Cachexia is a major cause of suffering and death among patients with late stage cancers and the current treatment options are limited and ineffective. We have identified a novel Activin A inhibitory protein, Cryptic, that can potentially eliminate the muscle wasting activity of Activin in cachexia. Activin A has been previously validated as a target using other ligand traps, such as the Activin receptors ActRIIA and ActRIIB, but those molecules are promiscuous in binding to other TGF-beta family ligands which leads to compromising side effects. Cryptic exhibits a far more targeted activity towards Activins and therefore may be an ideal therapeutic for Activin mediated conditions. Preliminary data with an Fc fusion, Cryptic-Fc, has shown in vivo efficacy in an osteoporosis model system with both bone and muscle restorative effects observed. The goal of this project is to test Cryptic-Fc in a mouse model of cachexia. Mice implanted with the C26 colon adenocarcinoma cell line, which rapidly manifest cachexia, will be used to evaluate both prevention as well as the reversal of cachexia. In specific aim 1, various Cryptic deletion constructs will be prepared and analyzed for Activin binding and pharmacokinetics to identify optimal candidates for development. In specific aim 2 qualified Cryptic-Fc constructs will be tested in the mouse model. If successful, these studies will provide proof of concept for Cryptic-Fc in the treatment of cachexia and pave the way for more thorough pre-clinical development. This project is a collaboration between Abreos Biosciences and Dr. Martinez-Hackert, Assistant Professor at Michigan State University and the discoverer of Cryptic's Activin inhibiting functions. Abreos has secured exclusive rights to develop Cryptic for this and other indications.
Public Health Relevance Statement: PUBLIC HEALTH RELEVANCE Cachexia, also known as muscle wasting disease, is a common and debilitating side effect of many types of cancer. This project aims to develop a new treatment that can restore lost muscle for patients suffering from this disease.
NIH Spending Category: Cancer; Hematology; Osteoporosis; Prevention
Project Terms: activin A; Activin Receptor; Activins; Adenocarcinoma Cell; Adipose tissue; Adverse effects; Anemia; Angiotensin-Converting Enzyme Inhibitors; base; Binding (Molecular Function); Biological Models; bone; bone loss; bone morphogenetic protein receptors; Cachexia; cancer cachexia; Cancer Center; cancer type; Cell Line; Cell Nucleus; Cell surface; Cessation of life; chemotherapy; Clinical; Collaborations; Colon Adenocarcinoma; Comorbidity; cryptic protein; D Cells; Data; Development; Diagnostic Neoplasm Staging; Disease; Disulfides; Drug Kinetics; Erythrocytes; Erythropoiesis; Exhibits; Extracellular Domain; Faculty; Family; fighting; Funding; GDF8 gene; Gene Targeting; Goals; Growth; Hemorrhage; Implant; In Vitro; in vivo; inhibitor/antagonist; Legal patent; Ligand Binding; Ligands; Light; Link; Malignant Neoplasms; Mediating; Mediation; Methyl Green; Michigan; Modeling; mouse model; Mus; Muscle; novel; Oranges; Osteoporosis; Outcome; palliative; Patients; Phase; Phase II Clinical Trials; Phosphorylation; Phosphotransferases; pre-clinical; prevent; Prevention; professor; Proteins; public health relevance; Qualifying; receptor; receptor binding; Research Personnel; research study; Rights; Secure; Signal Transduction; skeletal; Skeletal muscle structure; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Structure of thyroid parafollicular cell; Testing; Therapeutic; Time; transcription factor; Transforming Growth Factor beta; tumor; Type I Activin Receptors; Type II Activin Receptors; Universities; wasting; Wasting Syndrome
