LRAT

导读：肝细胞癌(HCC)是最致命的第三大恶性肿瘤。肝癌中激活的肝星状细胞(aHSC)与癌症相关的成纤维细胞被认为是一个潜在的治疗靶点。5月8日，南加州大学研究人员在《Nature：Communications》上发表了名为“Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis”的文章，研究人员称发现了新的肝癌治疗靶点。https://www.nature.com/articles/s41467-023-38406-8研究背景 01 肝细胞癌(HCC)是第三大最致命的恶性肿瘤。肝细胞癌中激活的肝星状细胞(aHSC)在与癌症相关的成纤维细胞，被认为是一个潜在的治疗靶点。研究人员报道了Scd2（一种饱和酶）在肝星状细胞中抑制肿瘤和肿瘤微环境，并防止雄性小鼠患上肝脏肿瘤。细活化的肝星状细胞(aHSC)促进HCC成为癌症相关成纤维细胞(CAF)。代谢性肝病（如酒精性和非酒精性脂肪性肝炎）目前被认为是肝细胞癌的主要易感因素，取代了病毒性肝炎。然而，在这种情况下，aHSC-HCC串扰在HCC发展中的具体性质尚不清楚。研究方法 02研究人员首先验证了小鼠在肝星状细胞中选择性消融Scd2的作用。为此他们对小鼠肝细胞进行了单细胞RNA测序(scRNA-seq)。该分析确定了表达其标记基因的不同细胞类型的簇。其中，Scd2在内皮细胞、巨噬细胞、门静脉成纤维细胞(PF)、树突状细胞中表达。接下来，我们通过对肝肿瘤邻近组织的RNA测序探讨了aHSC、SCD2缺乏抗肿瘤作用的机制。研究人员认为这些被称为肿瘤邻近肝(TAL)的组织是研究肝星状细胞-肿瘤细胞串扰的理想组织，因为它们在显微镜下，尽管肿瘤并不明显。差异表达基因(DEGs)的热图描绘了不同转录组学景观(图1a)。Yap1的转录受到CTNNB112的正调控，Yap1和CTNNB1同时受到抑制，表示Yap1的抑制可能是由CTNNB1的减少引起的。研究人员还想知道这种调节是肝脏肿瘤发生所特有的，还是也与正常肝脏有关。为此分析了小鼠肝脏中主要在肝细胞和胆管细胞中缺乏CTNNB1的YAP1和Scd1/2的表达。IB分析显示肝脏中YAP1、TAZ、HuR和LRP6下调。CTNNB113和Yap1/ Wwtr1 mRNA的预期靶点Scd1/2也受到抑制。这表明即使在正常肝细胞中，CTNNB1也能正向调节Yap1/ TAZ和SCD-HuR-LRP6通路。SCD2是产生mufa所必需的酶，mufa通过延伸和去饱和产生多不饱和脂肪酸(PUFA)。因此，研究人员对Scd2f/f CC与Scd2f/f肝脏中的PUFA代谢物进行了脂质组学分析。为验证LTB4R2在HCC中的作用，研究人员检测了LTB4R2的药理学和遗传学抑制对人HCC细胞株Huh7生长的影响。LTB4R2拮抗剂LY255283的浓度抑制Huh7的生长。shRNA对LTB4R2的表达使其减少80%，但对LTB4R1 mRNA没有影响，证实了LTB4R2的促生长作用。LTB4R2 KD降低了nYAP1和CTNNB1。LTB4R2在2000年被发现为LTB4的低亲和力受体，随后12-HHTrE被鉴定为高亲和力LTB4R2配体。研究描述了LTB4R2通过激活CTNNB1和YAP1在肝脏肿瘤发展中的作用，CTNNB1和YAP1是两种促进肝脏肿瘤发生的转录激活因子。研究人员的scRNA-seq分析发现，Lrat+Fbln2+ aHSC亚群是CYP1B1催化的12-HHTrE生成的假定来源。scd2依赖性Cyp1b1上调的机制目前尚不清楚，但可能涉及CTNNB1-AhR对Cyp1a134的转录激活。TCGA-LIHC队列分析未能显示LTB4R2表达与不良生存率之间的正相关。研究人员发现的LTB4R2通路可能仅在肝癌生长的病灶区域有活性，并且可能无法通过RNA-seq准确评估。事实上对小鼠的RNA-seq分析未能检测到Ltb4r2表达降低，尽管IB或qPCR显著减少。TME中表达cyp1b1的aHSC群体相对较少。因此，只有那些被CYP1B1+ aHSC包围的HCC细胞才能表达LTB4R2——这是CYPB1-LTB4R2通路独特的局灶性和空间性。https://www.nature.com/articles/s41467-023-38406-8研究意义 03肝星状细胞（aHSC）依赖于SCD和CYP1B1的方式释放12-HHTrE，其条件培养基在HCC细胞中再现了ltb4r2介导的12-HHTrE促进肿瘤生长的作用。总之，研究结果表明肝星状细胞启动的12-hhtrer-ltb4r2-ctnnb1-yap1通路是潜在的肝细胞癌治疗靶点。参考资料：https://www.nature.com/articles/s41467-023-38406-8

VANCOUVER, Oct. 9 /PRNewswire-FirstCall/ - QLT Inc. announced today that it has initiated a Phase I safety study in healthy adults of QLT091001, an orally administered synthetic retinoid replacement therapy for 11-cis-retinal, which is a key biochemical component of the visual retinoid cycle. The drug is being developed for the potential treatment of Leber's Congenital Amourosis (LCA), an inherited progressive retinal degenerative disease that leads to retinal dysfunction and visual impairment beginning at birth. The Phase I study is an open-label, single center, ascending dose trial that will determine the safety and tolerance of multiple administrations of the synthetic retinoid drug in approximately 18 healthy adult volunteers. Participants will be enrolled in up to 6 cohorts of increasing doses. "We believe our retinoid synthetic drug program is a very interesting opportunity as there are no currently available treatments for patients with LCA, which affects one in one-hundred thousand newborns world-wide," said Bob Butchofsky, President and Chief Executive Officer of QLT. "This program also supports the Company's new ocular focus and we look forward to reporting the Phase I data in the first half of 2009. We hope that our findings will support further clinical studies in this orphan indication." About Synthetic Retinoid Drugs Genetic diseases in the eye such as Leber's Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP) arise from gene mutations of enzymes or proteins required in the biochemistry of vision. QLT091001 is a replacement for 11-cis-retinal which is an essential component of the retinoid-rhodopsin cycle and visual function. Two different gene mutations (Retinal pigment epithelium protein 65 (RPE65) and lecithin-retinol acyltransferase (LRAT)) result in an inadequate production of 11-cis-retinal and occur in approximately 10% of patients with LCA and to a lesser extent in RP. The basis for using synthetic retinoids as replacement therapy for conditions where genetic defects result in deficiency of 11-cis-retinal is founded on experiments in mouse genetic models. These experiments used mice that have mutations in either the RPE65 or LRAT genes, the same as those associated with LCA in humans. Both mouse models have clinical features of the human disease. The biological activity of the synthetic retinoid was monitored by measuring the level of pigment-related compounds in the eye. Retinal function was also assessed by detecting electroretinograms (ERGs), electrical nerve signals from the retina. Oral administration of