Abstract A099: Acoustic Cluster Therapy enhances the efficacy of chemotherapeutic regimens in patient-derived xenograft mouse models for pancreatic ductal adenocarcinoma
Authors: Ng Serina , Healey Andrew , Kvåle Svein , Kotopoulis Spiros , Hoff Daniel D Von , Sontum Per Christian , Han Haiyong 
Published: March 2020

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC), which has a five-year survival rate of less than 9%, is one of the most lethal types of malignancies. PDAC is notoriously resistant to conventional and targeted therapeutic agents. One of the main reasons for this extreme drug resistance is the desmoplastic and poorly vascularized stroma that forms a protective barrier around the PDAC cells. Acoustic Cluster Therapy (ACT) is a novel technology that utilizes microbubbles and ultrasound guidance to create localized openings in tumor vasculature, which leads to a transient increase in vascular permeability and allows drug to better penetrate the tumor bed. In this study we investigated the activity of ACT in enhancing the therapeutic effects of clinically used chemotherapeutic regimens in patient-derived xenograft (PDX) mouse models for PDAC. Method: PDAC patient-derived tumor xenografts were implanted subcutaneously into athymic nude mice which were enrolled into studies when tumor size reached between 150–180 mm3. The mice (10 mice/group) were treated with either chemotherapeutics alone or in combination with ACT. Two chemotherapeutic regimens were tested: the nab-paclitaxel (nab-pac, 15 mg/kg, i.v., QW×3) and gemcitabine (GEM, 60 mg/kg, i.p., QW×3) combination (nab-pac/GEM) and liposomal irinotecan (ONI, 15 mg/kg, i.v., QW×3). ACT given before or after the chemotherapies was evaluated. Results: nab-pac/GEM or ONI alone treatment showed significant inhibition of the tumor growth at the doses used. However, application of ACT before or after the chemotherapy treatment dramatically enhanced the activity and markedly induced tumor shrinkage (even &gt; 100 days after the last dose of treatment). Applying ACT following the dosing of nab-pac/GEM resulted in a 90% reduction in tumor volume compared to nab-pac/GEM alone at Day 50 after the initial drug dosing (P= 0.001). Some of mice had complete remissions. At Day 120, 50% of the mice in nab-pac/GEM + ACT group were still in complete remission vs. 10% in the nab-pac/GEM alone group. Similar activity was also observed with ONI treatment. At Day 50 after the initiation of study, ONI + ACT induced a 85% reduction in tumor volume compared to ONI alone (P=0.024). At Day 120, 60% of the mice in the ONI + ACT treated group were still in complete remission vs. 10% in the ONI alone group. Applying ACT right before the dosing of chemotherapeutics also showed improvement of efficacy, but is slightly less than applying after the chemotherapy. Overall, these findings demonstrate the potential utility of ACT in improving the therapeutic efficacy of nab-pac/GEM and ONI treatments in PDAC and provide solid preclinical evidence that supports evaluation in patients. The data also provides insights for the design of clinical trials.
Citation Format: Serina Ng, Andrew Healey, Svein Kvåle, Spiros Kotopoulis, Daniel D Von Hoff, Per Christian Sontum, Haiyong Han. Acoustic Cluster Therapy enhances the efficacy of chemotherapeutic regimens in patient-derived xenograft mouse models for pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A099. doi:10.1158/1535-7163.TARG-19-A099