Targeting Adipocyte Lipases to Treat Pancreatic Cancer-Associated Cachexia

描述（由申请方提供）：恶病质是一种脂肪组织和骨骼肌的进行性萎缩，发生在超过85%的胰腺导管腺癌（PDAC）患者中。它是患者死亡率的主要因素，也是生存期较短的独立预测因素。恶病质显著降低PDAC患者的生活质量，并增加治疗失败和毒性的风险。针对恶病质的治疗是姑息性的， 性质：对于癌症相关的恶病质没有有效的治疗方法。最近，越来越多的兴趣集中在试图通过逆转与恶病质相关的代谢改变来解决恶病质。癌症恶病质的一个关键特征是脂肪组织的损失。对人类的研究表明，增加脂肪细胞脂解，而不是减少脂肪生成或增加脂肪细胞死亡，是癌症恶病质中脂肪损失的主要原因。用解决作为恶病质基础的脂肪细胞功能障碍的药剂与标准抗肿瘤剂组合治疗癌症患者，可以显著提高他们的生活质量和抗肿瘤治疗成功的机会。 所有已知参与脂肪细胞脂解的酶（ATGL、HSL、MGLL）都是丝氨酸水解酶。脂肪甘油三酯脂肪酶（ATGL）和激素敏感性脂肪酶（HSL）的基因消融在较小程度上可以防止癌症相关的恶病质，证明脂肪细胞功能障碍的纠正确实是一种可行的方法来逆转癌症相关的恶病质。然而，预测这些丝氨酸水解酶的全身性抑制具有有害作用，其排除了这种治疗恶病质的方法。例如，ATGL缺失小鼠在心脏中积累脂质并过早死亡。 整合表型筛选与化学蛋白质组学方法，我们最近确定了另一个丝氨酸水解酶，Ces3，调节脂肪细胞脂解。Ces3的药理学抑制改善了2型糖尿病的多种特征（另一种涉及脂肪细胞脂解速率增加的病症），而不会引起副作用。我们打算评估 的Ces3抑制胰腺癌相关的恶病质，并确定其他注释不佳的丝氨酸水解酶，可能作为癌症相关的恶病质的目标。

DESCRIPTION (provided by applicant): Cachexia is a progressive atrophy of adipose tissue and skeletal muscle that occurs in more than 85% of pancreatic ductal adenocarcinoma (PDAC) patients. It is a major contributor to the mortality of patients and an independent predictor of shorter survival. Cachexia dramatically reduces the quality of life of PDAC patients and increases the risk of treatment failure and toxicity. Treatments against cachexia are palliative in nature: there is no effective therapy for cancer-associated cachexia. Recently, increased interest has focused on tackling cachexia by attempting to revert the metabolic alterations that are associated with cachexia. A key feature in cancer cachexia is the loss of adipose tissue. Studies in humans have shown that increased adipocyte lipolysis, not reduced lipogenesis or increased fat cell death, is the primary cause of fat loss in cancer cachexia. Treating cancer patients with agents that address the adipocyte dysfunction that is the basis of the cachexia, in combination with standard antineoplastic agents, may dramatically enhance their quality of life and the chances of success of the anti-tumor treatment. All enzymes known to be involved in adipocyte lipolysis (ATGL, HSL, MGLL) are serine hydrolases. Genetic ablation of adipose triglyceride lipase (ATGL) and to a lesser extent hormone sensitive lipase (HSL) can protect from cancer-associated cachexia, demonstrating that correction of the adipocyte dysfunction is indeed a viable approach to reverse cancer-associated cachexia. However, systemic inhibition of these serine hydrolases is predicted to have deleterious effects that preclude this approach to treat cachexia. For example, ATGL null mice accumulate lipid in the heart and die prematurely. Integrating phenotypic screening with chemoproteomic methods, we recently identified another serine hydrolase, Ces3, which regulates adipocyte lipolysis. Pharmacologic inhibition of Ces3 ameliorates multiple features type 2 diabetes (another condition that involves increased rate of adipocyte lipolysis) without inducing side effects. We intend to evaluate the therapeutic potential of Ces3 inhibition in pancreatic cancer-associated cachexia, and to identify additional poorly annotated serine hydrolases that may serve as targets in cancer-associated cachexia.