TVR Project 7 - IDO-silencing Salmonella therapy for the treatment of primary and metastatic PDAC.

Advanced pancreatic ductal adenocarcinoma (PDAC) is often inoperable, and is only transiently responsive to existing therapies. Overexpression of indoleamine 2,3-dioxygenase (IDO) in PDAC plays a major role in accelerating disease progression by suppressing antitumor immunity. Current IDO inhibitors inadequately reverse immunosuppression while systemic off target effects contribute to their toxicity. ShIDO-ST is a novel Salmonella typhimurium (ST)-based therapy that expresses a small hairpin (sh)RNA to specifically silence tumor-derived IDO with decreased toxicity. ST as an shRNA delivery vehicle offers superior penetration against desmoplastic PDAC tissue and anti-metastatic function due to its motility and affinity for poorly vascularized, hypoxic tissue. The combination of IDO silencing and abundant ST tumor colonization increases intratumoral local reactive oxygen species through the recruitment and activation of polymorphonuclear neutrophils (PMN), which can cause oxidative stress-induced apoptosis of tumor cells, cancer stem cells (CSC), and vascular stroma to inhibit PDAC progression. PMN are also known to have anti-metastatic function, thus providing additional protection against tumor spread. To best assess the capabilities of this therapeutic class to suppress tumor growth, we will apply it to the KrasG12D;Trp53R127H;Brca1;Pdx1-Cre genetically engineered mouse model (KPC-GEMM) that recapitulates desmoplasia and metastasis characteristic of human PDAC. Incorporation of luciferase into the KPC-GEMM model allows for longitudinal measurements of tumor growth and metastasis by intravital imaging systems (IVIS). We have obtained breeding pairs of these mice by MTA with OSUMC. To improve penetration of tumors by shIDO-ST, we are investigating PEGylated human recombinant hyaluronidase (PEGPH20, Halozyme Inc. by MTA), which depletes hyaluronan abundant in PDAC tissue and increases vascular permeability. The long-term objective is to develop shIDO-ST into a suitable, effective therapy for the treatment of patients with advanced inoperable PDAC that can also be explored with other solid tumors.

Personnel
Edwin R. Manuel, Ph.D.
Staff Scientist, Division of Translational Vaccine Research
Conducts investigations and interprets findings

Joseph Kim, M.D.
Director, Surgical Oncology Training Program
Provides tissues and background on GI malignancies

Massimo d’Apuzzo, M.D.
Neuropathologist and Anatomic Pathologist, Division of Pathology
Interprets ultrastructural information from tumors

Vincent Chung, M.D.
Staff Physician, Department of Medical Oncology & Therapeutics Research
Enrolls and consents patients