(PQD6) Mechanistic insights into treatment of cancer anorexia and cachexia

描述(申请人提供)：癌症恶病质/厌食症是许多恶性肿瘤的一种常见的破坏性表现，对患者的发病率和死亡率有很大影响。癌症恶病质/厌食症的病因是多因素的，现有的治疗策略令人失望。最近的研究发现，降钙素/降钙素基因相关肽(CT/CGRP)神经元是后脑中因感染、炎症和疼痛而导致厌食和体重减轻的特定神经元组-而后脑的这个区域，臂旁核，已知在临床前癌症模型中被激活。新的小鼠遗传模型阐明了CT/CGRP神经元在“疾病”减肥模型中的作用，也可以用于明确测试这些神经元在癌症恶病质/厌食症中的机制作用。重要的是，我们建议的研究评估了导致渐进性恶病质/厌食症的小鼠癌症模型-更类似于临床情况。CT/CGRP神经元可诱导抑制的新的小鼠遗传模型使我们能够研究癌症诱导的体重减轻的治疗策略，而不仅仅是关注恶病质的预防。第二个遗传策略将聚焦于一个关键的弓状核神经元群体-NPY/AgRP神经元-并确定这些神经元的肿瘤相关抑制是否有助于癌症恶病质/厌食症的机制，以及这些神经元的可诱导激活是否可以预防或治疗癌症恶病质/厌食症。关键的是，我们的研究还将确定治疗癌症厌食症的干预措施对瘦体重和生存的影响。我们的建议有可能发现治疗癌症厌食症的新疗法，从而潜在地改善癌症患者的生活质量。

DESCRIPTION (provided by applicant): Cancer cachexia/anorexia is a common, devastating manifestation of many malignancies and contributes significantly to patient morbidity and mortality. The etiology of cancer cachexia/anorexia is multifactorial and existing treatment strategies are disappointing. Recent work has identified calcitonin/calcitonin-gene relate peptide (CT/CGRP) neurons as the specific neuronal group in the hindbrain that causes anorexia and weight loss due to infection, inflammation and pain - and this same area of the hindbrain, the parabrachial nucleus, is known to be activated in pre-clinical cancer models. The novel genetic mouse models that elucidated the role of CT/CGRP neurons in 'illness' models of weight loss can also be used to definitively test the mechanistic role of these neurons in cancer cachexia/anorexia. Importantly, our proposed studies evaluate mouse cancer models causing gradual, progressive cachexia/anorexia - more similar to clinical situations. The novel genetic mouse models of inducible inhibition of CT/CGRP neurons allow us to investigate treatment strategies for cancer-induced weight loss rather than focusing merely on cachexia prevention. A second genetic strategy will focus on a key Arcuate nucleus neuronal population - NPY/Agrp neurons - and determine whether tumor- related inhibition of these neurons contributes to the mechanism of cancer cachexia/anorexia and whether inducible activation of these neurons can either prevent or treat established cancer cachexia/anorexia. Critically, our studies will also determine the impact of interventions to treat cancer anorexia on lean body mass and survival. Our proposal has the potential to discover novel therapies for treatment of cancer anorexia and thereby potentially improve the quality of life of patients with cancer.