Perelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia; Linnaeus Therapeutics Inc, Philadelphia, Pennsylvania.
Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
Cell Mol Gastroenterol Hepatol. 2020;10(4):868-880.e1. doi: 10.1016/j.jcmgh.2020.04.016. Epub 2020 May 4.
BACKGROUND & AIMS: Female sex is associated with lower incidence and improved clinical outcomes for most cancer types including pancreatic ductal adenocarcinoma (PDAC). The mechanistic basis for this sex difference is unknown. We hypothesized that estrogen signaling may be responsible, despite the fact that PDAC lacks classic nuclear estrogen receptors.
Here we used murine syngeneic tumor models and human xenografts to determine that signaling through the nonclassic estrogen receptor G protein-coupled estrogen receptor (GPER) on tumor cells inhibits PDAC.
Activation of GPER with the specific, small molecule, synthetic agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically administered G-1 was well-tolerated in PDAC bearing mice, induced tumor regression, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. We detected GPER protein in a majority of spontaneous human PDAC tumors, independent of tumor stage.
These data, coupled with the wide tissue distribution of GPER and our previous work showing that G-1 inhibits melanoma, suggest that GPER agonists may be useful against a range of cancers that are not classically considered sex hormone responsive and that arise in tissues outside of the reproductive system.
女性的多数癌症类型（包括胰腺导管腺癌[PDAC]）发病率较低，临床预后较好。这种性别差异的机制尚不清楚。我们假设雌激素信号可能是其原因，尽管 PDAC 缺乏经典的核雌激素受体。
在这里，我们使用鼠同源肿瘤模型和人异种移植模型来确定肿瘤细胞上的非经典雌激素受体 G 蛋白偶联雌激素受体（GPER）信号转导可抑制 PDAC。
用特异性小分子合成激动剂 G-1 激活 GPER 可抑制 PDAC 增殖，耗竭 c-Myc 和程序性死亡配体 1（PD-L1），并增加肿瘤细胞的免疫原性。在患有 PDAC 的小鼠中，全身性给予 G-1 耐受性良好，可诱导肿瘤消退，显著延长生存时间，并显著提高 PD-1 靶向免疫治疗的疗效。我们在大多数自发的人类 PDAC 肿瘤中检测到 GPER 蛋白，与肿瘤分期无关。
这些数据，加上 GPER 的广泛组织分布，以及我们之前的工作表明 G-1 可抑制黑色素瘤，表明 GPER 激动剂可能对一系列不被认为是经典激素反应的癌症以及发生在生殖系统外组织的癌症有用。
