Targeting Hepatocyte Growth Factor Processing and Activation in Lung Cancer

ABSTRACTInnate or acquired resistance represents a major limitation of targeted cancer therapyThe broader goal of this application is to develop drugs that prevent resistance to targeted therapy in lung cancer patientsIn addition to cell autonomous mechanisms of resistancefactors in the tumor microenvironment have been shown to block the response to therapyThe microenvironment mediated resistance to targeted therapy is frequently mediated by Hepatocyte Growth FactorHGFwhich activates its receptorMETexpressed on cancer cellsThe rate limiting step in HGF MET signaling is the proteolytic activation of pro HGF by one of the three serine proteasesmatriptasehepsin or HGFATo mimic the activity of the endogenous HGF Activator InhibitorsHAIand HAIwe developedtriplexinhibitors of hepsinmatriptase and HGFA from two chemical series of ketobenzothiazoleKbtsand cyclic urea benzamidinesCubsWe confirmed that these compoundsjust like HAIsblock pro HGF activation and thus refer to them as synthetic HAIssHAIsOur strong preliminary data confirmed that sHAIs inhibit HGF MET signalingprevent HGF mediated scatteringmigration and survival of cancer cellsIn additionwe demonstrated that sHAIs overcome therapeutic resistance to marketed drugs which target EGFR or MET in vitroThe goal of this application is to identify sHAI with optimal pharmacological properties and to provide evidence that the lead sHAI prevents overcomes resistance to targeted therapy in animal models of lung cancerBecause murine HGF does not activate human MET expressed on human cancer cellsall in vivo experiments will be performed in human HGF knock in micehHGF KIon a SCID backgroundOur specific aims areSpecific aimTo characterize lead sHAIs for their pharmacokinetic properties in vitro and in vivoand dosedependent toxicity miceaDetermine metabolic stabilitysolubilityplasma protein bindinghalf life and clearance of lead sHAIs thathave the best combination of potency and target selectivitybPerform maximum tolerated doseMTDstudies on selected sHAIs to prioritize two compounds for invivo efficacy studiesSpecific aimTo demonstrate that prioritized sHAIs exert anticancer activity in animal models of lung cancer and overcome resistance to targeted therapyaDemonstrate that two lead sHAIs inhibit HGF dependent tumor formationusing Hlung cancer cellsthat form tumors only in the presence of HGFsuch as in human HGF knockin micebShow that sHAI overcomes HGF dependent resistance of lung cancer cells to EGFR inhibitors and toMET kinase inhibitors in hHGF knockin miceCollectivelythese studies will provide a rationale to include sHIAs into treatment regimens to prevent or to overcome HGF dependent resistance to targeted therapyand to improve the treatment outcome in lung cancer patientswho do not respond to standard therapy PROJECT NARRATIVE Targeted cancer therapies are a new class of anticancer drugs that inhibit targets which are specifically up regulated or activated in tumorsthus minimizing the damage to normal cellsWhile cancer patients initially respond to targeted therapyrapidly acquired resistance to kinase inhibitors remains one of the biggest challenges in the treatment of lung cancer patientsIncreased production of Hepatocyte growth factorHGFis a common mechanism of this resistanceAccordinglylevels of HGF are elevated in the tumor microenvironment and in the sera of lung cancer patients that fail to respond to targeted therapyCurrentlythere is no approved drug that would target HGFProteXase Therapeutics is developing the first small molecule inhibitors of HGF activationSynthetic HGF Activator InhibitorssHAIsWe have shown that sHAIs have potent anticancer activity and can overcome resistance to EGFR and METtargeted therapeutic agents in colon and lung cancer cell linesThe objective of this project is to confirm that lead sHAIs are capable of preventing resistance to these therapies in mouse models of lung cancera necessary step in enabling the drug development of sHAIs as a more effective treatment option for lung cancer patients