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Activin A antagonist for treatment of cancer-associated cachexia

激活素 A 拮抗剂用于治疗癌症相关恶病质

基本信息

批准号：
9046615
负责人：
BRADLEY T MESSMER
金额：
$ 22.5万
依托单位：
ABREOS BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2016-03-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9046615
关键词：
Activin Receptor Activins Adenocarcinoma Cell Adipose tissue Adverse effects Anemia Angiotensin-Converting Enzyme Inhibitors Binding Biological Models Cachexia Cancer Center Cell Line Cell Nucleus Cell surface Cessation of life Clinical Collaborations Colon Adenocarcinoma Comorbidity D Cells Data Development Diagnostic Neoplasm Staging Disease Disulfides Drug Kinetics Erythrocytes Erythropoiesis Exhibits Extracellular Domain Faculty Family Funding GDF8 gene Gene Targeting Goals Growth Hemorrhage Implant In Vitro Legal patent Ligand Binding Ligands Light Link Malignant Neoplasms Mediating Mediation Methyl Green Michigan Modeling Mus Muscle Oranges Osteoporosis Outcome Patients Phase Phase II Clinical Trials Phosphorylation Phosphotransferases Prevention Proteins Qualifying Research Personnel Rights Secure Signal Transduction Skeletal Muscle Small Business Innovation Research Grant Small Business Technology Transfer Research Structure of thyroid parafollicular cell Testing Therapeutic Time Transforming Growth Factor beta Type I Activin Receptors Type II Activin Receptors Universities Wasting Syndrome activin A base bone bone loss bone morphogenetic protein receptors cancer cachexia cancer type chemotherapy cryptic protein fighting in vivo inhibitor/antagonist mouse model novel palliative pre-clinical prevent professor public health relevance receptor receptor binding research study skeletal transcription factor tumor wasting

项目摘要

DESCRIPTION (provided by applicant) 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.

描述（由申请人提供）恶病质是晚期癌症患者痛苦和死亡的主要原因，目前的治疗选择有限且无效。我们已经发现了一种新的激活素A抑制蛋白，隐藏蛋白，消除恶病质中Activin的肌肉消耗活性。激活素A先前已被验证为使用其他配体陷阱（例如激活素受体ActRIIA和ActRIIB）的靶标，但这些分子在与其他TGF-β家族配体结合时是混杂的，这导致损害副作用。隐藏蛋白对激活素表现出更强的靶向活性，因此可能是激活素介导的病症的理想治疗剂。Fc融合体（隐藏-Fc）的初步数据已显示在骨质疏松症模型系统中的体内功效，观察到骨和肌肉恢复效果。该项目的目标是在恶病质小鼠模型中测试隐藏Fc。植入C26结肠腺癌细胞系的小鼠（其迅速表现恶病质）将用于评价恶病质的预防以及逆转。在具体目标1中，将制备各种隐藏缺失构建体并分析激活素结合和药代动力学，以鉴定用于开发的最佳候选物。在具体目标中，将在小鼠模型中测试2个合格的隐藏-Fc构建体。如果成功，这些研究将为治疗恶病质的Cryptic-Fc提供概念证明，并为更彻底的临床前开发铺平道路。该项目是Abreos Biosciences和Martinez-Hackert博士的合作，Martinez-Hackert博士是密歇根州立大学的助理教授，也是Cryptic激活素抑制功能的发现者。Abreos已经获得了为这种适应症和其他适应症开发Cryptic的独家权利。