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

PQB3：机制

• 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
• 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

 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中不可避免的死亡的预兆，这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。肌肉损失导致化疗毒性，生活质量差，对治疗反应差，并且通常被归咎于高达30%的癌症死亡。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，阻断肌肉萎缩可以延长癌症小鼠的功能和生命，尽管肿瘤持续生长。这些研究结果表明，肌肉损失是癌症发病率和死亡率的主要因素，它可以有针对性地增加癌症患者的寿命和生活质量。我们的目标是了解恶病质的分子途径，以形成合理的治疗，以防止它。音刺猬（Shh）调节增殖和分化的祖细胞在成人和肌肉发育和调节肌肉再生是必不可少的。在这里，我们提供了恶病质诱导细胞因子和肿瘤刺激肌肉中Shh信号传导的证据。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通路活化。在小鼠和细胞培养物中，Shh信号传导的激活导致肌肉萎缩，而拮抗作用导致肥大。令人鼓舞的是，FDA批准的Shh通路抑制剂GDC-0449/vismodegib减少了癌症恶病质小鼠的肌肉和脂肪消耗。Shh通路促进肌肉中的泛素相关蛋白水解，这被Shh抑制逆转。此外，Shh作用促进成肌细胞增殖，同时阻断正常的肌源性分化。从这些数据中，我们假设Shh通路激活通过对肌纤维中的蛋白质催化剂和肌肉祖细胞分化的双重作用驱动肌肉萎缩。肌肉祖细胞的积累导致细胞因子的表达，这反过来诱导肌纤维的消耗。肌纤维中的信号传导直接导致蛋白质损失和浪费。因此，Shh信号传导是预防癌症恶病质的治疗靶点。在这里，我们将测试这一假设，并确定这一途径的相关性，人类胰腺癌恶病质的潜在治疗和病理生物学。这些研究将塑造未来针对癌症恶病质的临床试验，以改善癌症的治疗反应和生存率。