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

 描述(申请人提供)：恶病质有时被视为癌症不可避免死亡的预兆，只能通过治愈疾病来解决。虽然治愈癌症应该能治愈恶病质，但许多癌症的治愈率令人沮丧。肌肉萎缩会导致化疗毒性、生活质量差、对治疗的反应差，通常被认为是高达30%的癌症死亡的罪魁祸首。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，尽管肿瘤持续生长，但阻止肌肉萎缩可以延长患有癌症的小鼠的功能和寿命。这些发现表明，肌肉损失是癌症发病率和死亡率的主要原因，可以针对它来增加癌症患者的长度和生活质量。我们的目标是了解恶病质的分子通路，以便形成合理的治疗方法来预防它。Sonic Hedgehog(Shh)调节成体祖细胞的增殖和分化，对肌肉发育和肌肉再生是必不可少的。在这里，我们提供了恶病质诱导的细胞因子和肿瘤刺激肌肉中Shh信号的证据。高细胞因子和癌症恶病质患者和小鼠的骨骼肌表现出Shh途径的激活。在小鼠和细胞培养中，Shh信号的激活会导致肌肉萎缩，而拮抗会导致肥大。令人鼓舞的是，FDA批准的Shh途径抑制剂GDC-0449/vismodegib减少了癌症恶病质小鼠的肌肉和脂肪浪费。Shh途径促进了肌肉中泛素相关的蛋白分解，但这一作用被Shh抑制而逆转。此外，Shh作用促进成肌细胞的增殖，同时抑制正常的成肌细胞分化。根据这些数据，我们假设Shh通路的激活通过对肌肉纤维中的蛋白质分解代谢和肌肉前体细胞的分化的双重影响来推动肌肉萎缩。肌祖细胞的积累会导致细胞因子的表达，进而导致肌纤维的损耗。肌纤维中的信号直接导致蛋白质的丢失和浪费。因此Shh信号是预防癌症恶病质的治疗靶点。在这里，我们将检验这一假说，并确定这一途径与人类胰腺癌恶病质的潜在治疗和病理生物学的相关性。这些研究将塑造未来针对癌症恶病质的临床试验，以提高癌症的治疗反应和存活率。

 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.