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.
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
Relapse is a major obstacle to maximizing curative potential of allogeneic HCT (aHCT) therapy for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL)) and myelodysplastic syndrome (MDS). It has been shown that relapse can be detected through longitudinal application of quantitative PCR (qPCR) measurement techniques before patients (Pts) develop symptoms and that early intervention to delay or stop relapse can improve patient outcome. However, such tests apply only to a small percentage of Pts with fusion gene transcripts and specific mutations. WT1 has been investigated as a tumor marker in a variety of studies which have shown its association with disease progression and relapse. In our pilot work, based on WT1 kinetics data in a small cohort of Pts, we have shown the striking correspondence of increasing WT1 transcript levels with future relapse and the specific time frame between molecular relapse detected by the WT1 PCR test and hematologic relapse confirmed by clinical observations. Our plan is to establish ranges of WT1 transcript levels characteristic of Pts after aHCT that do not relapse, a high threshold level that can serve as a specific biomarker for relapse with close to or 100% specificity, and a less stringent threshold level with lower specificity to identify more Pts that relapse and at earlier times. We will also define the time interval when relapse is detected molecularly by qPCR methods, and later confirmed morphologically by standard clinical methods. Our hypothesis is that many of the Pts that will ultimately relapse will have a period of minimal residual disease that may be detected by repeated elevations of WT1 not exceeding the determined WT1 threshold levels. The ultimate purpose of our study is to apply this important biomarker as part of standard diagnostic procedures for detection of relapse in the highest-risk individuals – acute leukemia and MDS Pts undergoing aHCT.
Anna Israyelyan, Ph.D.
Postdoctoral Fellow, Division of Translational Vaccine Research
Research Associate II, Division of Hematology/Bone Marrow Transplantation
Clinical Research Analyst, Clinical Trials Office
Leanne Streja, Ph.D.
Senior Programmer Analyst, Department of Information Sciences