MRI biomarkers for pancreatic ductal adenocarcinoma

Navid Farr¹, Paolo Provenzano², Joshua Park³, Sunil Hingorani², and Donghoon Lee³

¹Department of Bioengineering, University of Washington, Seattle, WA, United States, ²Fred Hutchinson Cancer Research Center, Seattle, WA, United States, ³Department of Radiology, University of Washington, Seattle, WA, United States

Synopsis

Pancreatic cancer is a devastating disease with poor prognosis. Pancreatic tumor therapy has been ineffective in part because pancreatic tumors have a dense stroma inhibiting penetration of chemotherapeutic drugs into the tumor. We performed multi-parametric MRI at high resolution to noninvasively assess tumor progression and responses to effective treatment. We used T1 and T2 relaxation, diffusion, magnetization transfer effects along with 3 dimensional volume measurements to characterize the tumors. MR measurements were then compared with histopathological results.

Purpose

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States (1). The overall 5-year survival rate of all types of pancreatic cancer is less than 5% (2). To date, most of the evaluation of the tumor stroma in preclinical studies for pancreatic cancer has been performed post necropsy. One major challenge with monitoring stromal changes in pancreatic tumors is the inability to assess treatment efficacy in real-time and noninvasively. More effective MRI biomarkers are needed to monitor treatment responses of pancreatic tumors treated systematically with, for example, an enzymatic agent. This study noninvasively assessed the degree of stromal depletion after systemic injection of an enzymatic agent and correlated high resolution MRI findings with interstitial fluid pressure (IFP) measurements and histopathology.

Methods

We used a genetically engineered KPC mouse model that has been recognized as the gold standard for human pancreatic cancer (3). We conducted multi-parametric MRI at 14T (Paravision 5.1 software, Bruker Corp, Billerica, MA) to assess tumor progression and responses to an effective therapy. Noninvasive MRI was performed for a tumor bearing KPC mouse treated with an enzymatic agent (4) followed by chemotherapy. T2 relaxation, ADC values and tumor volumes were longitudinally monitored over the course of the combination treatment with PEGPH20 followed by gemcitabine.

Results and Discussion

A pre-treatment MRI was conducted as shown in Figs. 1A, 1D and 1G. Following the pre-treatment MRI, the enzymatic agent was injected followed by gemcitabine administration, both via tail vein, and MRI was repeated 24 hours post injection to acquire quantitative images (Figs. 1B, 1E and 1H). Another set of MRIs were performed after 4 weeks of therapy to obtain quantitative T2, ADC and volumes for the tumor (see Figs. 1C, 1F and 1I). Tumor volumes were measured (87, 78 and 63 mL, respectively) over the course of three time points showing clear evidence of tumor volume reduction. This may also be due to interstitial pressure reduction and fluid mobilization in tumors after the enzymatic agent administration. We plan to conduct systematic studies with more KPC mice in the future to further investigate the relationship of specific MRI parameters with tumoral changes including perfusion, hydration level and interstitial fluid pressure.

Conclusions

Multi-parametric MRI utilizing T2, ADC and 3D volume measurements has feasibility in identifying and monitoring the disease progression and treatment responses in the KPC mouse model of pancreatic ductal adenocarcinoma. Also, this noninvasive study demonstrated that the enzymatic agent was effective for chemotherapy in treating the KPC mouse model of pancreatic ductal adenocarcinoma.

Acknowledgements

This work was supported by NIH CA161112, CA188654 and EB008166.

References

1. Sun, H., Ma, H., Hong, G., Sun, H. & Wang, J. Survival improvement in patients with pancreatic cancer by decade: A period analysis of the SEER database, 1981–2010. Sci. Rep. 2014; 4, 6747.

2. Ades, T. et al. Cancer Facts and Figures 2014. American Cancer Society, Inc. 2014; http://www.cancer.org

3. Hingorani, S. R. et al. Trp53 and Kras cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005; 7, 469–483.

4. Provenzano, P. P. et al. Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2014; 21, 418–429.

Figures

Figure 1. T2 relaxation (A – C) and apparent diffusion coefficient (ADC) (D – F) distributions and segmented volumes (G – I) measured for cystic region of pancreatic tumor tail at three time points: prior to (A, D and G) and 24 hours (B, E and H) and 24 days (C, F and I) after PEGPH20 administration followed by gemcitabine injection via tail vein.

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)

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