SBIR/STTR Award attributes
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 risk factors of liver fibrosis, cirrhosis, and hepatitis B/C, with limited efficacy conferred by existing treatments at advanced stages of the disease. Systemic therapy with tyrosine kinase inhibitors, most notably sorafenib, is now recommended by most guidelines for those patients not eligible for liver resection. The vast majority of HCCs 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 in the damaged liver and the TME. Accordingly, there remains a high unmet medical need for new approaches for the treatment of HCC. An emerging new target in HCC is the G protein-coupled, protease-activated receptor 2 (PAR2). PAR2 is a signaling receptor for coagulation and tumor-associated proteases that is highly abundant in various liver cells (hepatocytes, endothelium, stellate cells, inflammatory cells) which controls fibrotic, inflammatory and metabolic processes that lead towards severe NASH, liver cirrhosis and HCC. PAR2 expression in HCC tumors is significantly correlated with poor survival, poor differentiation and advanced tumor-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 and Raf-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 that PAR2 pepducin treatment may potentially suppress HCC tumor development that will be validated in detail using in vitro and in vivo hepatocellular mouse models of tumor growth and survival. Aims 1 and 2 outline bridging 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 into the 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/toxicity assessments (andgt;10-fold therapeutic safety index) of combination therapy with sorafenib (Aim 2). If this Phase I STTR study is successful in accomplishing the outlined efficacy and safety milestones, this would provide the basis for a preIND meeting with the FDA, IND submission, and initiating a Phase 1 clinical trial in HCC patients.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.
