文章：

FABP5抑制对抗PTEN突变型治疗抵抗性前列腺癌

FABP5 Inhibition againstPTEN-Mutant Therapy Resistant Prostate Cancer

原文发布日期：21 December 2023

DOI: 10.3390/cancers16010060

类型: Article

开放获取: 是

英文摘要：

Resistance to standard of care taxane and androgen deprivation therapy (ADT) causes the vast majority of prostate cancer (PC) deaths worldwide. We have developed RapidCaP, an autochthonous genetically engineered mouse model of PC. It is driven by the loss of PTEN and p53, the most common driver events in PC patients with life-threatening diseases. As in human ADT, surgical castration of RapidCaP animals invariably results in disease relapse and death from the metastatic disease burden. Fatty Acid Binding Proteins (FABPs) are a large family of signaling lipid carriers. They have been suggested as drivers of multiple cancer types. Here we combine analysis of primary cancer cells from RapidCaP (RCaP cells) with large-scale patient datasets to show that among the 10 FABP paralogs, FABP5 is the PC-relevant target. Next, we show that RCaP cells are uniquely insensitive to both ADT and taxane treatment compared to a panel of human PC cell lines. Yet, they share an exquisite sensitivity to the small-molecule FABP5 inhibitor SBFI-103. We show that SBFI-103 is well tolerated and can strongly eliminate RCaP tumor cells in vivo. This provides a pre-clinical platform to fight incurable PC and suggests an important role for FABP5 inPTEN-deficient PC.

摘要翻译： 

对标准治疗药物紫杉烷和雄激素剥夺疗法（ADT）的耐药性是导致全球绝大多数前列腺癌（PC）患者死亡的原因。我们开发了RapidCaP模型，这是一种原发性的基因工程小鼠前列腺癌模型。该模型由PTEN和p53基因缺失驱动，这两种基因缺失是危及生命的前列腺癌患者中最常见的驱动事件。与人类ADT治疗情况类似，对RapidCaP动物进行手术去势无一例外地会导致疾病复发，并最终因转移性肿瘤负荷而死亡。脂肪酸结合蛋白（FABPs）是一个庞大的信号脂质载体家族，已被认为是多种癌症类型的驱动因子。本研究结合对RapidCaP原代癌细胞（RCaP细胞）的分析与大规模患者数据集，发现在10个FABP旁系同源基因中，FABP5是与前列腺癌相关的关键靶点。进一步研究表明，与一组人类前列腺癌细胞系相比，RCaP细胞对ADT和紫杉烷治疗均表现出独特的低敏感性，但对小分子FABP5抑制剂SBFI-103却具有高度敏感性。我们证实SBFI-103耐受性良好，并能有效清除体内RCaP肿瘤细胞。这为攻克难治性前列腺癌提供了临床前研究平台，并提示FABP5在PTEN缺陷型前列腺癌中具有重要作用。

原文链接：

FABP5 Inhibition againstPTEN-Mutant Therapy Resistant Prostate Cancer