Engineering enzymatic activity of a cancer therapeutic tospecifically target extracellular matrix in the tumor microenvironment

This project provides the first step toward the long term goal of developing an enzyme drug for commercialization acting on the extracellular matrix to enhance the efficacy of broad range of cancer therapeutics in solid tumorsThe extracellular matrixECMsurrounding all cells is crucial for biological functions in tissues throughout the bodyIn solid tumorsthe extracellular matrix can limit the ability of cancer drugs to penetrate and act on cancer cellsIn this project we propose to engineer an enzyme that acts to specifically degrade the ECM in tumorsallowing cancer drugs to penetrate and act in tumors more effectivelyDegradation of the ECM of solid tumors has been demonstrated both preclinically and clinically to to enhance a range of cancer drugsincluding potentially traditional chemotherapeutics and newer agents such as antibodies and immuno oncology agentsPreviously used ECM degrading enzymes are not specific for tumors and degrade the ECM in peripheral tissues as wellleading to well characterizedmechanisticadverse eventsThese adverse events limit the dose of the ECM degrading enzymes which compromises the efficacy of the co administered cancer drugsThis project proposes to target the activity of the ECM degrading enzyme to the tumor microenvironmentincreasing the efficacy of co administered cancer drugswhile also decreasing peripheral ECM degradation and reducing adverse eventsTo design this enzyme we will first use a computational approach to analyze the enzymeandapos s structure and predict how changes in the enzyme might target enzyme action to the distinct conditions found associated with cancer in the tumor microenvironmentSecondbased on these predictions we will create different versions of the target enzyme and test their activity in conditions representing the environment in tumors compared with conditions found in normal tissueverifying that the predicted changes in the enzyme produce the desired activity specifically targeting tumorsThirdwhen a versionor versionsof the enzyme are found to specifically target the tumor microenvironmentwe will produce larger quantities of this enzyme in preparation for future studies that will characterize the action of the enzyme in both cancer modelstesting enhanced efficacyand in safety models demonstrate the decrease of mechanistic adverse effectsThe proposed outcome of this project will be an enzymeor enzymessuitable for preclinical pharmacology studiesthe first step in producing a clinical candidate that would ultimately advance into testing in clinical trialstargeting pancreatic cancer and other solid tumors in which the extracellular matrix limits the action of cancer drugs The extracellular matrix plays a key role in solid tumor progression and limits the efficacy of a broad range of oncology therapeuticsprimarily by decreasing the ability of drugs to penetrate tumorsWe propose to engineer an enzyme to specifically degrade the extracellular matrix in tumors and improve the action of cancer drugs while avoiding side effects associated with degradation of the extracellular matrix in other tissues