A Phase II, Open-label, Single-arm Study of NEoadjuvant Zanzalintinib (XL092) Plus NivoLumab in Patients with LOcally Advanced And/or InopeRable ClEar Cell Renal Cell Carcinoma with or Without Non-measurable Metastasis (EXPLORE-RCC)

All subjects will receive zanzalintinib 100mg orally (PO) once daily plus nivolumab standard of care dosing (i.e., 240mg IV every 2 weeks or 480mg IV every 4 weeks) for a total of 12 weeks, followed by restaging scan/evaluation for surgical operability and an adaptive approach that includes (1) surgical resection if the participant is eligible for surgery (Cohort A), (2) up to 48 weeks total (from Cycle 1 Day 1) of zanzalintinib plus nivolumab if the participant has partial response or stable disease but remains inoperable (Cohort B1), or (3) stopping protocol mandated treatment to receive standard of care systemic therapy and continue follow up per protocol if the participant has disease progression (Cohort B2).

开始日期2025-11-01

申办/合作机构

Hoosier Cancer Research Network

[+2]

NCT06667973

/ Not yet recruiting临床2期IIT

A Phase 2, Open-label, Multicentre Study Investigating Tolerability and Efficacy of Gilteritinib in Combination With Fludarabine, Cytarabine and Idarubicin (FLAI) as Induction Therapy of Newly Diagnosed Non-M3 FLT3-positive Acute Myeloid Leukemia

The goal of this clinical trial is to evaluate the efficacy of gilteritinib as induction therapy in FLT3-positive adult acute myeloid leukemia patients. The main question it aims to answer is:
Is gilteritinib in combination to chemotherapy able to improve the complete remission rate of FLT3-positive AML?
Participants will receive up to 2 induction cycles with gilteritinib in combination with FLAI (fludarabine, cytarabine, idarubicine) and up to 3 consolidation cycles with gilteritinib and high-dose cytarabine.

开始日期2025-06-01

申办/合作机构

Gruppo Italiano Malattie EMatologiche dell'Adulto

NCT06795009

/ Not yet recruiting临床1期IIT

Phase I/IB Study of Zanzalintinib in Combination With Paclitaxel in Recurrent High Grade Uterine Cancer

The purpose of this study is to determine the recommended Phase 2 dose of zanzalintinib when given in combination with paclitaxel in patients with recurrent high-grade uterine cancer. Other objectives include overall safety and tolerability as well as rates of response.

开始日期2025-05-31

申办/合作机构

Washington University School of Medicine

[+2]

100 项与 AXL x TAM family 相关的临床结果

登录后查看更多信息

100 项与 AXL x TAM family 相关的转化医学

登录后查看更多信息

0 项与 AXL x TAM family 相关的专利（医药）

登录后查看更多信息

2,638

项与 AXL x TAM family 相关的文献（医药）

2025-04-01·Anti-Cancer Agents in Medicinal Chemistry

Emerging AXL Inhibitors in Oncology: Chemical and Biological Advances in Targeted Cancer Therapy

Article

作者: Saha, Sunam ; Gopal, Krishan ; Kumar, Shivendra ; Shah, Kamal

AXL, a receptor tyrosine kinase, has emerged as a critical player in tumorigenesis, metastasis, and resistance to conventional therapies. Its aberrant activation drives cell proliferation, survival, and angiogenesis, making it an attractive target for cancer treatment. In recent years, significant progress has been made in the development of AXL inhibitors. Chemical approaches have led to the discovery of small molecules that selectively bind to and inhibit AXL, disrupting its downstream signaling pathways. These inhibitors exhibit diverse structural features, including ATP-competitive and allosteric binding modes, offering potential advantages in terms of selectivity and potency. In addition to chemical approaches, biological strategies have also been explored to target AXL. These include the use of monoclonal antibodies, which can neutralize AXL ligands or induce receptor internalization and degradation. Furthermore, gene therapy techniques have been investigated to downregulate AXL expression or disrupt its signaling pathways. Despite these advancements, challenges remain in the development of AXL inhibitors. Selectivity is a critical concern, as AXL shares homology with other receptor tyrosine kinases. Drug resistance is another obstacle, as cancer cells can develop mechanisms to evade AXL inhibition. Furthermore, to address these challenges, combination therapies are being explored, such as combining AXL inhibitors with other targeted agents or conventional treatments. In conclusion, developing AXL inhibitors represents a promising avenue for improving cancer treatment outcomes. Continued research efforts are essential to overcome the existing challenges and translate these compounds into effective clinical therapies.

