A Phase 1, Open Label, Dose Escalation, Dose Expansion, Multicenter, First in Human Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of Oral AUR107 in Patients With Relapsed Advanced Malignancies (SHAKTI-1)

An open-label, first-in-human, Phase 1 study in adult patients with relapsed advanced malignancies will be done to assess AUR107 safety, tolerability, pharmacokinetics, pharmacodynamics, and optimal biological dose.

开始日期2023-09-05

申办/合作机构

Aurigene Oncology Ltd.

CTRI/2023/05/052954

/ Recruiting临床1期

A Phase 1, Open Label, Dose Escalation, Dose Expansion, Multicenter, First in Human (FIH) Study Evaluating the Safety, Pharmacokinetics and Pharmacodynamics of Oral AUR107 in Patients with Relapsed Advanced Malignancies (SHAKTI-1) - SHAKTI-1

开始日期2023-06-12

申办/合作机构

Aurigene Oncology Ltd.

100 项与 EP300 x CREBBP 相关的临床结果

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100 项与 EP300 x CREBBP 相关的转化医学

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0 项与 EP300 x CREBBP 相关的专利（医药）

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项与 EP300 x CREBBP 相关的文献（医药）

2025-04-01·Obesity Research & Clinical Practice

Impact of fish oil on epigenetic regulation in perirenal adipose tissue of obese mice

Article

作者: Alonso-Vale, Maria Isabel ; de Jesus Simão, Jussara ; Plata, Victor Tadeu Gonçalves ; de Sousa, Andressa França Bispo ; Armelin-Correa, Lucia

It has been demonstrated that fish oil (FO), a source of omega-3 polyunsaturated fatty acids (n-3 PUFA), offers partial protection to mice from the adverse effects of a high-fat diet (HFD) by altering the expression of genes involved in adipogenesis and adipocyte metabolism. Histone 3 lysine 27 (H3K27) modifiers, namely Ezh2, Kdm6a, Kdm6b, Crebbp and Ep300, are vital for the appropriate differentiation and metabolism of adipocytes, as they can either silence or activate transcription. The expansion of perirenal adipose tissue (AT) in obesity is associated with a number of complications, including hypertension and kidney disease. The aim of this study was to assess the expression of H3K27 modifiers and genes involved in adipogenesis and adipocyte metabolism in perirenal AT of HFD-fed and FO-treated (5DHA:1EPA) mice using real-time PCR. This study demonstrates, for the first time, that a high-fat diet (HFD) increases the expression of Kdm6b (H3K27 demethylase) in perirenal AT, and that treatment with FO can completely reverse this effect. Conversely, the expression of the Acly gene, which encodes an enzyme that provides a substrate for histone acetylases, was found to be reduced in HFD-fed mice and this was not reversed by FO treatment. Additionally, transcription factor genes, such as Tbx1, exhibited diminished expression in perirenal AT of mice fed an HFD. These observations suggest that a HFD affects the expression of chromatin modifiers, transcription factors, and metabolic genes in perirenal AT, and that FO can reverse some of these effects, offering a promising avenue for the treatment of obesity.

2025-04-01·International Journal of Surgical Pathology

High-Grade Appendiceal Mucinous Neoplasm Mimicking Appendiceal Tubulovillous Adenoma: A Case Report and Literature Review

Review

作者: Zhang, Shuhong ; Liu, Weihua ; Chen, Guangyong ; Shao, Huilin

High-grade appendiceal mucinous neoplasm (HAMN) has been separated from appendiceal adenocarcinoma recently as an independent entity and categorized into appendiceal mucinous neoplasms. These neoplasms demonstrate distinct histological characteristics, including architectures and appendiceal mural changes similar to low-grade appendiceal mucinous neoplasm but with high-grade cytology, and no infiltrative invasion. Overt mucinous feature are not evident in some cases as the high-grade neoplastic epithelium may show intracytoplasmic mucin reduction. Occasionally, the neoplastic epithelial cells show florid proliferation and tubulovillous configuration and may be misdiagnosed as appendiceal tubulovillous adenoma. We report the case of a 67-year-old woman with appendicular dilatation and luminal mucin. She underwent an ileocecoectomy. The appendiceal lesion was found histologically to be a HAMN, which closely resembled appendiceal tubulovillous adenoma. The tumor cells demonstrated wild-type p53 expression and mismatch repair proficiency by immunochemistry. Molecular testing showed 1 KRAS mutation, 2 PIK3CA mutations, and 1 BRCA2 , EP300 , TGFBR2 , CHD4 , CREBBP , FANCC , PKHD1 mutation each in the tumor. The patient was followed up for 1 year with no evidence of disease.

