Lung fibrosis, a group of incurable lung diseases with high mortality rates, is characterized by inflammatory cell infiltration, fibroblast proliferation, and excessive deposition of extracellular matrix proteins (ECM) in lung parenchyma. Globally, five million people are affected by lung fibrosis. In the U.S. alone, 200,000 suffer from this disease. Of these more than 40,000 die annually, equivalent to the number who die from breast cancer, and forty times more than those who die from cystic fibrosis. The effect of lung fibrosis on quality of life is severe. Lung fibrosis of unknown causes is known as idiopathic pulmonary fibrosis (IPF). Lung fibrosis also develops as a consequence of multiple causes, including radiotherapy and chemotherapy for lung neoplasms. Radiation-induced lung fibrosis is a major concern for radiotherapy for cancer patients. Therapy-induced fibrosis often limits the efficacy of the combination of chemotherapy and radiotherapy in numerous cancers. Currently, there are no effective non-surgical treatments for lung fibrosis. Hence there is an urgent need to develop therapeutic agents that prevent and ameliorate lung fibrosis. Accumulating evidence indicates that transforming growth factor-( (TGF-() plays an important role in its pathogenesis. Animal studies have shown that antagonizing TGF-( by treatment with TGF-( binding proteins appears to ameliorate lung fibrosis. Therefore synthetic TGF-( antagonists may serve as important therapeutic agents for lung fibrosis. We recently developed a class of synthetic TGF-( peptide antagonists (termed TGF-( peptantagonists) that block TGF-( binding to TGF-( receptors and antagonize TGF-( activity in cultured cells. Topical application of gel containing a TGF-( peptantagonist in standard animal skin injury models promotes wound healing and attenuates fibrosis. However, the use of TGF-( peptantagonists to treat lung fibrosis is limited by its poor solubility in aqueous solution at neutral pH. In recent studies, we have developed a novel pegylated TGF-( peptantagonist (termed PEG-TGF-( peptantagonist) which has excellent solubility in aqueous solution at neutral pH, potent antagonist activity as measured using cultured cells, and epithelial regeneration activity as determined using cyclophosphamide-induced bladder injury in rats. Intranasal administration of this PEG-TGF-( peptantagonist effectively prevents bleomycin-induced lung fibrosis in mice and attenuates established lung fibrosis as well. These results suggest that PEG-TGF-( peptantagonist may be a valuable therapeutic agent for prevention and treatment of lung fibrosis in humans. We hypothesize that our PEG-TGF-( peptantagonist is effective in ameliorating radiation-induced lung fibrosis. The major goal of this proposal is to test this hypothesis. The results from the proposed phase I studies should provide the basis for Phase II and clinical trials of this novel PEG-TGF-( peptantagonist. We predict that the clinical availability of our PEG-TGF-( peptantagonist will benefit millions of patients worldwide.
Public Health Relevance: The goal of this proposal is to develop novel TGF-( peptantagonist as a drug candidate for treating radiation-induced lung fibrosis which currently lacks effective treatments. The availability of such drug will benefit millions of patients worldwide.
Public Health Relevance Statement: Relevance The goal of this proposal is to develop novel TGF-¿ peptantagonist as a drug candidate for treating radiation- induced lung fibrosis which currently lacks effective treatments. The availability of such drug will benefit millions of patients worldwide.
