FAK1

2023年7月12日，中国科学院生物物理研究所薛愿超团队在《Nature》杂志在线发表了题为"Complementary Alu sequences mediate enhancer-promoter selectivity"的研究论文。转录调控在维持细胞功能和正常发育过程中起着关键作用。其中，增强子（enhancer）作为调控基因转录的重要元件，往往需要通过远距离染色质环化与目标启动子（promoter）相互作用，从而决定基因的时空表达特异性。这一过程不仅参与了细胞命运的决定，还在多种疾病的发生发展中扮演着重要角色。增强子能够精确地选择需要激活的目标启动子，以准确调节特定基因的转录时间和转录水平。然而，增强子和启动子配对选择的特异性是如何实现的依然是未解之谜。为了解决这一关键科学问题，薛愿超团队利用实验室之前开发的RNA原位构象测序技术RIC-seq（Nature, 2020），系统捕获了增强子RNA（eRNA）和启动子来源的非编码RNA（uaRNA或 PROMPTs）之间的相互作用，并构建了高分辨率增强子-启动子RNA互作（EPRI）图谱。与传统的染色质构象捕获技术如Hi-C、HiChIP、ChIA-PET等不同，RIC-seq技术可直接鉴定增强子和启动子非编码RNA之间的空间互作位点，并据此推导增强子-启动子的链接网络，因此在解析增强子-启动子互作的序列特征方面具有更高的分辨率。基于EPRI图谱，该研究团队发现增强子与启动子之间的配对选择特异性受到基因组重复序列Alu的调控。Alu序列是哺乳动物尤其是人类基因组中广泛分布的重复元件。研究人员发现，增强子和启动子RNA中的Alu序列充当了增强子-启动子之间相互交流的中介，并通过多种实验证明增强子RNA和启动子RNA中反向互补的Alu序列可通过碱基配对形成RNA双链，从而决定了增强子-启动子的配对选择特异性。这一发现不仅揭示了Alu在基因表达调控中的新机制，还为理解增强子和启动子非编码RNA在转录激活的功能提供了新视角。此外，研究人员通过将非编码区突变映射到增强子-启动子RNA互作（EPRI）图谱，构建了"突变-功能"图谱，系统地注释了非编码突变（尤其是Alu元件的删除和插入）影响的靶标基因，为理解疾病发生提供了宝贵的资源。研究团队进一步发现，位于Alu元件中的突变可能会影响众多蛋白质编码基因的转录，从而对细胞命运产生重要影响。如癌基因PTK2增强子中的多态性Alu元件删除能够显著降低癌细胞增殖和侵袭能力，这为Alu元件突变与癌症易感性之间的关联提供了重要线索。"增强子-启动子互作图谱"以及"突变-功能图谱"构建该研究工作从非编码RNA的角度上揭示了增强子-启动子配对选择特异性的原则，并将非编码风险变异与其分子功能联系了起来，为我们深入理解基因转录调控的分子机制，以及疾病发生发展提供了新范式。该项工作得到了国家重点研发计划、国家自然科学基金委、中科院先导项目和王宽诚教育基金等多项基金资助。中国科学院生物物理所博士后梁良，副研究员曹唱唱、吉蕾，特别研究助理蔡兆奎为本文共同第一作者，薛愿超研究员为唯一通讯作者。河南师范大学硕士研究生王若言和白志博参与了该项研究工作。该研究工作还得到了广东省人民医院朱平教授和河南师范大学杨献光教授的帮助和指导。此外，生物物理所生物成像平台和实验动物平台也为该研究提供了技术支持。文章链接：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41586-023-06323-x会议推荐会议详情会议名称：2023（第14届）细胞与基因治疗国际研讨会暨抗体工程与创新免疫治疗技术论坛暨2023细胞免疫治疗专业委员会年会主办单位：生物谷、梅斯医学、同济大学附属同济医院、南京可缘大会时间：9月22-23日大会地点：上海 大会规模：1500人2010年至今，生物谷联合各合作单位已经顺利召开了13届细胞与基因治疗国际研讨会，与全球致力于细胞治疗行业同仁们一同成长沉淀，在提供行业信息交流平台的同时，也为基础研究提供了技术/产品等产业化的孵化平台。基于此，本届会议将继续以转化医学为切入点，以基础研究与临床应用相结合，针对细胞治疗的临床前沿研究、临床监管、治疗规范、细胞治疗安全性，免疫细胞新型疗法、实体瘤治疗、干细胞与癌症、抗体药物、核酸药物、基因编辑、肿瘤免疫治疗等热门议题进行讨论，诚邀国内外产学研医专家共聚，共绘产业发展新蓝图！长按识别二维码立即报名参会

– Abstracts highlight pipeline programmes in precision oncology, including novel LSD1 inhibitor – – Further detail on A2A programme, including novel biomarker for patient selection to be presented – OXFORD, England--(BUSINESS WIRE)--Exscientia Ltd. (Nasdaq: EXAI) today announced that four abstracts have been accepted for poster presentation at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2023, being held April 14-19, 2023, at the Orange County Convention Center in Orlando, FL. These abstracts highlight the components of Exscientia's approach to precision discovery, design and personalised medicine as well as planned innovation in the clinic. “The clinical and preclinical data showcased at AACR further validate Exscientia's functional precision medicine platform and translational research capabilities,” said Andrew Hopkins, D.Phil, founder and Chief Executive Officer of Exscientia. “These new data demonstrate the potential of integrating outstanding science with cutting-edge AI, to efficiently identify novel targets with the potential for increased probability of clinical success. We also believe that our platform can be used to predict outcomes that help identify cancer patients with high unmet need who may benefit most from treatment. We look forward to advancing these programmes and expanding our pipeline with the goal of developing precision-designed, truly personalised medicines for patients around the world.” Abstracts Accepted for Poster Presentation: Title: Identification of transcript adenosine fingerprint to enrich for A2AR and PD-1 inhibition responders Session Title: Biomarkers of Therapeutic Benefit 2 Abstract Number: #2151 Date/Time: Monday, April 17 / 9:00 AM - 12:30 PM EDT Next generation precision cancer medicine mandates a deep understanding