Cholesterol-lowering drugs for treatment of pancreatitis: validation of a clinically significant novel therapeutic target and approach

Abstract public domain (NIH RePORTER)

Pancreatitis is a common, potentially fatal, disease of the exocrine pancreas. There are 2 major forms of pancreatitis: acute (AP), which usually produces an episode of temporary illness, and chronic (CP), associated with severe pain, poor quality of life, and increased risk for the deadliest pancreatic cancer. Pancreatitis is the third most common reason for hospital admissions in those with GI disease and a heavy burden on the U.S. healthcare system Major AP responses include inappropriate/intra-acinar activation of digestive enzymes, increased serum level of amylase, neutrophil-driven inflammation, and acinar cell death. Key pathologic features of CP are loss of acinar tissue, chronic inflammation and fibrosis, ultimately leading to the loss of exocrine and endocrine pancreatic function. It is believed that CP results from repetitive subclinical or clinically evident bouts of AP. Excessive alcohol consumption is a major risk factor for both forms of pancreatitis; other key risk factors are smoking and age. The prevalence of these factors results in high pancreatitis incidence in Veterans as well as in military personnel. The pathogenesis of pancreatitis remains obscure and no effective treatment is available, primarily because we do not understand the underlying molecular and cellular mechanisms. Recent studies indicate that the lysosomal/autophagy pathways – a key catabolic mechanism by which cells eliminate damaged or defective cytoplasmic organelles and recycle their constituents for energy and biogenesis needs – are disrupted in pancreatitis. Our recent study revealed that these pathways are critical for maintaining cholesterol homeostasis in pancreas and their disordering results in acinar cell cholesterol overload. We further showed that the cholesterol-lowering drug simvastatin alleviated experimental pancreatitis. Taken together, these findings suggest that cholesterol metabolism is a clinically relevant modulator of pancreatitis severity. To validate the role of cholesterol dysregulation in driving pancreatitis and establish cholesterol synthesis pathway as a therapeutic target amenable to pharmacologic intervention in pancreatitis, we propose to examine the effects of cholesterol- lowering drugs with different action mechanism, simvastatin and bempedoic acid (BemA), on disease severity in several dissimilar mouse and ex-vivo (cellular) pancreatitis models. These preclinical AP and CP models reflect the spectrum of disease severity and etiologies, such as excessive alcohol consumption, gallstones, and ERCP. Statins came to medical use 30 years ago; BemA, which elicits fewer adverse effects than statins, was recently approved by FDA for lowering cholesterol. The proposed studies will examine the effects of these drugs on pancreatic cholesterol levels and disease severity using various regimens of drug administration in both preventive and therapeutic modes. The Specific Aims will determine the effects of simvastatin and BemA on pancreatitis parameters in preclinical models of AP (Aim 1) and CP (Aim 2) and changes in cholesterol levels in these models (Aim 3A); and compare simvastatin’s effects on ex-vivo pancreatitis responses in mouse versus human acinar cells (Aim 3B). If successful the study will provide information necessary to de-risk future clinical trials to validate the repurposing of simvastatin and/or BemA for pancreatitis treatment, and thus address the unmet clinical needs of Veterans. Comparative analysis of drugs’ effects in several preclinical pancreatitis models will allow us to select the best candidate(s) for clinical trials by excluding treatment regimens with toxic effects in the pancreas, insufficient cholesterol-lowering capacity, and/or little beneficial impact on pancreatitis responses. Repurposing FDA-approved drugs can significantly speed up and lower the cost of these trials. Thus, the proposed detailed

Abstract public domain (NIH RePORTER)

study in preclinical models is a necessary prerequisite for clinical trials to assess the risks and benefits of our novel approach to address Veteran healthcare needs.

Public health relevance public domain (NIH RePORTER)

Pancreatitis is a progressive, sometimes fatal, disorder characterized by inflammation, fibrosis, and loss of pancreas functions. It is associated with severe pain, poor quality of life, and increased risk for the deadliest pancreatic cancer. Excessive alcohol consumption, smoking, and age are major risk factors for pancreatitis. The prevalence of these factors results in high pancreatitis incidence in Veterans. In addition, Veterans with pancreatitis have much greater risk of pancreatic cancer than non-Veteran patients. Currently, there is no specific or efficient treatment for pancreatitis, primarily because we do not understand underlying molecular mechanisms. Our recent findings revealed a previously unrecognized role of cholesterol dysregulation in disease pathogenesis and suggest repurposing the available cholesterol-lowering drugs for pancreatitis treatment. The present proposal will validate these results in preclinical mouse and cellular models in order to de-risk future clinical trials and drug development studies. Thus, the proposal addresses unmet and urgent clinical needs of Veterans.