Hepatocellular Malignant Neoplasm, NOS

Emeryville, California, April 2nd, 2024 – Eureka Therapeutics, Inc., a clinical-stage biotechnology company developing novel T-cell therapies to treat cancer, today announced the activation of UCSF Benioff Children’s Hospitals as the first California site to join the ARYA-2 clinical trial (NCT04634357). The ARYA-2 trial is evaluating Eureka’s investigational ARTEMIS® ET140203 T-cell therapy which targets the alpha-fetoprotein (AFP)-peptide/HLA-A2 complex. This therapy is designed to treat pediatric subjects (1 to 21 years) with relapsed or refractory liver cancer, including hepatoblastoma (HB), hepatocellular neoplasm not otherwise specified (HCN-NOS), and hepatocellular carcinoma (HCC). “Multiply relapsed or refractory liver cancers in children and adolescents are highly complex and lack effective treatment options, especially given the rarity of these conditions,” said Dr. Arun Rangaswami, MD, Professor of Clinical Pediatrics and a senior solid tumor faculty member at UCSF. “We are excited to collaborate with Eureka to bring the promise of next-generation engineered T-cell therapy to this pediatric population with high unmet medical needs.” “We are proud to contribute to the collaborative effort aimed at developing cutting edge therapies for treating pediatric cancer ,” said Dr. Abla Creasey, PhD, Vice President of Therapeutics Development, at the California Institute for Regenerative Medicine (CIRM). “Our recent $10.6 million grant towards Eureka’s ARYA-2 program underscores our commitment to improving the lives of young patients battling cancer.” “Our ARTEMIS T-cells are designed to overcome challenges in safely and effectively treating solid tumors,” said Dr. Cheng Liu, President and CEO of Eureka Therapeutics. “UCSF’s participation significantly accelerates progress in bringing this potentially life-saving therapy to young patients with liver cancer.” This expansion builds upon Eureka’s ongoing efforts with the ARYA-2 trial, which is also actively recruiting patients at the Dana-Farber Cancer Institute. For more information on the ARYA-2 trial, Eureka’s T-cell therapy platform, and the potential of this treatment, please visit eurekaconnectme.com. ABOUT EUREKA THERAPEUTICS, INC. Eureka Therapeutics, Inc. is a privately held clinical-stage biotechnology company focused on developing novel T-cell therapies to treat cancers. Its core technology centers around its proprietary ARTEMIS® cell receptor platform and E-ALPHA® antibody discovery platform for the discovery and development of potentially safer and