Metabolic Reprogramming in LAM: Novel Therapeutic Strategies

描述（由申请人提供）：淋巴管平滑肌瘤病（LAM）是一种女性进行性多系统疾病，其中平滑肌样“LAM细胞”在肺中增殖，伴有肺实质囊性破坏，通常导致氧依赖、肺移植和/或青年期死亡。肾血管平滑肌脂肪瘤是一种良性肿瘤，可引起疼痛和危及生命的自发性出血，发生在约60%的LAM患者中。LAM是由TSC 2基因中的失活突变引起的，导致雷帕霉素（mTOR）复合物1（mTORC 1）的哺乳动物靶标的超活化和自噬的抑制。mTORC 1和自噬调节细胞代谢稳态。TSC 2缺陷细胞通过重新编程其细胞代谢来补偿这一点，从而产生代谢脆弱性，为重新编程的细胞提供具有高度特异性的治疗机会。如何在LAM中靶向重编程代谢途径尚不完全清楚，这代表了一个关键的知识缺口。在最近发表的数据中，我们发现TSC 2缺陷细胞在体外和体内都依赖于自噬生存。在未发表的数据中，我们发现TSC 2缺陷细胞在谷氨酰胺代谢和戊糖磷酸途径中具有独特的自噬依赖性脆弱性。我们的概念验证数据表明，TSC 2缺陷细胞的代谢脆弱性可以使用目前可用的药物选择性靶向，而无需使用mTORC 1抑制剂。我们的中心假设是代谢靶向治疗策略在LAM的临床前模型中具有高度特异性的疗效，这将在三个具体目标中得到解决：1） 定义LAM患者来源的细胞的代谢被重编程的机制; 2）确定代谢组学重编程对LAM患者来源的细胞的增殖和存活的影响; 3）确定代谢重编程在LAM临床前模型中的体内影响。该项目将通过促进LAM的全新、范式转变治疗概念的发展而产生高度的临床影响。我们的最终目标是使用高效和安全的方法阻止LAM女性肺功能的进行性丧失。

DESCRIPTION (provided by applicant): Lymphangioleiomyomatosis (LAM) is a progressive multisystem disease of women in which smooth muscle-like "LAM cells" proliferate in the lungs with cystic destruction of the lung parenchyma, often leading to oxygen-dependency, lung transplantation, and/or death in young adulthood. Renal angiomyolipomas, which are benign tumors that can cause pain and life-threatening spontaneous hemorrhage, occur in ~60% of LAM patients. LAM is caused by inactivating mutations in the TSC2 gene, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and inhibition of autophagy. mTORC1 and autophagy regulate cellular metabolic homeostasis. TSC2-deficient cells compensate for this by reprogramming their cellular metabolism, thereby creating metabolic vulnerabilities that provide therapeutic opportunities with high specificity to the reprogrammed cell. How to target reprogrammed metabolic pathways in LAM is incompletely understood, representing a key knowledge gap. In recently published data, we discovered that TSC2-deficient cells are dependent on autophagy for survival, both in vitro and in vivo. In unpublished data, we found that TSC2-deficient cells have distinctive autophagy-dependent vulnerabilities in glutamine metabolism and in the pentose phosphate pathway. Our proof-of-concept data indicate that the metabolic vulnerabilities of TSC2-deficient cells can be selectively targeted using currently available agents without the utilization of mTORC1 inhibitors. Our central hypothesis that metabolically-targeted therapeutic strategies will have highly specific efficacy in pre-clinical models of LAM will be addressed in three specific aims: 1) to define the mechanisms through which the metabolism of LAM patient-derived cells is reprogrammed; 2) to determine the impact of metabolomic reprogramming on the proliferation and survival of LAM patient-derived cells; 3) to determine the in vivo impact of metabolic reprogramming in preclinical models of LAM. This project will have high clinical impact by facilitating the development of completely novel, paradigm-shifting therapeutic concepts for LAM. Our ultimate goal is to halt the progressive loss of lung function in women with LAM, using approaches that are highly effective and safe.