Molecularly Targeted Therapy for Pancreatitis
Abstract
This proposal is responsive to the Fiscal Year 2014 Peer Reviewed Medical Research Program overarching challenge Chronic Pancreatitis (CP). People with CP have persistent inflammation of the pancreas associated with prominent fibrosis that leads to permanent damage. CP is one of the serious consequences of alcohol abuse since more than 70% of all cases of CP is associated with heavy alcohol consumption and accompanied by chronic, severe abdominal pain (90% cases). Since heavy alcohol use remains a constant problem in the military, it is anticipated that military personnel and Veterans are at high risk for CP compared to civilians. CP is currently an incurable condition, and no drug has emerged yet in patients. As the first demonstration, we propose a new way of curing CP by molecularly targeting an originator of CP, activated pancreatic stellate cells (PSCs) in the pancreas. PSCs are the key mediators of pancreatic fibrosis, a characteristic feature of CP. During pancreatic injury, normal PSCs transform into proliferative, activated PSCs (aPSCs), which initiate fibrosis by secreting collagen that comprise fibrous tissues. Therefore, selective eradication of aPSCs over normal PSCs is a logical way to prevent, stop, or reverse the progress of CP. However, there is no practical method to target and kill only aPSCs in humans. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand that selectively induces cell death through binding to its death receptors (DRs) typically overexpressed in most cancer cells while leaving normal cells unharmed. However, an extremely short blood circulation half-life and low in vivo potency of TRAIL hamper its clinical application. As an alternative, we developed a new TRAIL variant, TRAILPEG, with a longer blood circulation time. For a clinical perspective, we validated TRAILPEG pharmacokinetics in monkeys and proved its safety in human hepatocytes isolated from humans. As the first demonstration, we recently discovered that an intravenously administered TRAILPEG specifically targets and eradicates activated primary human hepatic stellate cells (aHSCs), an originator of liver fibrosis, and reverses liver fibrosis/cirrhosis previously thought to be impossible. Lessons from that work and the fact that PSC characteristics resemble that of HSCs, we hypothesized that our TRAILPEG therapy applied to liver fibrosis could be applied to treat CP and its complication, pain, by stopping or reversing CP. Our pilot study results strongly support our concept. We confirmed that activated PSCs, not normal PSCs, isolated from humans exponentially upregulate TRAIL receptors and become highly sensitive to TRAILPEG, like we observed in liver fibrosis models. Particularly, in a small number of alcohol- and injury-induced acute and CP animal models, intravenously administered TRAILPEG clearly ameliorated pancreatic fibrosis and, in particular, treated CP-associated pain. Encouraged by our highly motivating observations, we propose to (a) investigate the unexplored role of TRAIL signaling among PSC activation, progression of pancreatic fibrosis, and CP-associated pain and (b) determine the feasibility of utilizing TRAILPEG as a novel antifibrotic and anti-pain agent for CP therapy. To realize our hypothesis, we aim to answer the fundamental and translational questions: How do TRAIL signaling molecules affect PSC activation during fibrogenesis and CP-associated pain at the molecular level? Can systemically administered TRAILPEG reverse CP and ameliorate pain? Can TRAIL signaling be a validated target for CP therapy and imaging in the clinic? Lastly, is TRAILPEG non-toxic in order to move to the next step towards clinical development? For smooth progress of the proposed study, the research team will be comprised of clinicians and basic science researchers with diversified expertise in CP, fibrosis, immunology, TRAIL biology, clinical molecular imaging, and translational d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510302
Entities
People
- Pankaj J Pasricha
Organizations
- Johns Hopkins University
- United States Army