more effective T-cell therapies for the treatment of solid tumors and hematologic malignancies. The company currently has two clinical programs, ET140203 (ARYA-1 for adults and ARYA-2 for pediatrics) and ECT204 (ARYA-3), in Phase I/II US trials in patients with advanced liver cancer. Eureka Therapeutics, Inc. is headquartered in the San Francisco Bay Area. For more information on Eureka, please visit www.eurekatherapeutics.com. ARTEMIS and E-ALPHA are registered trademarks owned by Eureka. About the California Institute for Regenerative Medicine (CIRM) At CIRM, we never forget that we were created by the people of California to accelerate stem cell treatments to patients with unmet medical needs, and act with a sense of urgency to succeed in that mission. To meet this challenge, our team of highly trained and experienced professionals actively partners with both academia and industry in a hands-on, entrepreneurial environment to fast track the development of today’s most promising stem cell technologies. With $5.5 billion in funding and more than 150 active stem cell programs in our portfolio, CIRM is one of the world’s largest institutions dedicated to helping people by bringing the future of cellular medicine closer to reality. For more information go to www.cirm.ca.gov CONTACTS: Eureka Therapeutics, Inc. Natalie Liu Investor Relations 510-318-9215 IR@eurekainc.com

EMERYVILLE, Calif.--(BUSINESS WIRE)-- Eureka Therapeutics, Inc., a clinical-stage biotechnology company developing novel T-cell therapies to treat cancer, today announced the activation of UCSF Benioff Children’s Hospitals as the first California site to join the ARYA-2 clinical trial (NCT04634357). The ARYA-2 trial is evaluating Eureka’s investigational ARTEMIS® ET140203 T-cell therapy which targets the alpha-fetoprotein (AFP)-peptide/HLA-A2 complex. This therapy is designed to treat pediatric subjects (1 to 21 years) with relapsed or refractory liver cancer, including hepatoblastoma (HB), hepatocellular neoplasm not otherwise specified (HCN-NOS), and hepatocellular carcinoma (HCC). “Multiply relapsed or refractory liver cancers in children and adolescents are highly complex and lack effective treatment options, especially given the rarity of these conditions,” said Dr. Arun Rangaswami, MD, Professor of Clinical Pediatrics and a senior solid tumor faculty member at UCSF. “We are excited to collaborate with Eureka to bring the promise of next-generation engineered T-cell therapy to this pediatric population with high unmet medical needs.” “We are proud to contribute to the collaborative