of the disease milieu and drug function to create complex patient selection biomarkers, more than single mutations. To enrich for patients who will most likely respond to EXS21546 (‘546), Exscientia's clinical stage A2AR-selective antagonist targeting the adenosine pathway, Exscientia researchers leveraged a combination of single cell functional and transcriptomics from complex primary patient samples to identify an adenosine-induced immunosuppression biomarker signature (adenosine burden score or ABS). The ABS correlates with checkpoint inhibitor (CI) response prediction to potentially predict patients likely to benefit from combined A2AR antagonism and CI. Here, researchers show that the adenosine burden, as monitored by ABS, is reduced following antagonism of A2AR with ‘546, which in turn restores CI response potential. The ABS is being confirmed retrospectively in the ongoing IGNITE Phase 1/2 clinical study of ‘546 in combination with a PD-1 inhibitor in relapsed/refractory renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). Title: Characterizing antitumor responses to EXS74539, a novel, reversible LSD1 inhibitor with potential in small-cell lung cancer Session Title: Epigenetics Abstract Number: #6290 Date/Time: Wednesday, April 19 / 9:00 AM - 12:30 PM EDT LSD1 is an epigenetic target with critical roles in oncology, notably demethylating histones and other proteins, thereby suppressing the expression of genes required for cellular differentiation. Historically, LSD1 inhibitors in development have been unable to achieve the combination of appropriate pharmacokinetics, good brain penetrance and a reversible mechanism of action. By leveraging generative design algorithms and active learning, Exscientia designed a highly differentiated LSD1 inhibitor, EXS74539 (‘539). ‘539 is a potent, selective and reversible brain-penetrant molecule, combining the potential to treat tumours and metastases in the brain with potential clinical safety benefits through reversible inhibition of LSD1. ‘539 is currently in IND-enabling studies as a potential treatment across oncology and haematology. Preclinical data has shown that ‘539 has potent anti-proliferative activity in in vitro models of small cell lung cancer (SCLC), with anti-tumour activity observed in selected SCLC xenograft tumour-bearing mice. Title: Discovering novel targetable pathways by combining functional and multi-omic data from primary ovarian cancer samples Session Title: Novel Targets and Pathways Abstract Number: #4956 Date/Time: Tuesday, April 18 / 1:30 PM - 5:00 PM EDT Mapping and interpreting single cell functional and multi-omics data at baseline and after perturbation of complex primary model systems reveals a previously unexplored convergent putative target landscape that Exscientia is further validating as potential next-generation anticancer nodes. The high unmet medical need in indications such as high grade serous ovarian cancer (HGSOC) drives a requirement for innovation to uncover novel targets. Standard target discovery processes that often heavily rely upfront on outgrown cell line models with well-averaged readouts have hindered approval rates for drugs entering trials. This study highlights ongoing work using Exscientia's precision medicine platform in combination with proprietary methodology for multi-omics and multi-modal dataset mapping which could have the potential to improve patient outcomes by uncovering clinical relevance at the target discovery stage. Here, researchers report a novel way of uncovering several high confidence convergent putative targets, seemingly overlooked in cell line studies. By