a Division of Basic Research , Instituto Nacional de Cancerologia , Mexico City , Mexico.
b Unit of Biomedical Research in Cancer , Instituto de Investigaciones Biomedicas, UNAM/Instituto Nacional de Cancerologia , Mexico City , Mexico.
Expert Opin Investig Drugs. 2018 May;27(5):475-489. doi: 10.1080/13543784.2018.1471132. Epub 2018 May 10.
Cancer cells have increased glycolysis and glutaminolysis. Their third feature is increased de novo lipogenesis. As such, fatty acid (FA) synthesis enzymes are over-expressed in cancer and their depletion causes antitumor effects. As fatty acid synthase (FASN) plays a pivotal role in this process, it is an attractive target for cancer therapy.
This is a review of the lipogenic phenotype of cancer and how this phenomenon can be exploited for cancer therapy using inhibitors of FASN, with particular emphasis on orlistat as a repurposing drug.
Disease stabilization only has been observed with a highly selective FASN inhibitor used as a single agent in clinical trials. It is too early to say whether the absence of tumor responses other than stabilization results because even full inhibition of FASN is not enough to elicit antitumor responses. The FASN inhibitor orlistat is a 'dirty' drug with target-off actions upon at least seven targets with a proven role in tumor biology. The development of orlistat formulations suited for its intravenous administration is a step ahead to shed light on the concept that drug promiscuity can or not be a virtue.
癌细胞具有增强的糖酵解和谷氨酰胺分解作用。它们的第三个特征是增加从头合成脂肪。因此，脂肪酸（FA）合成酶在癌症中过度表达，其耗竭会引起抗肿瘤作用。由于脂肪酸合酶（FASN）在这个过程中起着关键作用，因此它是癌症治疗的一个有吸引力的靶点。
这是对癌症的生脂表型的综述，以及如何利用 FASN 抑制剂来利用这种现象进行癌症治疗，特别强调了奥利司他作为一种重新定位药物。
在临床试验中，仅使用高度选择性的 FASN 抑制剂作为单一药物观察到疾病稳定。现在还为时过早，无法确定除稳定外是否没有肿瘤反应，因为即使完全抑制 FASN 也不足以引起抗肿瘤反应。FASN 抑制剂奥利司他是一种“肮脏”的药物，至少有七种靶点的作用与其在肿瘤生物学中的作用有关。开发适合于其静脉内给药的奥利司他制剂是向前迈进的一步，以阐明药物混杂性可能是或不是一种美德的概念。