effort aimed at developing cutting edge therapies for treating pediatric cancer,” said Dr. Abla Creasey, PhD, Vice President of Therapeutics Development, at the California Institute for Regenerative Medicine (CIRM). “Our recent $10.6 million grant towards Eureka’s ARYA-2 program underscores our commitment to improving the lives of young patients battling cancer.” “Our ARTEMIS T-cells are designed to overcome challenges in safely and effectively treating solid tumors,” said Dr. Cheng Liu, President and CEO of Eureka Therapeutics. “UCSF’s participation significantly accelerates progress in bringing this potentially life-saving therapy to young patients with liver cancer.” This expansion builds upon Eureka’s ongoing efforts with the ARYA-2 trial, which is also actively recruiting patients at the Dana-Farber Cancer Institute. For more information on the ARYA-2 trial, Eureka’s T-cell therapy platform, and the potential of this treatment, please visit eurekaconnectme.com. ABOUT EUREKA THERAPEUTICS, INC. Eureka Therapeutics, Inc. is a privately held clinical-stage biotechnology company focused on developing novel T-cell therapies to treat cancers. Its core technology centers around its proprietary ARTEMIS® cell receptor platform and E-ALPHA® antibody discovery platform for the discovery and development of potentially safer and more effective T-cell therapies for the treatment of solid tumors and hematologic malignancies. The company currently has two clinical programs, ET140203 (ARYA-1 for adults and ARYA-2 for pediatrics) and ECT204 (ARYA-3), in Phase I/II US trials in patients with advanced liver cancer. Eureka Therapeutics, Inc. is headquartered in the San Francisco Bay Area. For more information on Eureka, please visit . ARTEMIS and E-ALPHA are registered trademarks owned by Eureka. About the California Institute for Regenerative Medicine (CIRM) At CIRM, we never forget that we were created by the people of California to accelerate stem cell treatments to patients with unmet medical needs, and act with a sense of urgency to succeed in that mission. To meet this challenge, our team of highly trained and experienced professionals actively partners with both academia and industry in a hands-on, entrepreneurial environment to fast track the development of today’s most promising stem cell technologies. With $5.5 billion in funding and more than 150 active stem cell programs in our portfolio, CIRM is one of the world’s largest institutions dedicated to helping people by bringing the future of cellular medicine closer to reality. For more information go to