2025-03-01·Clinical Genetics

Skipping of Exon 20 in EP300: A Novel Variant Linked to Rubinstein–Taybi Syndrome With Atypical and Severe Clinical Manifestations

Article

作者: Rzasa, Jessica ; Sadikovic, Bekim ; Balzo, Maria ; De Sanctis, Luisa ; Trajkova, Slavica ; Ferrero, Giovanni Battista ; Sorasio, Lorena ; Mantovani, Giovanna ; Buxbaum, Joseph D. ; McConkey, Haley ; Todd, Emily ; Brusco, Alfredo ; Cardaropoli, Simona ; Pavinato, Lisa ; Tartaglia, Marco ; De Rubeis, Silvia ; Bruselles, Alessandro ; Kerkhof, Jennifer ; Carestiato, Silvia

ABSTRACTRubinstein–Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder linked to haploinsufficiency of CREBBP (RSTS1) and EP300 (RSTS2) genes. Characteristic features often include distinctive facial traits, broad thumbs and toes, short stature, and various degrees of intellectual disability. The clinical presentation of RSTS is notably variable, making it challenging to establish a clear genotype–phenotype correlation, except for specific variants which cause the allelic Menke–Hennekam syndrome. Trio exome analysis, data collection via networking and GeneMatcher platforms, transcript processing analysis, and DNA methylation profiling were performed. We identified two unrelated patients with de novo variants in EP300 (NM_001429.4: c.3671+5G>C; c.3671+5_3671+8delGTAA) predicted to cause in‐frame exon 20 skipping, confirmed in one patient. In silico 3D protein modeling suggested that exon 20 deletion (comprising 27 amino acids) likely alters the structural conformation between the RING_CBP‐p300 and HAT‐KAT11 domains. Clinically, both patients displayed severe RSTS2‐like clinical features, including autism spectrum disorder, speech delay, hearing loss, microcephaly, developmental delay, and intellectual disability, alongside ocular, respiratory, and cardiovascular abnormalities. Additionally, one patient developed early‐onset colorectal cancer. DNA methylation profiling in Subject #1 confirmed RSTS but did not align with the specific episignatures for RSTS1 or RSTS2. We propose that skipping of exon 20 in EP300 is associated with a distinct form of Rubinstein–Taybi syndrome featuring clinical characteristics not fully aligning with RSTS1 or RSTS2. Our findings increase the understanding of RSTS genetic and molecular basis and stress the need for further research to establish definitive genotype–phenotype correlations.

项与 EP300 x CREBBP 相关的新闻（医药）

2025-03-20

·GlobeNewswire-Health Care

Pathos AI Doses First Patient in Phase 1b/2a Clinical Trial of Pocenbrodib, a CBP/p300 Inhibitor

CHICAGO, March 20, 2025 (GLOBE NEWSWIRE) -- Pathos AI, (www.pathos.com), a clinical-stage biotechnology company focused on re-engineering drug development through artificial intelligence, announced the first patient has been dosed in the Company’s Phase 1b/2a clinical trial evaluating pocenbrodib, a CBP/p300 inhibitor, alone and in combination with abiraterone acetate, olaparib or 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC), (P300-02-001, NCT06785636). Pocenbrodib is Pathos’ first clinical-stage asset in its pipeline. "The clinical promise of pocenbrodib, our potential best-in-class CBP/p300 inhibitor, lies not only in its remarkable efficacy in resistant prostate cancer models, but also in our sophisticated biomarker strategy that identifies patients most likely to benefit," said Dr. Jens Renstrup, Chief Medical Officer. "Our precision medicine approach allows us to target the underlying resistance mechanisms to AR-targeted therapy through CBP/p300 inhibition, addressing a significant area of high unmet need for patients with advanced prostate cancer. By integrating multiomic data tied to real-world outcomes to identify specific molecular signatures, our PathOS™ platform enables us to select the right patients for treatment, potentially improving outcomes in a disease with limited therapeutic options as resistance develops. This study builds on the previously reported data from COURAGE study (NCT04575766) in metastatic castration-resistant prostate cancer and reinforces our confidence in pocenbrodib's potential to improve outcomes for these patients." Study P300-02-001 is a multicenter, open-label, dose-finding Phase 1b/2a clinical trial to confirm the safety, pharmacokinetics (PK), preliminary antitumor activity, and pharmacodynamics (PD) of pocenbrodib alone or in combination with abiraterone acetate, olaparib or 177Lu-PSMA-617, in adults with metastatic castration-resistant prostate cancer (mCRPC). The study is expected to enroll approximately 203 patients with mCRPC who have progressed despite prior therapy and have been treated with at least one anti-androgen therapy (enzalutamide, apalutamide, abiraterone acetate, or darolutamide). The primary objectives of the study are to assess the safety, objective response rate, and PSA decline of pocenbrodib alone and in combination with abiraterone acetate, olaparib or 177Lu-PSMA-617, and to define a preliminary recommended Phase 2 dose (RP2D) of pocenbrodib in combination with abiraterone acetate, olaparib or 177Lu-PSMA-617. About pocenbrodibPocenbrodib is an oral, small molecule inhibitor that has the potential to provide clinical benefit for patients with advanced prostate cancer, either alone or in combination with other treatments. Pocenbrodib works by inhibiting CREBBP/EP300 (also known as CBP/p300), which are proteins that activate genes that promote cancer cell growth and proliferation. Inhibiting these proteins impacts the expression of key cancer drivers, including the androgen receptor (AR) and its variants, making pocenbrodib relevant not only to advanced prostate cancer, but also to other cancer indications, either alone or in combination with other treatments. About Pathos AIPathos is a clinical-stage biotechnology company powered by advanced AI that is re-engineering drug development by optimizing patient selection strategies in phase 2 clinical trials. Through partnerships with pharmaceutical companies, Pathos leverages AI-driven computational approaches across multimodal real-world data and patient-derived biological models to accelerate precision medicine development. Pathos has raised over $100 million to expand its AI platform and bring targeted treatments to patients faster. Additional information can be found at www.pathos.com. ContactsBusiness Development: bd@pathos.comPress Inquiries: press@pathos.com