2025-03-04·MOLECULAR CANCER THERAPEUTICS

Denfivontinib Activates Effector T Cells Through the NLRP3 Inflammasome, Yielding Potent Anticancer Effects by Combination with Pembrolizumab

Article

作者: Kim, Mi Hyun ; Cho, Byoung Chul ; Lee, Wongeun ; Ye, Sang-Kyu ; Kim, Jae Hwan ; Sohn, Jie-Ohn ; Yang, Seung Min ; Lim, Sun Min ; Kim, Dong Kwon ; Park, So Young ; Synn, Chun-Bong ; Lee, Gang-Taik ; Han, Yu Jin ; Choi, Su-Jin ; Han, Heekyung ; Kang, Seong-san ; Lee, Jii Bum ; Park, Young Joon ; Hong, Min Hee ; Hwang, Joon Yeon ; Baek, Sujeong ; Na, Kwangmin ; Jo, Ha-Ni ; Kim, Youngtaek ; Pyo, Kyoung-Ho ; Lee, Chai Young ; Lee, Seul

Abstract:

Various combination therapies have been investigated to overcome the limitations of using immune checkpoint inhibitors. However, determining the optimal combination therapy remains challenging. To overcome the therapeutic limitation, we conducted a translational research to elucidate the mechanisms by which AXL inhibition enhances antitumor effects when combined with anti–PD-1 antibody therapy. Herein, we demonstrated improved antitumor effects through combination treatment with denfivontinib and pembrolizumab which resulted in enhanced differentiation into effector CD4+ and CD8+ memory T cells, accompanied by an increase in IFN-γ expression in the YHIM-2004 xenograft model derived from patients with non–small cell lung cancer. Concurrently, a reduction in the number of immunosuppressive M2 macrophages and myeloid-derived suppressor cells was observed. Mechanistically, denfivontinib potentiated the NOD-like receptor pathway, thereby facilitating NLRP3 inflammasome formation. This leads to macrophage activation via NF-κB signaling pathway activation. We have confirmed that the positive interaction between macrophages and T cells arises from the enhanced antigen-presenting machinery of activated macrophages. Furthermore, the observed tumor effects in AXL knockout mice confirmed that AXL inhibition by denfivontinib enhances the antitumor effects, thus opening new avenues for therapeutic interventions aimed at overcoming limitations in immunotherapy. To demonstrate the extent to which our findings reflect clinical results, we analyzed bulk RNA sequencing data from 21 patients with non–small cell lung cancer undergoing anti–PD-1 immunotherapy. The NLRP3 inflammasome score influenced enhanced immune responses in patient data undergoing anti–PD-1 immunotherapy, suggesting a role for the NLRP3 inflammasome in activating immune responses during treatment.

2025-03-03·JOURNAL OF CLINICAL INVESTIGATION

Tumor-initiating cells escape tumor immunity via CCL8 from tumor-associated macrophages in mice

Article

作者: Ling, Rongsong ; Wang, Xiaochen ; Xiong, Jianqi ; Zhu, Yan ; Chen, Demeng ; Cheng, Maosheng ; Peng, Zhenwei ; Huang, Chen-Song ; Zhou, Bin ; Zhang, Caihua ; Peng, Liang ; Xiong, Gan ; Tian, Guoli ; Chen, Shuang ; Zhou, Ruoxing ; Ma, Jieyi ; Zhang, Zhihui ; Li, Kang ; Li, Heping

