Factors in the tumor microenvironment promote the growth of tumors and impact their response to therapy. Hepatocyte Growth Factor (HGF), frequently upregulated in the tumor microenvironment, activates the receptor tyrosine kinase MET expressed on cancer cells which contributes to tumor progression and confers therapeutic resistance. Because cancer cells become addicted to HGF/MET signaling, both HGF and MET are valid therapeutic targets. Although various agents have been developed to target HGF/MET signaling, there are currently no approved drugs that would inhibit HGF or block MET activity specifically. The rate-limiting step in the HGF/MET signaling is the proteolytic processing of pro-HGF to active HGF by one or more of the three serine proteases, matriptase, hepsin or HGF activator (HGFA). We have developed the first small molecule inhibitors of HGF activation which mimic the activity of the endogenous inhibitors of HGF activation, HAI-1 and HAI-2. These triplex inhibitors of hepsin, matriptase and HGFA are from two chemical series of ketobenzothiazoles (kbts) and cyclic urea benzamidines (cubs). We confirmed that these inhibitors block HGF activation and thus refer to them as synthetic HAIs (sHAIs). We have shown that sHAIs inhibit MET signaling and prevent HGF-mediated scattering, migration and survival in multiple types of cancer cells. We have shown that the lead sHAI, PTX2173, overcomes resistance to EGFR inhibitors in vitro and impedes HGF-dependent growth of lung cancer in vivo. The goal of this application is to continue lead optimization and to confirm its in vivo activity in colon cancer. We will show that PTX2173 blocks HGF-mediated growth and metastasis of colon cancer and prevents/overcomes resistance to EGFR inhibitors in vivo.
Our specific aims are:
Aim 1 : To optimize sHAIs for improved metabolic stability and pharmacokinetic (PK) properties. To rationally design, synthesize and evaluate analogues for their HGFA, matriptase and hepsin inhibitory activity: a) cyclic peptide and b) unnatural amino acid containing kbt Inhibitors. c) To determine the in vitro metabolic stability, physical properties and in vivo PK of lead sHAIs.
Aim 2 : To demonstrate that PTX2173 blocks HGF-dependent tumor growth/metastasis and overcomes resistance to EGFR inhibitors in colon cancer. a) To show that PTX2173 blocks tumor growth and metastasis in two syngeneic colon cancer models that are driven by HGF, CT26 and MC38. b) To confirm that PTX2173 prevents HGF-dependent primary resistance and overcomes tumor microenvironment-mediated therapeutic resistance to EGFR targeting agents in vivo. Collectively, these studies will provide a rationale to include sHAIs into treatment regimens to block HGF- dependent tumor progression and to prevent or to overcome HGF-dependent resistance to targeted therapy, significantly improving the outcome of colon cancer patients.
At ProteXase Therapeutics we have developed the first small molecule inhibitors of HGF activation, which we termed Vynthetic HGF Activator Inhibitors (sHAIs). We have shown that sHAIs block HGF activation, have potent anticancer activity and overcome resistance to EGFR targeting drugs in colon cancer cell lines. The objective of this project is to confirm that lead compoundV 37; DQG PTX2173 block tumor progression and prevent resistance to targeted therapy in mouse models of colon cancer; a necessary step before we can validate the activity of sHAIs in clinical trials. !