临床2期

2025-01-24

·ioncology

许彭鹏教授：外周T细胞淋巴瘤发病机制与精准治疗新进展丨2025年CSCO血液肿瘤学术大会

点击蓝字关注我们编者按 2025年1月17日至19日，中国临床肿瘤学会（CSCO）白血病、淋巴瘤及骨髓瘤专家委员会工作会议暨2025年CSCO血液肿瘤学术大会在海口召开。会议现场，《肿瘤瞭望-血液时讯》特邀上海交通大学医学院附属瑞金医院许彭鹏教授，就外周T细胞淋巴瘤的发病机制、精准治疗策略以及未来研究方向进行了深入的分享与探讨。 01 《肿瘤瞭望-血液时讯》外周T细胞淋巴瘤在血液系统恶性肿瘤中具有独特的发病特点，其发病率相对较低但侵袭性较强，严重影响患者的生活质量与预后。您能否详细阐述一下目前研究发现的主要发病机制，以及这些机制对我们理解该疾病的发展进程有何重要意义呢？许彭鹏教授：实际上，外周T细胞淋巴瘤（PTCL）的发病机制颇为错综复杂，涵盖了表观遗传学以及免疫微环境等变化，这些因素协同作用，共同塑造了PTCL的高度异质性特征。从病理学的角度细分，PTCL可被进一步划分为众多具有独特性的亚型。尤为重要的是，各病理亚型的患者往往伴随着各不相同的信号通路异常及发病机制的特异性变化。鉴于此，针对外周T细胞淋巴瘤患者的治疗策略，未来极有可能会依据其个体化的发病机制进行精准定制。这标志着治疗方式的重大转变，不再局限于当前普遍采用的如CHOP（环磷酰胺、阿霉素、长春新碱、泼尼松）等标准化治疗方案。随着我们对PTCL发病机制认知的不断深化，治疗方案势必会逐步得到革新与优化，以期为患者提供更加精准有效的治疗途径。 02 《肿瘤瞭望-血液时讯》外周T细胞淋巴瘤由于其异质性，在诊断和治疗方面都面临诸多挑战。您在讲座中着重探讨了靶向治疗探索，在当下靶向治疗药物不断涌现的背景下，针对外周 T 细胞淋巴瘤，目前有哪些具有潜力的靶向治疗靶点被发现，它们为治疗该疾病带来了哪些新的希望和突破？许彭鹏教授：此前，我们团队开展了一项开放标签、多中心、Ⅱ期GUIDANCE-03研究，旨在评估靶向药物联合经典CHOP方案作为外周T细胞淋巴瘤初诊患者一线治疗方案的疗效及安全性概况。鉴于不同基因突变患者体内信号传导通路及免疫微环境各异，该研究依据患者特有的基因突变情况（TP53、TET2、CREBBP/EP300及KMT2D等），个性化地引入了不同靶向药物进行联合治疗。在深入探索针对不同亚型患者的联合治疗方案时，我们初步见证了CHOP-X方案在疗效方面的显著提升。相较于传统的CHOP治疗方案，CHOP-X策略为患者提供了无进展生存期（PFS）上的额外优势，这一积极趋势预示着有可能转化为总生存期（OS）的延长，从而为患者预后带来积极影响。展望未来，随着我们对PTCL这一复杂疾病理解的日益深化，期待能够持续优化针对不同分子亚型的靶向治疗方案。有理由相信，通过实施这些精细化的治疗策略，将有望进一步提升高危、难治性PTCL患者的治疗效果，为患者群体带来更为显著且持久的生存获益。 03 《肿瘤瞭望-血液时讯》您在讲座中强调了深入研究外周 T 细胞淋巴瘤发病机制对于精准治疗的重要性。鉴于目前临床实践中，传统治疗方法对外周 T 细胞淋巴瘤的疗效存在一定局限性，那么基于对发病机制的了解，我们在靶向治疗药物的研发和应用方向上，未来应如何更好地优化和创新，以提高患者的生存率和生活质量？许彭鹏教授：在针对某一疾病的药物研发过程中，首要且关键的步骤在于对其发病机制的深刻理解和透彻洞察。唯有当我们对疾病的本质有了更为全面和深入的认识，才有望研发出更加精准的治疗药物。近年来，外周T细胞淋巴瘤的靶向药物研发领域取得了令人瞩目的显著进展。这些进步不仅体现在对传统药物的改良和优化上，更体现在一系列新型药物的涌现上，如表观遗传学药物、JAK抑制剂等。这些创新药物已逐步融入临床实践，并取得了令人欣慰的良好疗效。展望未来，随着细胞免疫治疗技术，特别是CAR-T治疗等领域的不断成熟和完善，以及我们对PTCL靶点认知的持续深化，有理由相信这些新兴的治疗方式将为患者带来更多治疗希望。它们不仅可能超越传统治疗手段，实现更为优越的治疗效果，还可能为PTCL患者开辟全新的治疗路径，从而显著改善患者的预后，为他们的生活质量带来实质性的提升。（来源：《肿瘤瞭望–血液时讯》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