Tumor-initiating cells (TICs) play a key role in cancer progression and immune escape. However, how TICs evade immune elimination remains poorly characterized. Combining single-cell RNA sequencing (scRNA-seq), dual-recombinase-based lineage tracing, and other approaches, we identified a WNT-activated subpopulation of malignant cells that act as TICs in vivo. We found intensive reciprocal interactions between TICs and immune regulatory tumor-associated macrophages (Reg-TAMs) via GAS6-AXL/MERTK signaling pathways, which facilitated the immune escape of TICs. Our study employed chemical inhibitors and Axl/Mertk conditional double knockout mice to demonstrate that inhibiting the interaction between TIC-derived GAS6 and AXL/MERTK in Reg-TAMs reactivated anti-tumor immune responses. We identified CCL8 as a critical mediator of the GAS6/AXL/MERTK pathway, primarily by inhibiting regulatory T cell (Treg) infiltration into the tumor. Furthermore, the AXL/MERTK signaling blockade sensitized tumor cells to anti-PD-1 treatment. Thus, we elucidated a detailed mechanism by which TICs evade tumor immunity, providing insights into strategies to eradicate TICs that escape conventional immunotherapy.

343

项与 AXL x TAM family 相关的新闻（医药）

2025-03-05

·药学进展

学科前沿 | 复旦大学郁金泰教授团队联合袁鹏教授团队、中科院上海有机化学研究所刘聪教授团队在帕金森病发病机制研究方面取得进展

“ 点击蓝字关注我们复旦大学郁金泰教授团队联合袁鹏教授团队、中科院上海有机化学研究所生物与化学交叉研究中心刘聪教授团队在帕金森病发病机制研究方面取得进展 PPS 在国家自然科学基金项目（批准号：82271471、82401676、92249305）等资助下，复旦大学附属华山医院郁金泰教授团队联合复旦大学脑科学转化研究院袁鹏教授团队、中科院上海有机化学研究所生物与化学交叉研究中心刘聪教授团队在帕金森病发病机制研究方面取得进展。研究成果以“神经元FAM171A2介导α-突触核蛋白纤维摄取并促进帕金森病发生（Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease）”为题，于2025年2月20日在线发表于《科学》（Science）杂志，论文链接：https://www.science.org/doi/10.1126/science.adp3645。帕金森病（Parkinson's disease, PD）是第二常见的神经退行性疾病，我国65岁以上老年人群中帕金森病患病率为1.7%，到2030年，我国帕金森病患者数预计将达500万，几乎占到全球患者数的一半。既往研究发现α-突触核蛋白在病理条件下会发生错误折叠并聚集形成病理性α-突触核蛋白，破坏神经元功能并导致其死亡，是PD的关键致病蛋白。这些致病蛋白还会像“种子”一样播散，入侵邻近神经元，募集神经元内α-突触核蛋白单体发生错误折叠，形成更多的致病“种子”。这些致病“种子”可以在神经元间传播，当传播到中脑黑质区域时，可导致多巴胺能神经元死亡，从而出现动作迟缓、静止性震颤、肌强直等PD运动症状。但目前病理性α-突触核蛋白在神经元间传播机制尚不清楚，临床仍然缺乏有效干预手段。研究团队首先通过大规模人群的全基因组关联分析，发现FAM171A2是PD风险基因；并基于PD患者临床样本分析发现，患者大脑中FAM171A2蛋白含量增高，且FAM171A2含量越高的患者，其脑内病理性α-突触核蛋白含量也越高。进一步研究发现在神经元细胞膜上，FAM171A2可选择性的结合病理性α-突触核蛋白，并携带其进入到神经元中，诱导神经元内单体形式的α-突触核蛋白发生错误折叠，造成神经元死亡和其在神经元间的传播。团队随后研究证实敲除小鼠神经元上FAM171A2，可以有效控制小鼠帕金森样症状的进展。基于前述发现，研究团队利用人工智能的蛋白结构预测和虚拟筛选技术，从7000余种药物中成功筛选出候选小分子bemcentinib，并在体外实验和动物实验证实该小分子可有效抑制FAM171A2蛋白和病理性α-突触核蛋白结合，并抑制多巴胺能神经元对病理性α-突触核蛋白的摄取。该研究发现了神经元上病理性α-突触核蛋白潜在膜受体FAM171A2蛋白，揭示了FAM171A2蛋白是促进病理性α-突触核蛋白传播的关键，筛选出FAM171A2有效阻断剂bemcentinib是治疗PD的候选小分子。该研究结果为PD的治疗提供了潜在新靶点和新思路。文章来源：国家自然科学基金委员会美编排版：陈鑫茹文章审核：周碧远陈鑫茹罗琪【免责声明】以上内容来源于互联网，不代表本平台立场或观点；如有侵犯作者著作权，请及时与我们联系（Tel：025-83271227，或直接在微信平台留言），我们将及时更正或删除。《药学进展》杂志由国家教育部主管、中国药科大学和中国药学会共同主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。联系《药学进展》↓↓↓ 编辑部官网：pps.cpu.edu.cn；邮箱：yxjz@163.com；电话：025-83271227。欢迎投稿、订阅！往期推荐聚焦“兴药为民·2023生物医药创新融合发展大会”“兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航我知道你在看哟

