Abstract 5974: Multimodal molecular imaging detects early reoxygenation induced by hyaluronan depletion in pancreatic cancer model mouse
Authors: Saida Yu , Seki Tomohiro , Kishimoto Shun , Brender Jeffrey R. , Chandramouli Gadisetti VR. , Otowa Yasunori , Yamashita Kota , Yamamoto Kazutoshi , Devasahayam Nallathamby , Krishna Murali C. 
Published: June 2022

Abstract
[Purpose] In pancreatic ductal adenocarcinoma (PDAC) which is characterized by an intense desmoplastic feature, the extracellular matrix (ECM) can significantly influence the tumor microenvironment (TME). Hyaluronan (HA), a major component of ECM, is associated with elevated tumor pressure, vascular collapse, and poor perfusion in TME, conferring hypoxia. HA expression is also correlated with poor prognosis in the patients with PDAC. PEGylated human hyaluronidase (PEGPH20) enzymatically depletes hyaluronan in tumors. The resultant improvement in vascular patency and blood perfusion is expected to increase the delivery of therapeutic molecules. The aim of this study was to investigate the change in physiologic and metabolic profile of the tumor in response to treatment with PEGPH20 using multi-modal imaging techniques. We also investigated the capability of PEGPH20 to enhance treatment effect of radiation. [Methods] Athymic nude mice were inoculated with BxPC3 (human pancreatic adenocarcinoma) tumor cells transduced with hyaluronan synthase 3 (HAS3) to the right tibial periosteum. BxPC3-HAS3 tumor treated with PEGPH20 or control buffer were scanned with Electron paramagnetic Resonance imaging (EPRI), dynamic contrast enhanced (DCE) MRI, ultra-small superparamagnetic iron oxide (USPIO) MRI, Photoacoustic imaging (PAI), and Hyperpolarized 13C-MRI using [1-13C] pyruvate to evaluate intratumor pO2, intratumor perfusion, blood volume, O2 saturation, and glycolysis, respectively. [Results] EPRI showed significantly increased pO2 in PEGPH20 treated group. DCE-MRI and USPIO-MRI showed improved perfusion/permeability and local blood volume, respectively after PEGPH20 treatment, accounting for the increase in tumor oxygenation. PAI provided the evidence of immediate changes in tumor oxygenation after treatment. Hyperpolarized 13C-MRI using [1-13C] pyruvate suggested the decreased glycolytic flux evaluated by lactate/pyruvate ratio after PEGPH20 treatment. Combination of radiotherapy and PEGPH20 synergistically delayed tumor progression and prolonged the survival. [Conclusions] This study examined the effect of PEGPH20 on TME in PDAC xenograft model by using non-invasive multimodal imaging techniques. In summary, the non-invasive imaging modalities were useful in evaluating the changes in hemodynamics and metabolism in TME induced by modulation of ECM such as PEGPH20 treatment. PEGPH20 enhanced treatment effect of radiation therapy. The results validated the utility of the imaging methods to non-invasively monitor the changes in TME and predicted the radiosensitizing effect of hyaluronan depletion.
Citation Format: Yu Saida, Tomohiro Seki, Shun Kishimoto, Jeffrey R. Brender, Gadisetti VR. Chandramouli, Yasunori Otowa, Kota Yamashita, Kazutoshi Yamamoto, Nallathamby Devasahayam, Murali C. Krishna. Multimodal molecular imaging detects early reoxygenation induced by hyaluronan depletion in pancreatic cancer model mouse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5974.