Efficacy of Salmonella typhimurium A1‐R Versus Chemotherapy on a Pancreatic Cancer Patient‐Derived Orthotopic Xenograft (PDOX)

Abstract

The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R (A1-R) on pancreatic cancer patient-derived orthotopic xenografts (PDOX). The PDOX model was originally established from a pancreatic cancer patient in SCID-NOD mice. The pancreatic cancer PDOX was subsequently transplanted by surgical orthotopic implantation (SOI) in transgenic nude red fluorescent protein (RFP) mice in order that the PDOX stably acquired red fluorescent protein (RFP)-expressing stroma for the purpose of imaging the tumor after passage to non-transgenic nude mice in order to visualize tumor growth and drug efficacy. The nude mice with human pancreatic PDOX were treated with A1-R or standard chemotherapy, including gemcitabine (GEM), which is first-line therapy for pancreatic cancer, for comparison of efficacy. A1-R treatment significantly reduced tumor weight, as well as tumor fluorescence area, compared to untreated control (P = 0.011), with comparable efficacy of GEM, CDDP, and 5-FU. Histopathological response to treatment was defined according to Evans's criteria and A1-R had increased efficacy compared to standard chemotherapy. The present report is the first to show that A1-R is effective against a very low-passage patient tumor, in this case, pancreatic cancer. The data of the present report suggest A1-1 will have clinical activity in pancreatic cancer, a highly lethal and treatment-resistant disease and may be most effectively used in combination with other agents.

Tumor-targeting Salmonella typhimurium A1-R decoys quiescent cancer cells to cycle as visualized by FUCCI imaging and become sensitive to chemotherapy

“…S. typhimurium A1-R also targeted pancreatic cancer stem-like cells 21 and pancreatic cancer patient-like orthotopic xenograft (PDOX) models. 22 In the present report, we demonstrate that S. typhimurium A1-R can decoy quiescent G 0 /G 1 cancer cells to cycle to S/G 2 /M and become chemosensitive.…”

Combining Tumor-Selective Bacterial Therapy with <b><i>Salmonella typhimurium</i></b> A1-R and Cancer Metabolism Targeting with Oral Recombinant Methioninase Regressed an Ewing’s Sarcoma in a Patient-Derived Orthotopic Xenograft Model

“…S. typhimurium A1-R is auxotrophic for Leu-Arg that prevents it from mounting a continuous infection in normal tissues [17]. Tumor-targeting S. typhimurium A1-R was highly effective against many PDOX models [18-23]. Based on the recent findings, S. typhimurium A1-R could be used for metastatic cancers in the clinic in the future as it could inhibit or eliminate primary as well as metastatic tumors [12-16].…”

Intra-arterial administration of tumor-targetingSalmonella typhimuriumA1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model

“…S. typhimurium A1-R was effective against primary and metastatic tumors as monotherapy in nude mouse models of major cancers, including prostate, 22,23 breast, [24][25][26] lung, 27,28 pancreatic, 1,[29][30][31][32] ovarian, 33,34 stomach, 35 and cervical cancer. 36 In addition, S. typhimurium A1-R was effective against patientderived orthotopic models (PDOX) of pancreatic cancer, 1,32 sarcoma, 13,15,37 and melanoma. [18][19][20] Metastatic osteosarcoma is a recalcitrant disease.…”