NIH Spending Category: Cancer; Lung
Project Terms: 2H-1,3,2-Oxazaphosphorin-2-amine, N,N-bis(2-chloroethyl)tetrahydro-, 2-oxide; 2H-1,3,2-oxazaphosphorin-2-amine, N,N-is(2-chloroethyl)tetrahydro-,2-oxide; 4 Hydroxyproline; Abscission; Accelerated interstitial pneumonitis; Acute; Acute Interstitial Pneumonitis; Administration, Intranasal; Affect; Alveolar; Animal growth regulators, transforming growth factors; Animals; Antibodies; Attenuated; Binding; Binding (Molecular Function); Binding Proteins; Biopsy; Bladder Injury; Bleo; Bleomycin; Bleomycin Antibiotic; Blood Circulation; Blood capillaries; Bloodstream; Body Tissues; Bronchioalveolar Lavage; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Burn injury; Burns; CTX; CYCLO-cell; Cancer Patient; Cancer Radiotherapy; Cancer of Breast; Cancers; Capillaries; Capillary; Capillary, Unspecified; Carloxan; Cells; Cessation of life; Ciclofosfamida; Ciclofosfamide; Cicloxal; Circulation; Clafen; Claphene; Clinical; Clinical Trials, Phase I; Clinical Trials, Phase II; Combination Drug Therapy; Common Rat Strains; Cultured Cells; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamide; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cystic Fibrosis; Cytophosphan; Cytophosphane; Cytoxan; Death; Deposit; Deposition; Desquamative interstitial pneumonitis; Development; Diagnosis; Disease; Disorder; Drug Administration, Intranasal; Drug Administration, Topical; Drugs; Early-Stage Clinical Trials; Endoxan; Endoxana; Enduxan; Epithelial; Epithelium; Excision; Extirpation; Extracellular Matrix Proteins; FDA approved; Family suidae; Fibroblasts; Fibrosing Alveolitis; Fibrosis; Fosfaseron; Gel; Genoxal; Genuxal; Goals; Hamman-Rich syndrome; Heart; Human; Human, General; Hydrogen Oxide; Hydroxyproline; IV drip; Idiopathic ARDS; Idiopathic Interstitial Pneumonia; Individual; Infiltration; Inflammatory; Inflammatory Response; Injury; Intranasal Administration; Intravenous; Intravenous Drip; Intravenous Infusion; L-Proline, 4-hydroxy-, trans-; Lavage, Bronchopulmonary; Ledoxina; Lesion; Ligand Binding Protein; Lundbeck Brand of Bleomycin Sulfate; Lung; Lung Lavage; Lung Neoplasms; Lung Parenchyma; Lung Tissue; Lung diseases; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Breast; Malignant neoplasm of breast; Mammals, Mice; Mammals, Rabbits; Mammals, Rats; Man (Taxonomy); Man, Modern; Measures; Medication; Mice; Mitoxan; Modeling; Molecular Interaction; Mortality; Mortality Vital Statistics; Mucoviscidosis; Murine; Mus; Natural regeneration; Neosar; Non-specific interstitial neumonia/fibrosis; O element; O2 element; Obstruction; Operation; Operative Procedures; Operative Surgical Procedures; Oryctolagus cuniculus; Oxygen; Oxyproline; Pathogenesis; Patients; Peptides; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase 1 Clinical Trials; Phase 2 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase II Clinical Trials; Pigs; Play; Pneumonia; Pneumonitis; Polychemotherapy; Prevention; Process; Procytox; Pulmonary Diseases; Pulmonary Disorder; Pulmonary Fibrosis; Pulmonary Inflammation; Pulmonary Neoplasms; QOL; Quality of life; Rabbit, Domestic; Rabbits; Radiation; Radiation therapy; Radiotherapeutics; Radiotherapy; Rat; Rattus; Receptor Protein; Regeneration; Removal; Reporting; Respiratory Disease; Respiratory Disorder; Respiratory Failure; Respiratory System Disease; Respiratory System Disorder; Respiratory System, Lung; Respiratory physiology; Role; Route; Sendoxan; Skin; Solubility; Solutions; Staging; Structure; Structure of parenchyma of lung; Suidae; Surgical; Surgical Interventions; Surgical Procedure; Surgical Removal; Survival Rate; Swine; Syklofosfamid; Testing; Therapeutic Agents; Time; Tissues; Topical application; Transforming Growth Factors; Tumor Growth Factors; Tumor of the Lung; Usual Interstitial Pneumonia; Usual Interstitial Pneumonitis; Water; Wound Healing; Wound Repair; Zytoxan; aqueous; base; bronchopulmonary lavage therapy; capillary; chemotherapy; combination pharmacotherapy; diffuse interstitial pulmonary fibrosis; disease/disorder; drip infusion; drug candidate; drug/agent; effective therapy; idiopathic pulmonary fibrosis; intravenous administration; intravenous injection; irradiation; lung disorder; lung function; lung injury; malignancy; malignant breast neoplasm; neoplasm/cancer; new therapeutics; next generation therapeutics; novel; novel therapeutics; phase 1 study; phase 1 trial; phase 2 study; phase 2 trial; phase I trial; phase II trial; porcine; prevent; preventing; protocol, phase I; protocol, phase II; public health relevance; pulmonary; ray (radiation); receptor; regenerate; regenerate new tissue; regenerating damaged tissue; resection; respiratory function; respiratory insufficiency/failure; social role; study, phase II; suid; surgery; tissue regeneration; tissue repair; topical administration; topical drug application; topically applied; vein infusion; wound
