PQB3: Mechanisms & Targeting of Sonic Hedgehog Signaling in Muscle Wasting of Cancer Cachexia

PQB3：机制

基本信息

批准号：
9052746
负责人：
Teresa A Zimmers
金额：
$ 35.41万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2015-04-10 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052746
关键词：
Address Adult Biochemical Biological Preservation Cachexia Cancer Patient Catabolism Cell Culture Techniques Cessation of life Clinical Data Clinical Trials Correlative Study Data Disease Exhibits FDA approved Fatty acid glycerol esters Fiber Future GLI gene Goals Growth Health Housing Human Hypertrophy In Vitro Length Life Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Measures Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Development Muscle function Muscle satellite cell Muscular Atrophy Myoblasts Nuclear PAX7 gene Pathway interactions Patients Process Proteins Proteolysis Quality of life Rhabdomyosarcoma SHH gene Shapes Signal Transduction Skeletal Muscle Sonic Hedgehog Pathway Stem cells Testing Toxicity due to chemotherapy Treatment-Related Cancer Ubiquitin Work cancer cachexia clinically relevant cytokine improved in vivo inhibitor/antagonist mortality muscle form muscle regeneration pre-clinical prevent progenitor response small molecule inhibitor smoothened signaling pathway therapeutic target treatment response tumor tumor growth wasting

项目摘要

DESCRIPTION (provided by applicant): Cachexia is sometimes viewed as a harbinger of inevitable death in cancer, which only can be addressed by curing the disease. While curing cancer should cure cachexia, many cancers have dismal cure rates. Muscle loss causes chemotherapy toxicity, poor quality of life, poor response to therapies, and is often blamed for up to 30% of cancer deaths. However, compelling data from our lab and others show that blocking muscle wasting can prolong function and life in mice with cancer, despite continued growth of the tumor. These findings indicate that muscle loss is a major contributor to cancer morbidity and mortality and it can be targeted to increase length and quality of life for cancer patients. Our goal is to understand the molecular pathways responsible for cachexia in order to shape rational therapies to prevent it. Sonic hedgehog (Shh) regulates proliferation and differentiation of progenitor cells in the adult and is essential for muscle development and modulates muscle regeneration. Here, we provide evidence that cachexia-inducing cytokines and tumors stimulate Shh signaling in muscle. Skeletal muscle from mice and patients with high cytokines and cancer cachexia exhibit Shh pathway activation. In mice and cell cultures, activation of Shh signaling causes muscle atrophy, while antagonism results in hypertrophy. Encouragingly, an FDA-approved inhibitor of the Shh pathway, GDC-0449/vismodegib, reduced muscle and fat wasting in mice with cancer cachexia. The Shh pathway promoted ubiquitin-associated proteolysis in muscle, which was reversed by Shh inhibition. Additionally, Shh action promoted proliferation of myoblasts, while blocking normal myogenic differentiation. From these data we hypothesize that Shh pathway activation drives muscle wasting through dual effects on protein catabolism in myofibers and differentiation of muscle progenitors. Accumulation of muscle progenitors leads to expression of cytokines, which in turn induces wasting of myofibers. Signaling in myofibers leads directly to protein loss and wasting. Thus Shh signaling is a therapeutic target to prevent cancer cachexia. Here we will test this hypothesis and define the relevance of this pathway to the potential treatment and pathobiology of human pancreatic cancer cachexia. These studies will shape future clinical trials for targeting cancer cachexia to improve treatment response and survival in cancer.