Navid Farr1, Yak-Nam Wang2, Samantha D’Andrea3, Kayla Gravelle3, Joo Ha Hwang1,3, and Donghoon Lee4
1Department of Bioengineering, University of Washington, Seattle, WA, United States, 2Applied Physics Laboratory, University of Washington, Seattle, WA, United States, 3Department of Medicine, University of Washington, Seattle, WA, United States, 4Department of Radiology, University of Washington, Seattle, WA, United States
Synopsis
The lethal nature of the
pancreatic cancer is apparent in the 5-year survival rate of less than 5%.
Choosing the right animal model is of utmost importance in oncology drug
development research. There is a dire necessity for noninvasive techniques to
monitor and characterize the tumors in different models to properly design drug
delivery studies. We performed multi-parametric MRI at a high resolution to
noninvasively identify the tumor and assess tumor volume characteristics. We
used T1 and T2 relaxation, diffusion, and magnetization transfer effects along
with 3 dimensional volume measurements. MR measurements were then compared with
quantifiable histopathological results.Target
audience
Researchers working on new therapies for pancreatic cancer and groups working on preclinical studies with interest in noninvasive monitoring technique will benefit from this work.
Purpose
Pancreatic
ductal adenocarcinoma (PDA) is among the most lethal human cancers. In
addition, PDA is among the few cancers in which death rates have risen in the
21st century (1). Many conventional chemotherapeutic regimens have
failed the standard of care, as only a minority of patients have had survival
prolonged by several weeks (2,3).
Oncology drug development relies heavily on mouse models bearing tumors for
efficacy testing of delivery and efficacy of therapeutic agents. Therefore,
choosing the right mouse model with characteristics similar to human PDA is
essential. Also, noninvasive techniques are necessary to monitor and
characterize the tumors in different models for properly designed drug delivery
studies. Characterizing the tumor tissue can be used to predict the response to
chemotherapy (4). The purpose of this study was to characterize the different
properties of PDA tumors in three different mouse models. Alongside T2-weighted
MRI, which was used to accurately identify and measure the size of the tumor,
multi-parametric MR techniques were utilized to identify the tumor
characteristics.
Methods
In addition to a genetically
engineered KPC mouse model, which spontaneously develops PDA (5), we used
orthotopic and subcutaneous xenograph mouse models. We conducted
multi-parametric MRI at 14T (Paravision 5.1 software, Bruker Corp, Billerica,
MA) to identify the tumor and surrounding organs and measured the stroma level
and diffusion of each tumor model. MRI measurements include quantitative T2,
ADC, magnetization transfer suppression ratio and three-dimensional (3D) volume
measurements. Noninvasive MRI was performed for 8 animals of each tumor
model. T2 relaxation, ADC values and tumor volumes were longitudinally recorded.
The magnetization transfer ratio (MTR) was measured by utilizing a gradient
echo sequence with an offset frequency of 7000 Hz. The MTR was compared to
quantified fibrotic tissue measured from Masson’s trichrome staining of tumor
samples.
Results and Discussion
T2 relaxation times of three tumor types were very similar
but there was a statistically significant difference between the tumors and
surrounding organs. Thus it will be helpful in detecting pathological tissues
due to their elongated T2 relaxation times (Fig. 1). 3D reconstruction of each tumor is made
possible by high resolution two-dimensional imaging, which generates thin
multislice images that can then be used to calculate the volume of the tumor. ADC
values of the tumor tissue in KPC tumor model were significantly lower than the
other two types of orthotopic and subcutaneous models. This result might be
associated with increased cellularity of the tumor in comparison to the other
tumor models. Histology data revealed that the KPC model consistently
demonstrated significantly greater levels of fibrosis and associated collagen
deposition as shown in Fig. 2. The comparison of MTR and histologyc data indicates there is a
correlation (r = 0.87) between MT ratio and the amount of stroma in each
tissue (see Fig. 3). The data confirms that the MTR can be used as a noninvasive biomarker
of stroma measurement.
Conclusions
Multi-parametric MRI
utilizing T2, ADC, MTR and 3D volume measurements have feasibility in the
identification and monitoring of the disease progression. Moreover,
quantitative MR techniques are reliable noninvasive biomarkers of tumor characteristics.
Acknowledgements
This work was
supported by NIH grants R01 CA154451 and R01 CA188654.References
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