC;Apc
). An endoscope was used to ...visualize adenomas in
CPC;Apc
mice weekly for 10 weeks. The lesion surface areas were measured using a distance gauge and digitally generated grid. Coronal scans were performed on magnetic resonance imaging (MRI) to localize adenomas, and tumor volumes were measured from regions of interest drawn on consecutive axial scans. Rapamycin (5 mg/kg) was administered intraperitoneally daily for 5 weeks. Endoscopy and MRI were performed weekly to monitor adenoma regression. Caliper measurements and immunohistochemistry (IHC) were performed on adenomas postmortem. Dimensions from
n
= 30 adenomas in
n
= 7 animals were measured. Adenoma surface areas on endoscopy correlated with volumes on MRI and with postmortem caliper measurements,
R
2
= 0.84 and
R
2
= 0.81, respectively. The mean adenoma doubling times on endoscopy and MRI were 0.95 ± 0.14 and 1.21 ± 0.16 weeks, respectively. The minimum detectable adenoma surface area and volume on endoscopy and MRI was 0.69 mm
2
and 1.76 mm
3
, respectively. On histology, the rapamycin-treated adenomas showed limited regions of dysplasia. Rapamycin therapy resulted in much lower mammalian target of rapamycin signaling and cell proliferation. Lower expression of phospho-S6 and reduced numbers of Ki67-positive cells were seen on IHC compared to vehicle-treated lesions. Endoscopy can be validated by MRI as a robust methodology for quantitative monitoring of therapy, representing a promising approach for future preclinical efforts to assess utility of novel colorectal cancer prevention strategies.
Abstract
Genetically engineered mouse models combined with noninvasive functional imaging provide unique opportunities to evaluate molecularly targeted agents. To this end, we evaluated the ...effectiveness of targeted agents against the Ntv-a PtenloxP/loxp/Ink4a-Arf−/−RCAS/PDGF(+)/Cre(+) genetically engineered mouse glioma model. Agents targeting Akt (perifosine) and mTOR (CCI-779) were evaluated alone and in combination for their therapeutic effectiveness. Therapeutic efficacy was quantified using diffusion weighted magnetic resonance imaging (DW-MRI) and contrast-enhanced MRI to assess changes in tumor cellularity and growth rate, respectively. MRI scans were performed daily for the first week then every second day until the animals expired or become moribund in which case the animals were sacrificed. Two animals from each group were sacrificed for histological analysis of the tumors 24 hours following the final day of treatment using H&E, PCNA, pS6RP and TUNEL. Over the course of the study, CCI-779 treated animals either alone or in combination had statistically smaller tumor volumes versus controls. Tumors treated with perifosine alone were found to be statistically smaller than controls at day 5 but larger than CCI-779 alone and in combination at days 4 and 3, respectively. No difference was observed in tumor volumes between CCI-779 treatment alone or in combination. A 10-15% increase in tumor diffusion values were observed in perifosine and CCI-779 groups on days 3-6 post-treatment initiation. The combination therapy produced a 25-35% increased in tumor ADC values over this same time frame indicating that while each individual therapy provided some level of cell death, the combination was more effective. PCNA stains revealed a decrease in proliferation for perifosine treated tumors with a more profound decrease seen in CCI-779 and in the combination treatment group. Down regulation of the oncogenic signaling molecule pS6RP which is located downstream of mTOR and Ras was observed slightly for perifosine and nearly completely for the CCI-779 and combination treatment groups. Finally, TUNEL staining for the presence of apoptosis revealed slight positivity for perifosine and CCI-779, however, the combination treatment group appeared to have more TUNEL positivity than the other treatment groups. Improvement in overall survival was observed for all treatment groups versus control. Between treatments, CCI-779 and combination therapy were found to have a significant improvement in survival over perifosine. In conclusion, inhibition of mTor and Akt was found to elicit potent antitumor activity alone and were found to be more efficacious in combination. Finally, changes in tumor diffusion values as quantified using DW-MRI appeared to correlate and predict treatment effectiveness and may be useful as a molecular imaging biomarker for clinical translation of targeted agents for brain tumor trials.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4190.
The receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor/scatter factor (HGF/SF) modulate signaling cascades implicated in cellular proliferation, survival, migration, invasion, ...and angiogenesis. Therefore, dysregulation of HGF/c-Met signaling can compromise the cellular capacity to moderate these activities, and lead to tumorigenesis, metastasis, and therapeutic resistance in various human malignancies. To facilitate studies investigating HGF/cMet receptor coupling or c-Met signaling events in real time and in living cells and animals, we here describe a genetically engineered reporter wherein bioluminescence can be used as a surrogate for c-Met tyrosine kinase activity. C-Met kinase activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to the activation or inhibition of the HGF/c-Met signaling pathway. Treatment of tumor bearing animals with a c-Met inhibitor and the HGF neutralizing antibody stimulated the reporter’s bioluminescence activity in a dose dependent manner and led to a regression of U-87 MG tumor xenografts. Results obtained from these studies provide unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate c-Met activity and validate c-Met as a target for human glioblastoma therapy.
PDF