PI3K通路是肿瘤经典通路，科学家几十年来对PI3K的研究非常多，但目前获批上市的肿瘤药物却屈指可数，已经上市的药物市场表现也一般般。2022年1月，上市六年的PI3Kδ抑制剂idelalisib被吉利德撤出市场，紧跟着，Incyte也宣布撤回PI3Kδ抑制剂Parsaclisib的IND。与其市场表现相关，PI3K抑制剂受到药物耐受性差、内在耐药性和获得性耐药性以及中和 PI3K 抑制的信号反馈回路的阻碍，这或许和PI3K靶点的特性以及药物的结构及特性有密不可分的关系。    PI3K PI3K是一组质膜相关脂质激酶，由三个亚基组成：p85调节亚基、p55调节亚基和p110催化亚基。根据其不同的结构和特定的基材，PI3K分为3类：I类，II类和III类，Ⅰ型型PI3K 与肿瘤细胞生长关系最为密切，具有PI3Kα、PI3Kβ、PI3Kδ和PI3Kγ、4种关键亚型。 PI3Kα 是PI3K家族中作为癌症治疗的主要靶点，它的高表达与结肠癌、乳腺癌、前列腺癌、胃癌、直肠癌、卵巢癌等肿瘤的发生发展密切相关。PI3Kβ在磷酸酶-张力蛋白基因( PTEN) 缺失的癌症患者中发挥着重要作用。PI3Kδ 只限表达于白细胞中，是治疗血液恶性肿瘤和白血病的关键靶标，而PI3Kγ在骨髓细胞中起着更重要的作用。 PI3K通过PI3K-AKT-MTOR通路来影响一系列的下游通道。磷脂酰肌醇-3-激酶（PI3K）/AKT/哺乳动物雷帕霉素（mTOR）信号传导靶标是最重要的细胞内途径之一，可调节细胞生长、存活、代谢和血管生成。 PI3K/AKT/mTOR通路在几乎所有人类癌症（如乳腺癌、结直肠癌和血液系统恶性肿瘤）中都失调，PI3K/AKT/mTOR通路的激活通过多种机制促进肿瘤的发展，使抗癌治疗产生耐药性。 1、 肿瘤抑制因子PTEN的丧失或失活 PTEN是PI3K途径的负调节剂，通过PIP3的去磷酸化作为PI3K作用的直接拮抗剂 2、 PI3K的突变或扩增 在癌症中最常见的突变或扩增是编码p110α亚基的基因，PI3KCA（磷脂酰肌醇3-激酶，催化，α多肽）。突变主要有以下几种类型：螺旋磷脂酰肌醇激酶同源结构域中的E545K（外显子9）突变，其降低调节亚基p85对p110α的抑制。H1047（外显子20）突变，H1047靠近催化结构域的末端，这增加了p110α与脂质膜的相互作用。E542K突变。 3、 PI3K上游酪氨酸激酶生长因子受体（如HER2，IGF-1），细胞粘附分子（如整合素，GPCR）或癌基因的激活。    全球药物研发现状 目前全球共研发了300多款PI3K药物，仅有5款药物上市，2款提交上市申请，59款处于临床阶段，65款处于临床前研究，23款处于药物发现阶段，138款终止研究或无研究进展。 已上市或提交上市申请的PI3K药物   PI3K抑制剂 大多数 PI3K 抑制剂为ATP竞争性抑制剂。PI3K各亚型之间的ATP结合位点几乎相同，ATP结合口袋位于激酶结构域的两个裂片之间的裂隙中，裂隙末端有一个铰链缬氨酸残基（如下图所示）。该缬氨酸在所有I类PI3K同种型中的结合位点几乎相似，并与ATP的嘌呤环形成H键。因此，迄今为止确定的所有ATP竞争性PI3K抑制剂都接受来自该缬氨酸残基的H键。 并且PI3K抑制剂对肿瘤细胞具有细胞抑制作用而不是杀灭作用，它们作为单一药物的细胞内在影响主要导致肿瘤稳定，而不是消退。 PI3K抑制剂按功能分为以下几种： 1、泛PI3K抑制剂：非选择性 PI3K 抑制剂同时作用于 α、β、δ、γ 四个亚型，非选择性 PI3K 抑制剂可能会因抑制了 4 个亚型更加有效；但也存在选择性低、易脱靶，同时抑制四个亚型时需较高剂量，患者可能不耐受以及会产生较多不良反应。 copanlisib 2017年，静脉注射的泛I类PI3K抑制剂copanlisib（拜耳）被批准用于复发性FL的成年患者。 2、异构体特异性PI3K抑制剂：异构体特异性PI3K 抑制剂是选择性抑制 p110α、p110β、p110δ 或 p110γ 催化亚基的药物。即PI3Kα抑制剂、PI3Kδ抑制剂、PI3Kγ抑制剂；相比泛PI3K抑制剂。高选择性的抑制剂的脱靶毒性更小，因此受到更多公司的青睐。 PI3Kα抑制剂 Alpelisib是FDA批准的第一个PI3Kα抑制剂，用于乳腺癌治疗。Alpelisib的PI3Kα选择性及其药代动力学在乳腺癌试验中成功验证，FDA在2019年批准了该药物。 然该药是PI3Kα特异性药物，但却有严重的浓度依赖性副作用和耐药性。主要原因是该药物和以前开发的药物一样，都是ATP竞争性的，而PI3K各亚型之间的ATP结合位点几乎相同，当给药浓度增加，不可避免地对其它亚型产生抑制作用。 PI3Kδ抑制剂 Idelalisib是第一款PI3Kδ抑制剂，于 2014 年获批用于治疗 CLL、复发性 FL 和复发性小淋巴细胞淋巴瘤（SLL）。 Idelalisib单药的加速批准是基于一个单臂、多中心、开放标签的积极II期临床结果。该临床实验招募了123位复发性的“惰性”非霍奇金淋巴瘤（iNHL）和小淋巴细胞淋巴瘤（SLL）患者。病人每天接受两次，每次150毫克idelalisib治疗，一级实验终点是总应答率（ORR），二级实验终点是应答时间和无进展生存期。其中FL和SLL患者的总应答率分别为54%和58%。后者应答时间的中位数为11.9个月。这个结果和标准疗法的通常疗效相比相当或更好。 Linperlisib Linperlisib是江苏恒瑞医药股份有限公司和上海璎黎药业有限公司联合研发的一款PI3Kδ抑制剂。 在Linperlisib与Gemox联合治疗复发和/或难治性弥漫性大B细胞淋巴瘤的单臂1b/2期试验中，Linperlisib与GEMOX联合使用耐受性良好。总体反应率为60%（21/35），其中5人达到完全反应（CR，14%），16人达到部分反应（PR，46%），疾病控制率为71%（DCR），中位反应时间为36天。中位无进展生存期为193天，未达到中位反应持续时间，研究中仍有17个可评估点（48.6%）。治疗相关不良事件（TRAE）发生率为39%，其中大多数是1级或2级（83.9%）。