申请上市

2025-02-26

·Endpoints

Harbour BioMed inks deal up to $395M; ORIC refines plans for two drugs

Plus, news about Idorsia, Enveda, Zymeworks, BerGenBio and Ignota Labs: Harbour BioMed does another deal: The Shanghai-based biotech’s subsidiary, called HBM Alpha Therapeutics, inked a pact with an undisclosed company for up to $395 million in upfront fees and biobucks, plus the potential for a minority stake. The undisclosed partner also gets exclusive ex-China global rights to an antibody known as HAT001/HBM9013 for congenital adrenal hyperplasia (CAH) and other rare endocrine disorders. HBMAT raised a seed round of undisclosed size in January 2023, and Harbour did a NewCo deal for an anti-TSLP antibody with Windward Bio last month. — Kyle LaHucik ORIC ‘refines’ development plans for two drugs: The ORIC-944 program is set to start a Phase 3 trial in the first half of 2026 looking at patients with metastatic castration-resistant prostate cancer. Its ORIC-114 candidate is expected to begin registrational trials sometime in 2026 in the first-line lung cancer setting. Its stock $ORIC was up about 13% on Wednesday morning. — Max Gelman Idorsia’s big updates: The Swiss drugmaker said an undisclosed party opted not to move forward with a deal for the global rights to Idorsia’s experimental hypertension drug, called aprocitentan, but it will keep the $35 million exclusivity fee that it got in December. Meanwhile, Idorsia and Viatris adjusted the terms of their collaboration for selatogrel and cenerimod, with Idorsia contributing $100 million less toward development while losing $250 million in potential milestone payments from Viatris. It is also restructuring its debt and getting new funding . — Kyle LaHucik Sanofi backs Enveda with $20M: The French pharma giant is joining the Series C of the Colorado biotech, which mines plant chemistry to find new drugs. The Series C now totals $150 million, up from the $130 million disclosed in November . — Kyle LaHucik Zymeworks’ $14M milestone: The company received the payment from GSK from a bispecific antibody deal they inked in 2016 and then expanded in 2019. — Jaimy Lee BerGenBio discontinues lung cancer study, to seek strategic alternatives: The company was evaluating whether bemcentinib, an AXL kinase inhibitor, could treat patients with first-line non-squamous non-small cell lung cancer in combination with standard of care. Patients also needed to have a mutation of the STK11 gene. In a statement, CEO Olav Hellebø said the results were not strong enough for BerGenBio to obtain additional financing and is now looking for a merger, sale or other transaction. — Max Gelman Ignota Labs closes £5.5M seed round: The startup’s goal is to “turn around failed drugs” using AI, acquiring assets from bigger companies that stopped being developed and then testing them in new clinical trials. Its first asset is a PDE9A inhibitor, which the company says has potential in cardiovascular, metabolic and neurodegenerative diseases. — Max Gelman

