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 tumors. The extracellular matrix (ECM) surrounding all cells is crucial for biological functions in tissues throughout the body. In solid tumors, the extracellular matrix can limit the ability of cancer drugs to penetrate and act on cancer cells. In this project we propose to engineer an enzyme that acts to specifically degrade the ECM in tumors, allowing cancer drugs to penetrate and act in tumors more effectively. Degradation of the ECM of solid tumors has been demonstrated both preclinically and clinically to to enhance a range of cancer drugs, including potentially traditional chemotherapeutics and newer agents such as antibodies and immuno-oncology agents. Previously used ECM degrading enzymes are not specific for tumors and degrade the ECM in peripheral tissues as well, leading to well-characterized, mechanistic, adverse events. These adverse events limit the dose of the ECM degrading enzymes which compromises the efficacy of the co-administered cancer drugs. This project proposes to target the activity of the ECM degrading enzyme to the tumor microenvironment, increasing the efficacy of co-administered cancer drugs, while also decreasing peripheral ECM degradation and reducing adverse events. To design this enzyme we will first use a computational approach to analyze the enzyme's structure and predict how changes in the enzyme might target enzyme action to the distinct conditions found associated with cancer in the tumor microenvironment. Second, based 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 tissue, verifying that the predicted changes in the enzyme produce the desired activity specifically targeting tumors. Third, when a version, or versions, of the enzyme are found to specifically target the tumor microenvironment, we will produce larger quantities of this enzyme in preparation for future studies that will characterize the action of the enzyme in both cancer models, testing enhanced efficacy, and in safety models demonstrate the decrease of mechanistic adverse effects. The proposed outcome of this project will be an enzyme (or enzymes) suitable for preclinical pharmacology studies, the first step in producing a clinical candidate that would ultimately advance into testing in clinical trials, targeting pancreatic cancer and other solid tumors in which the extracellular matrix limits the action of cancer drugs.
Public Health Relevance Statement: The extracellular matrix plays a key role in solid tumor progression and limits the efficacy of a broad range of oncology therapeutics, primarily by decreasing the ability of drugs to penetrate tumors. We 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.
Project Terms: Active Sites; Adverse effects; Adverse event; Affect; Antibodies; Antineoplastic Agents; base; Biological Process; cancer cell; Cancer Model; Cells; chemotherapeutic agent; Clinical; clinical candidate; Clinical Trials; commercialization; Computer Simulation; Computer software; Data; Dependence; design; Dose; Drug Kinetics; efficacy study; Engineering; Environment; Enzymatic Biochemistry; Enzyme Interaction; enzyme structure; Enzyme Tests; Enzymes; Extracellular Matrix; Extracellular Matrix Degradation; Family; Future; Glycoside Hydrolases; Goals; Human; Hyaluronidase; Hydrogen Bonding; Immunooncology; improved; In Vitro; in vitro activity; large scale production; Malignant neoplasm of pancreas; Malignant Neoplasms; Mammalian Cell; member; Methods; Modeling; mutant; Mutate; Mutation; New Agents; Normal tissue morphology; oncology; Outcome; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology Study; physical property; Play; pre-clinical; Preparation; Process; Production; Property; Proteins; Publishing; Safety; Solid Neoplasm; SPAM1 gene; stable cell line; Structure; Testing; Therapeutic; Tissues; Toxic effect; tumor; tumor microenvironment; tumor progression; Variant
