Demyan, Lyudmyla, Standring, Oliver, Chung, Taemoon, Gazzara, Emma, Lyons, Scott, Park, Youngkyu, King, Daniel, Jonas, Oliver, Tuveson, David, Weiss, Matthew (2023) Feasibility of Implantable Microdosing Devices to Perform in vivo Pharmacotyping in Pancreatic Cancer. In: Annual International Conference of the Society-of-Surgical-Oncology (SSO) on Surgical Cancer Care, MAR 22-25, 2023, Boston, MA.
Abstract
INTRODUCTION: *These authors contributed to work equally Current biomarkers offer modest predictive capacity for drug sensitivity testing in pancreatic cancer. Patient-specifc pharmacotyping offers the potential for a more direct, personalized prediction model. Recently, an implantable microdevice was developed to facilitate in situ multi-agent pharmacotyping and has since entered clinical trials in multiple cancer types, but had not yet been tested in pancreaticcancer. Here we evaluated the use of a microdosing device (microdevice) model in a mouse xenotransplant model of pancreatic cancer as proof of principle to inform future translation to the clinic. METHODS: A microdevice consists of a cylindrical frame and 18 wells embedded with a triplicate of standard chemotherapy agents (5 FU, gemcitabine, SN 38, paclitaxel, oxaliplatin), a non-toxic polyethylene glycol (PEG) matrix as control, and a duplicate of doxorubicin, the auto-fuorescent properties of which allow us to determine the distance of drug diffusion for each tumor. Devices were implanted into murine xenotransplanted human organoids (hM1A and hM1E Table 1). Microdevices retrieved at 4h, 8h, and 24h post-implantation together with tumors were fixed in 10% formalin. The tissue was embedded in formalin and sectioned parallel to the device. A distance-dependent drug diffusion rate and concentration profles with doxorubicin were evaluated. Co-immunohistochemistry (IHC) for cleaved caspase-3 (CC3), gamma H2AX (apoptosis markers), and human mitochondria (human cancer cell marker) was performed in the area of drug diffusion to determine the cytotoxic effects of chemotherapy. RESULTS: A total of 15 animals were enrolled in the experiment with 100% postoperative survival. One device per animal was placed, and all devices were successfully placed and retrieved. Microdevice insertion and exposure to PEG negative control had no effect on tumor integrity. At 250-350µm from the well, we observed signal intensity from doxorubicin suggesting successful drug diffusion. The signal on differential response to drugs was detected as early as 4 hours. CONCLUSIONS: Utilization of implantable microdevice to predict cancer drug sensitivity is feasible in organoid transplantation animal models of pancreatic cancer, and drug sensitivity can be obtained as early as 4 hours. Future work is needed to expand this model to other cancer drugs and biomarkers to evaluate the cancer drug sensitivity and to test the feasibility of this model to study the effects of chemotherapy on the tumor microenvironment.
| Item Type: | Conference or Workshop Item (Poster) |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > drugs and therapies > chemotherapy diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Lyons lab CSHL labs > Tuveson lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2023 |
| Date Deposited: | 12 Sep 2023 15:34 |
| Last Modified: | 08 Jan 2024 18:59 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/40896 |
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