引进/卖出抗体药物偶联物

2025-02-25

·生物谷

肝脏，作为人体的“化工厂”，承担着500多种合成与代谢功能，对维持生命活动至关重要。当肝脏出现严重问题，发展到终末期时，肝移植成为了许多患者的“救命稻草”。然而，供体肝脏的严重短缺，极大地限制了肝移植的广泛应用。近年来，肝类器官的研究成为攻克这一难题的新方向，而近期一项发表于Mater Today Bio的研究3D bioprinting lobule-like hepatorganoids with induced vascularization for orthotopic implantation为该领域带来了重大突破。肝类器官有望解决肝脏供体不足的困境，它不仅能模拟肝脏的部分功能，还可借助生物制造技术实现标准化、工业化生产，降低治疗成本。在肝类器官的研究中，血管化是影响其功能和存活的关键因素。因为充足的血管网络能够为类器官提供氧气和营养物质，维持细胞的正常代谢和功能。但目前，实现血管化肝类器官的原位移植仍面临诸多挑战，比如生物制造精度难以满足构建微毛细血管网络的需求，血管化功能材料有待优化，关键分子机制也尚不明确。针对这些问题，研究团队开展了深入研究。他们运用3D生物打印技术，以GelMA水凝胶为基础，成功制备出小叶状肝类器官，并进一步构建了血管化的小叶状肝类器官（VLH）。在体外实验中，小叶状肝类器官表现优异。其缺氧水平明显低于其他结构的类器官，这意味着细胞能获得更充足的氧气，为维持正常功能创造了有利条件。在功能方面，小叶状肝类器官的白蛋白和尿素分泌量较高。白蛋白分泌量高，反映出其强大的蛋白质合成能力；尿素分泌量高，则体现了良好的代谢功能，这些都充分证明了该类器官具有较高的活性。图 1：3D打印小叶样肝类器官的特性表征对于血管化的小叶状肝类器官VLH，研究发现其体内表现出色。RNA测序结果显示，VLH中GAS6/AXL和LAMB3/ITGA3信号通路显著上调，这两条信号通路在血管生成和细胞增殖过程中发挥着关键作用。在原位移植实验中，VLH的优势十分明显。与其他类型的肝类器官相比，VLH在体内的存活时间更长。血清学指标显示，其血清标志物水平升高，表明VLH在体内能够有效维持功能。组织学分析也发现，VLH移植后的血管化程度更高，丰富的血管网络为类器官提供了充足的氧气和营养物质，有力地保障了类器官的正常功能。图 2：HUVECs和GelMA/NHS/VEGF协同诱导3D打印小叶状肝类器官的血管化图 3：血管化小叶状肝类器官原位植入后的长期活力维持这项研究具有里程碑式的意义，它创新性地实现了3D打印小叶状肝类器官，并成功诱导血管化和进行原位移植。同时，揭示了促进血管化和维持功能活性的关键机制，为临床治疗急性和慢性肝损伤、肝切除术后肝功能不足等肝脏疾病提供了全新的策略和方向。相信在科研人员的不断努力下，这一成果将逐步从实验室走向临床，为广大肝脏疾病患者带来新的希望，推动肝脏疾病治疗领域迈向新的高度。未来，我们期待看到更多基于这一成果的深入研究和应用，为人类健康事业做出更大的贡献。参考文献： Yan J, Ye Z, Lu Y, et al. 3D bioprinting lobule-like hepatorganoids with induced vascularization for orthotopic implantation. Mater Today Bio. 2025;31:101515. Published 2025 Jan 22. doi:10.1016/j.mtbio.2025.101515 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

临床研究