mechanistically characterising one such functional sensitivity node, ALK/FAK1/IGF1R, the study reveals tumour necrosis factor (TNF) via the nuclear factor kappa B (NFкB) pathway as a promising focus area for HGSOC via the evaluation of malignant pleural effusion and ascites from patients with late stage ovarian cancer. Title: Data from first-in-human study of EXS21546, an A2A receptor antagonist, now progressing into Phase 1 in RCC/NSCLC Session Title: Phase I Clinical Trials in Progress Abstract Number: #CT114 Date/Time: Monday, April 17 / 1:30 PM - 5:00 PM EDT Pharmacokinetics, pharmacodynamics, safety and tolerability of EXS21546 were confirmed in a healthy volunteer study, allowing selection of a starting dose for the ongoing IGNITE Phase 1/2 study ​​in combination with a PD-1 inhibitor in relapsed/refractory RCC and NSCLC. The IGNITE trial design was based on extensive simulations to enable the most efficient continuous reassessment method settings, and will allow further verification of the patient enrichment biomarker strategy (adenosine burden score or ABS). About Exscientia Exscientia is an AI-driven pharmatech company committed to discovering, designing and developing the best possible drugs in the fastest and most effective manner. Exscientia developed the first-ever functional precision oncology platform to successfully guide treatment selection and improve patient outcomes in a prospective interventional clinical study, as well as to progress AI-designed small molecules into the clinical setting. Our internal pipeline is focused on leveraging our precision medicine platform in oncology, while our partnered pipeline broadens our approach to other therapeutic areas. By pioneering a new approach to medicine creation, we believe the best ideas of science can rapidly become the best medicines for patients. Visit us at or follow us on Twitter @exscientiaAI. Exscientia Forward-Looking Statements This press release contains forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including with respect to Exscientia’s plans to present at AACR, the progress of discovery and development of candidate molecules, and the timing and progress of, and data reported from, pre-clinical studies and clinical trials of Exscientia’s product candidates. Any statement describing Exscientia’s goals, plans, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to a number of risks, uncertainties and assumptions, including those related to: initiation, scope and progress of Exscientia’s and its partners’ planned and ongoing pre-clinical studies and clinical trials and ramifications for the cost thereof; clinical, scientific, regulatory and technical developments; the process of discovering, developing and commercialising product candidates that are safe and effective for use as human therapeutics; and other factors. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section and other sections of Exscientia’s Annual Report on Form 20-F, filed with the Securities and Exchange Commission (SEC) on March 23, 2022 (File No. 001-40850), and other filings that Exscientia makes with the SEC from time to time (which are available at ), the events and circumstances discussed in such forward-looking statements may not occur, and Exscientia’s actual results could differ materially and adversely from those anticipated or implied thereby. Although Exscientia’s forward-looking statements reflect the good faith judgement of its management, these statements are based only on facts and factors currently known by the Company at the time of this press release. As a result, you are cautioned not to rely on these forward-looking statements.