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

PQB3：机制

基本信息

批准号：
9233076
负责人：
Teresa A Zimmers
金额：
$ 35.53万
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/9233076
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 Human Hypertrophy In Vitro Length Life Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Measures Modeling Molecular Morbidity - disease rate Morphology 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 cancer cachexia clinically relevant cytokine improved in vivo inhibitor/antagonist mortality muscle form muscle regeneration pre-clinical prevent progenitor prospective public health relevance 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（由适用提供）：恶病质有时被视为癌症中必然死亡的预兆，只能通过治愈该疾病来解决。虽然治愈癌症应治愈恶病质，但许多癌症的治愈率却很惨淡。肌肉损失会导致化学疗法毒性，生活质量差，对疗法的反应不佳，通常被指责为癌症死亡的30％。但是，我们实验室和其他人的引人注目的数据表明，阻断肌肉浪费可以延长癌症的小鼠的功能和寿命，从而持续肿瘤的生长。这些发现表明，肌肉丧失是导致癌症发病率和死亡率的主要因素，并且可以针对癌症患者的生活长度和寿命。我们的目标是了解导致恶病质的分子途径，以塑造理性疗法以防止它。 Sonic刺猬（SHH）调节成人祖细胞的增殖和分化，对于肌肉发育至关重要，并调节肌肉再生。在这里，我们提供的证据表明，缓存诱导的细胞因子和肿瘤会刺激肌肉中的SHH信号传导。来自小鼠的骨骼肌和高细胞因子和癌症患者暴露于SHH途径激活的患者。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，而拮抗作用会导致肥大。令人鼓舞的是，在患有癌症恶病质小鼠的小鼠中，SHH途径，GDC-0449/Vismodegib的FDA批准抑制剂减少了肌肉和脂肪浪费。 SHH途径促进了肌肉中与泛素相关的蛋白水解，这被SHH抑制作用逆转。此外，SHH作用促进了肌细胞的扩散，同时阻止了正常的肌源性分化。从这些数据中，我们假设SHH途径激活通过对肌纤维中蛋白质分解代谢的双重影响和肌肉祖细胞的分化来驱动肌肉。肌肉祖细胞的积累会导致细胞因子的表达，从而导致肌纤维浪费。肌纤维中的信号传导直接导致蛋白质丧失和浪费。 SHH信号传导是预防癌症恶病质的治疗靶标。在这里，我们将检验这一假设，并定义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的临床试验，以靶向癌症恶病质，以改善癌症的治疗反应和生存。