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.

描述（由申请人提供）：恶病质有时被视为癌症不可避免的死亡的预兆，只能通过治愈疾病来解决。虽然治愈癌症应该治愈恶病质，但许多癌症的治愈率很低。生活质量差、对治疗的反应不佳，通常被认为是高达 30% 的癌症死亡的原因。然而，来自我们实验室和其他实验室的令人信服的数据表明，阻止肌肉萎缩可以延长小鼠的功能和寿命。尽管肿瘤持续生长，但这些发现表明肌肉损失是癌症发病率和死亡率的一个主要因素，我们的目标是了解导致癌症患者生活长度和质量的分子途径。声波刺猬 (Shh) 调节成人祖细胞的增殖和分化，对于肌肉发育和调节肌肉再生至关重要。在此，我们提供了诱导恶病质的细胞因子和肿瘤的证据。刺激肌肉中的 Shh 信号传导。来自具有高细胞因子和癌症恶病质的小鼠和患者的骨骼肌表现出 Shh 信号通路激活。在小鼠和细胞培养物中，Shh 信号传导的激活会导致肌肉萎缩，而令人鼓舞的是，FDA 批准的一种抑制剂会导致肌肉肥大。 Shh 通路 GDC-0449/vismodegib 减少了癌症恶病质小鼠的肌肉和脂肪消耗。Shh 通路促进了泛素相关的蛋白水解。此外，Shh 作用促进了成肌细胞的增殖，同时阻止了正常的肌原性分化。根据这些数据，我们探索了 Shh 通路激活通过对肌纤维中的蛋白质分解代谢和肌肉祖细胞分化的双重作用而导致肌肉萎缩。肌肉祖细胞的积累导致细胞因子的表达，进而诱导肌纤维中的信号传导直接导致蛋白质损失和浪费。在这里，我们将测试这一假设，并确定该途径与人类胰腺癌恶病质的潜在治疗和病理学的相关性，这些研究将塑造未来针对癌症恶病质的临床试验，以改善治疗反应和治疗效果。癌症中的生存。