Poster 135 - Quantitative magnetization transfer ratio captures pancreatic cancer’s early responses to a novel KRAS inhibitor

Saturday, October 26, 2024

10:00 AM - 12:00 PM EST

Location: Exhibit Hall E, F & G

Presenting Author(s)

CF

Catherine Fan (she/her/hers)

High School Student
Harriton High School
Bala Cynwyd, Pennsylvania, United States

Co-Author(s)

MG

Mamta Gupta

Postdoctoral Researcher
Perelman School of Medicine at the University of Pennsylvania, United States
HC

Hoon Choi

Research Specialist and Lab Manager
Perelman School of Medicine at the University of Pennsylvania, United States

Primary Investigator(s)

RZ

Rong Zhou

Research Professor
Perelman School of Medicine at the University of Pennsylvania, United States

Introduction: Pancreatic ductal adenocarcinoma (PDA), is one of the leading causes of cancer death today. Because PDA is most commonly diagnosed at late stages, it has a high mortality rate. Though PDA can be treated with MRTX1133 which inhibits the KRAS(G12D) mutation commonly found within patients with pancreatic cancer, only ~50% of patients responded to the treatment despite the presence of the correct genetic mutation in biopsy specimens, making it important to assess early response to treatment. In order to evaluate early response to the KRAS inhibitor (KRASi) MRTX1133, we examined the utility of magnetization transfer (MT) imaging based on magnetization transfer ratio (MTR), which reflects the interaction of free water protons with surrounding macromolecules. We hypothesize that cell death and changes in the tumor microenvironment induced by the MRTX1133 treatment can be detected early using MTR.

Materials and

Methods: The MT imaging data was obtained by the Zhou lab at Penn Medicine. KPC, a genetically engineered mouse model of PDA mice with KRAS(G12D) and Trp53 mutation, was used. Male and female mice were enrolled into treatment (n=8) and control (n=8) groups. Mice in the treatment group were administered with MRTX1133 at 30 mg/kg BID while mice in the control group were administered with the same volume of phosphate-buffered saline (PBS) solution. MT imaging was performed pre-treatment and 48 hours after treatment using a 9.4T Bruker system with pulse sequences insensitive to respiratory motion. The tumor was defined manually and the MTR values were calculated using weighted and non-weighted MT images. The data was then analyzed by the mean MTR of each tumor and on a voxel-wise basis for each tumor, which was performed by registering after-treatment MT scans to their corresponding pre-treatment scans. Representative MT scan slices and MTR values are shown in Figure 1.

Results, Conclusions, and Discussions: A paired t-test on mean MTR values of tumors before and after the treatment across the treated mice indicated a significant decrease in the mean MTR (p < 0.05), with individual mean MTR values shown in Figure 2 (left). As shown in Figure 2 (right), the voxel-wise analysis revealed a significant decrease in MTR across all tumor voxels of MRTX1133 mice (p < 0.001). In contrast, no such decreasing pattern was found in the control group. Both the tumor regional and voxel-wise analyses indicate that MT imaging could detect a decrease in quantitative MTR value, which reflects a decrease in cell density within the tumor induced by the treatment, as early as 48 hours. This finding is also supported by an evaluation of cell death from tumor samples, which demonstrated reduced phospho-ERK expression, an indicator of the KRAS/RAF/MEK pathway, confirming that the treatment engaged with the tumor and caused a decrease in tumor density resulting from cell death.

Our findings demonstrate that MT imaging and MTR were able to detect changes in the tumor microenvironment, induced by the MRTX1133 treatment. Complementary statistical analysis at both regional and voxel-wise levels demonstrated a significant decrease in MTR values of the tumors after the treatment. Specifically, the voxel-wise analysis provides a fine-grained visualization of MTR changes induced by the treatment, supplementing the standard regional statistical analysis. Further investigation with a larger sample size should be performed to validate these results. The present study has demonstrated that the regional and voxel-wise MTR analyses have the potential to be applied in the clinical setting for early detection of treatment effect and provide insights into possible biological mechanisms of tumor cell death.

Acknowledgements (Optional): This study was partially supported by NIH grant of U24-CA231858 (Penn Pancreatic Cancer Imaging Resource)

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