QLT091001 showed evidence of having corrected the biochemical defect in the retinoid cycle in light-sensing cells (rods) and appeared to restore ERG responses to light in both models of LCA. About Leber's Congenital Amaurosis Leber Congenital Amaurosis (LCA) is an inherited degenerative retinal disease characterized by abnormalities such as roving eye movements and sensitivity to light, and manifesting in severe vision loss from birth. Eye examinations of infants with LCA reveal normal appearing retinas. However, low level of retinal activity, measured by electroretinography (ERG), indicates very little visual function. About QLT QLT Inc. is a global biopharmaceutical company dedicated to the discovery, development and commercialization of innovative therapies. Our research and development efforts are focused on pharmaceutical products in the fields of ophthalmology and dermatology. In addition, we utilize three unique technology platforms, photodynamic therapy, Atrigel(R) and punctal plugs with drugs, to create products such as Visudyne(R) and Eligard(R) and future product opportunities. For more information, visit our web site at In April of 2006, QLT entered into an exclusive worldwide co-development and licensing agreement with Retinagenix, LLC, to develop active synthetic retinoid products for the treatment of degenerative retinal diseases. Pre-clinical studies have demonstrated that orally administered synthetic retinoid drugs cause long-lasting restoration of retinal function. Under the terms of the agreement, QLT is responsible to develop and commercialize the products for use in ocular and all other human diseases. Retinagenix has participated in research in support of the co-development collaboration and is eligible to receive payments upon achievement of certain development, approval and sales milestones as well as a single digit royalty on net sales. QLT Inc. is listed on The NASDAQ Stock Market under the trading symbol "QLTI" and on The Toronto Stock Exchange under the trading symbol "QLT." Certain statements contained in this press release, which are not historical facts, are "forward-looking statements," of QLT within the meaning of the Private Securities Litigation Reform Act of 1995 and constitute "forward-looking information" within the meaning of applicable Canadian securities laws. Such statements include, but are not limited to: our beliefs regarding the potential benefits, targets, market opportunity and commercial success of our synthetic retinoid drug; our expectations regarding our clinical development plans and strategy for the technology and timelines associated with these; and statements which contain language such as "expects," "will", "plans," "estimates," "intends," "believes" and similar expressions that do not relate to historical matters. Forward-looking statements are predictions only which involve known and unknown risks, uncertainties and other factors that may cause our actual results to be materially different from the results expressed or implied by such statements. Many such risks, uncertainties and other factors are taken into account as part of our assumptions underlying these forward-looking statements and include, among others, the following: risks and uncertainties associated with the timing, expense and outcome of research and development programs and commercialization of products (including the difficulty of predicting the timing and outcome of the synthetic retinoid drug development efforts, clinical testing and regulatory approvals or actions); uncertainties regarding the impact of competitive products and pricing; risks and uncertainties associated with the safety and effectiveness of our technology; risks and uncertainties related to the scope, validity, and enforceability of our intellectual property rights and the impact of patents and other intellectual property of third parties; and other factors as described in detail in QLT's Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and other filings with the U.S. Securities and Exchange Commission and Canadian securities regulatory authorities. Forward-looking statements are based on the current expectations of QLT and QLT does not assume any obligation to update such information to reflect later events or developments except as required by law. CONTACT: QLT Inc. Media Contact: Vancouver, Canada, Karen Peterson, Telephone: (604) 707-7000 or 1-800-663-5486, Fax: (604) 707-7001; The Trout Group Investor Relations Contact: New York, USA, Christine Yang, Telephone: (646) 378-2929 or Marcy Strickler Telephone: (646) 378-2927