Hepatocellular carcinoma (HCC) has become the second leading cause of cancer-related death in the world,with a 72% mortality rate in the US. The rise in incidence of HCC is due to a steady increase in the major riskfactors of liver fibrosis, cirrhosis, and hepatitis B/C, with limited efficacy conferred by existing treatments atadvanced stages of the disease. Systemic therapy with tyrosine kinase inhibitors, most notably sorafenib, isnow recommended by most guidelines for those patients not eligible for liver resection. The vast majority ofHCCs occur with underlying hepatic damage (characterized by pathological vascular, inflammatory and pro-fibrotic responses); and a highly abnormal tumor microenvironment (TME) with exuberant angiogenesis,immunosuppression, and fibrosis. Sorafenib monotherapy does not effectively overcome these abnormalities inthe damaged liver and the TME. Accordingly, there remains a high unmet medical need for new approachesfor the treatment of HCC. An emerging new target in HCC is the G protein-coupled, protease-activatedreceptor 2 (PAR2). PAR2 is a signaling receptor for coagulation and tumor-associated proteases that is highlyabundant in various liver cells (hepatocytes, endothelium, stellate cells, inflammatory cells) which controlsfibrotic, inflammatory and metabolic processes that lead towards severe NASH, liver cirrhosis and HCC. PAR2expression in HCC tumors is significantly correlated with poor survival, poor differentiation and advancedtumor-node-metastasis stage. We found that hepatic PAR2 expression was greatly enhanced in patients(n=108) with high levels of liver fibrosis and cirrhosis. In addition to being involved in fibrosis and inflammation,PAR2 activates a number of hepatic cancer promoting pathways including Gi-PI3K, TGFb, phospho-AKT andRaf-MAPK signaling to stimulate cancer cell migration/invasion, EMT, metastasis, anti-apoptotic survival,proliferation, angiogenesis, and promotion of a permissive tumor microenvironment. Pilot data indicate thatPAR2 pepducin treatment may potentially suppress HCC tumor development that will be validated in detailusing in vitro and in vivo hepatocellular mouse models of tumor growth and survival. Aims 1 and 2 outlinebridging studies as a collaborative effort between Oasis Pharmaceuticals (Lexington, MA) and Tufts (Boston,MA) that would provide key feasibility milestones to advance the clinical development of PAR2 pepducin intothe HCC indication. The major milestones at the end of the 6 months is efficacy in HCC mouse models(significant suppression of tumor growth and improved survival) (Aim 1), and 28-day safety/toxicityassessments (>10-fold therapeutic safety index) of combination therapy with sorafenib (Aim 2). If this Phase ISTTR study is successful in accomplishing the outlined efficacy and safety milestones, this would provide thebasis for a preIND meeting with the FDA, IND submission, and initiating a Phase 1 clinical trial in HCCpatients.
Public Health Relevance Statement: Liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) are the most common causes of
death in patients with chronic liver disease, with limited effective treatment options. Protease-
activated receptor-2 (PAR2), a cell-surface receptor that is highly abundant in HCC tumors, is
an emerging therapeutic opportunity for the treatment of liver cancer using novel liver-homing
Pepducin technology.
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