CSCO会议

2024-06-01

·医药观澜

徐诺药业公布「艾贝司他」中国注册2期临床数据 | ASCO

▎药明康德内容团队报道5月31日，徐诺药业宣布，该公司将在2024年美国临床肿瘤学会（ASCO）年会上以壁报形式公布其研发管线艾贝司他治疗滤泡性淋巴瘤中国注册2期临床主要终点首次分析数据。在该研究中，艾贝司他显示了良好的客观缓解率和良好的总体耐受性。表观遗传改变（包括CREBBP或EP300突变等）是滤泡性淋巴瘤的主要驱动因素。组蛋白脱乙酰酶（HDAC）抑制剂有可能抵消CREBBP或EP300突变导致的组蛋白乙酰化缺失。艾贝司他是一种新型有效的口服泛HDAC抑制剂，允许通过每日两次（BID）给药维持足够的药物浓度以发挥抗肿瘤活性。本次在ASCO上公布的是中国注册2期研究，旨在评估艾贝司他治疗复发/难治性滤泡性淋巴瘤患者的疗效和安全性。截至2023年12月15日，有90例患者的数据可分析。在82例具有12周可评估疗效的患者中，IRC评估的客观缓解率（ORR）为67.1%，包括12.2%的完全缓解（CR）。既往治疗大于3线的患者的ORR为69.0%。中位无进展生存期（PFS）为13.77个月，中位缓解持续时间（DoR）为13.96个月。中位总生存期（OS）数据尚未成熟，42个月OS率为74.3%。该项研究结论：艾贝司他单药80mg每日两次治疗耐受性良好，在多线治疗后复发/难治性滤泡性淋巴瘤患者中表现出显著的疗效。徐诺药业专注于肿瘤药物开发，目前的产品管线主要包括3款候选药物，艾贝司他、XP-105和XP-102。其中，艾贝司他主要用于治疗淋巴瘤和肾癌。XP-105是一款ATP竞争性的mTORC1/2抑制剂，对多种实体瘤有效，目前处于临床2期阶段。XP-102是一款泛-RAF抑制剂，目前在临床1期阶段，主要用于治疗结直肠癌和肺癌。参考资料[1]2024 ASCO｜徐诺药业向全球发布艾贝司他治疗滤泡性淋巴瘤中国注册2期主要终点首次分析数据. Retrieved May 31 , 2024, from https://mp.weixin.qq.com/s/VnT8HFa00Heh7Q3bUpueMw本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

ASCO会议临床结果临床2期临床1期