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，患者肺内平滑肌样“LAM细胞”增生，肺实质囊性破坏，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TSC2基因突变失活引起的，导致哺乳动物雷帕霉素靶蛋白（mTOR）复合物1 （mTORC1）过度活化，抑制自噬。mTORC1和自噬调节细胞代谢稳态。tsc2缺陷细胞通过对其细胞代谢进行重编程来弥补这一点，从而产生代谢脆弱性，为重编程细胞提供高特异性的治疗机会。如何靶向LAM中的重编程代谢途径尚不完全清楚，这是一个关键的知识缺口。在最近发表的数据中，我们发现tsc2缺陷细胞依赖自噬存活，无论是在体外还是在体内。在未发表的数据中，我们发现tsc2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，使用目前可用的药物可以选择性地靶向tsc2缺陷细胞的代谢脆弱性，而无需使用mTORC1抑制剂。我们的中心假设，即代谢靶向治疗策略将在LAM临床前模型中具有高度特异性的疗效，将在三个具体目标中得到解决：1)

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 In unpublished data, we found that TSC2-deficient cells have distinctive autophagy-dependent vulnerabilities in glutamine metabolism and in the pentose phosphate pathway.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.