不良反应发生率较低。 PI3Kδ抑制剂的毒性可能来源于：PI3Kγ 和/或 p110β 的不完全 PI3K 异构体选择性、药物降解导致代谢物具有的肝毒性、使用可能不需要干扰肿瘤的最大耐受剂量——间质相互作用或免疫调节。 3、PI3K双亚型抑制剂：PI3Kδ/α抑制剂、PI3Kδ/γ抑制剂、PI3Kα/β duvelisib（Verastem）是一款口服双PI3Kγ / PI3Kδ抑制剂，FDA于2018年批准其用于复发或难治性CLL或SLL的成年患者以及复发性FL患者。 I期临床中，惰性非霍奇金淋巴瘤（iNHL）总体反应率，58%（n = 31）和6个完全反应（CR）;复发/难治性 慢性淋巴细胞白血病（CLL）， 56% （n = 55）， 1 CR;外周T细胞淋巴瘤（TCL），50%（n = 16），3 CR;和皮肤TCL，32%（n = 19）。中位反应时间为∼1.8个月。84%的患者发生了严重（≥3级）不良事件。 III期临床在duvelisib组中，使用研究者反应评估确定的中位PFS明显长于IRC评估的PFS（17.6个月对13.3个月），duvelisib的总体反应率显著更高（74%对45%;P < .0001）。 4、PI3K多靶点抑制剂 PI3K/mTOR、PI3K/HDAC、PI3K/AKT/mTOR、PDGFR/PI3K/EGFR/VEGFR2等抑制剂。 PI3K/mTOR 双重抑制剂对 PI3K 与 mTOR 均具有抑制作用。PI3K 单抑制剂会产生耐药性，使用 Akt 抑制剂虽然可阻断 PI3K/mTOR 信号通路，但会造成糖代谢失衡；而 mTOR 可反馈作用于 PI3K，所以 PI3K/mTOR 双重抑制剂可减少耐药性的发生同时不会造成糖代谢失衡。 Umbralisib是一种双 PI3Kδ/CK1ε 抑制剂。2020年，FDA授予umbralisib（PI3Kδ，CSNK1E靶点）与用于CLL的研究性CD20定向单克隆抗体ublituximab联合使用的快速通道指定，并且在2021年，FDA批准了umbralisib用于边缘区（MZ）淋巴瘤和FL的加速批准。  批准基于UTX-TGR-205（NCT02793583）的两个单臂试验。对于MZL患者，ORR为49%（95%CI：37.0，61.6），16%达到完全缓解。这些患者的中位DOR未达到（95% CI：9.3，NE）。对于FL患者，ORR为43%（95%CI：33.6，52.2），3%达到完全缓解。中位DOR为11.1个月（8.3，16.4）。3级及以上AE发生率为53.4%。 与idelalisib和duvelisib相比， umbralisib的不良反应率更低，可能有以下几方面原因：（1） 高选择性：相对PI3Kα和PI3Kβ，umbralisib对PI3Kδ的选择性更高，比PI3Kγ具有大约225倍的选择性;（2）与大多数其他激酶抑制剂不同，umbralisib不通过经典的细胞色素P450 3A4（CYP3A4）代谢途径代谢，毒性更低。（3）耐受度提高： 通过抑制CK1-ε（酪蛋白激酶1ε），防止扰乱调节性T细胞的功能，从而提高药物的耐受性。PI3K inhibitors are finally coming of age。    PI3K药物新策略 PI3K降解剂 蛋白水解靶向嵌合体 (PROTACs) 是一种异双功能小分子，由两个通过接头连接的募集配体组成。一个配体与感兴趣的蛋白质 (POI) 特异性结合，另一个配体与 E3连接酶连接 。PROTAC 通过将 POI 劫持到 E3 连接酶来运行降解过程，促进 POI 的泛素化，进一步导致 POI 通过泛素-蛋白酶体系统 (UPS) 减少。PROTACs 作为靶向蛋白质降解的一种手段是一种新兴且强大的癌症治疗方式，并已成功应用于PI3K降解剂的开发。 改善耐药策略 1、 结合PI3Kα正立构和变构药物变构药物 可以通过改变 ATP 结合位点并使其重新敏感来克服 PI3Kα 耐药性，即使其可接近空间阻断的 ATP 竞争性正构药物，或通过产生改变的、可成药的 PIP2 结合位点。 2、 抢救突变位置的变构药物 变构药物可以构成“锚”和“司机”。锚对接到一个变构口袋中，该口袋在非活动状态和活动状态之间的过渡期间构象保持不变。驱动因素“拉动”和/或“推动”蛋白质原子（侧链或骨架），并触发受体群体向药物结合有利的状态转移。 药物联用扩大治疗范围 口服可用的 parsaclisib (Incyte)  正在针对 B 细胞恶性肿瘤进行多项试验，并与抗 PD1 抗体联合用于一系列晚期实体瘤适应症 (NCT02646748, NCT03589651)目前已经完成试验，但还未透露试验结果。    小结 PI3K泛抑制剂和特异性抑制剂有不少硬伤，使其难以在肿瘤药市场大放异彩。PI3K抑制剂对肿瘤细胞是抑制作用而不是杀灭作用，不能完全消灭肿瘤。药物代谢产物产生毒性，耐受度低。抑制剂靶点选择性不够强，PI3K单抑制剂药物容易产生耐药。但或许可以通过改变给药途径，与其他药物联用，设计药物结构加强药物的安全性和靶点选择性，提高其耐药性，使其更好的融入市场。 参考来源： [1] PI3K inhibitors are finally coming of age. [2] Development of PI3K inhibitors: Advances in clinical trials and new strategies (Review)   | com. [3] PI3K inhibitors: review and new strategies. [4] Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma. [5] Targeting PI3K in cancer: mechanisms and advances in clinical trials. [6] 特异性PI3K亚型抑制剂抗肿瘤作用研究进展. [7] PI3K 选择性抑制剂作用机制的分子模拟研究. 内容来源于网络，如有侵权，请联系删除，谢谢。