MRTX-1133

Bringing medical advances from the lab to the clinic.（点击👆，免费获取美国NIH基金资助项目大数据分析）胰腺癌（Pancreatic Cancer）以胰腺导管腺癌（PDAC）最为常见，具有起病隐匿、早期转移、对化疗/免疫治疗敏感性差的特点，长期总体生存率低，仍是肿瘤学中预后最差的实体瘤之一。近年关键进展围手术期/新辅助治疗地位上升：对边界可切或可切除患者，基于 FOLFIRINOX 的新辅助方案被越来越多试验与指南采纳，以期提高切除率与长期疗效。基因驱动/靶向治疗的临床化尝试（BRCA/PARP 等）：对携带胚系 BRCA 突变的患者，铂类化疗后以 PARP 抑制剂（如 olaparib）维持可延长无进展期，成为可选的精准治疗路径。针对 KRAS 的变异型抑制剂进入临床探索；早筛与液体活检技术进步：新型 KRAS G12D 小分子抑制剂（如 MRTX1133）已进入早期人体试验，显示出在胰腺癌中重要的研发前景；同时基于血浆 cfDNA 甲基化或蛋白/酶活性的多癌种早筛（如 Galleri、PAC-MANN）与 ctDNA-MRD 检测正在快速发展，为早期诊断与术后复发监测提供新工具。主要临床痛点早诊率极低，诊断多在晚期 —— 大量患者在不可切或转移阶段确诊，错过根治性手术窗口；现有早筛方法尚未在一般人群中确立可行的低成本高敏感方案。总体疗效改善有限，转移/难治病人预后差 —— 虽有新方案延缓进展，但总体生存仍短、可治愈患者比例低。肿瘤分子异质性与可及性矛盾 —— 虽发现若干可“drug-gable”突变（BRCA、NTRK、部分 KRAS亚型等），但基因检测、靶向药物的可及性与疗效人群受限。免疫治疗总体无效且临床推广受限 —— 胰腺肿瘤的免疫抑制微环境使大多数免疫检查点抑制剂失效，仅在少数 MSI-H 患者中可见持续反应。术后/术中管理与微小残留病（MRD）指导策略尚不成熟 —— ctDNA-MRD 虽有希望用于风险分层与辅助治疗决策，但尚缺大规模前瞻性证据以改变常规实践。新药从实验室到临床失败率高、时间长 —— 许多针对基质/基质-肿瘤相互作用（例如早期的基质靶向）或小分子靶点在临床中未能显著改善生存，研发成本与失败风险高。患者支持性治疗与多学科协作仍不均衡 —— 疼痛、营养、并发症管理及围术期支持在不同地区差异大，影响生活质量与治疗容忍性。胰腺癌研究既有令人鼓舞的方向（新辅助策略、靶向 KRAS/BRCA 路径、液体活检与早筛技术），也面临早诊难、总体疗效改善有限与分子靶向/免疫可及性不足等顽固问题；未来关键在于把“早筛-分子分层-个体化组合治疗”这条链条真正在临床中落地并普及。我们仅对美国国立卫生研究院（NIH）资助的在研胰腺癌相关项目进行梳理，希望给同仁们的选题思路提供一点启发。2025年，以 "Pancreatic Cancer"为检索词、在题目中进行检索，美国NIH针对胰腺癌的在研有306项。一，谁获得了这些研究？1. 在研基金最多的PI：JAFFEE, ELIZABETH M，约翰·霍普金斯大学（JOHNS HOPKINS UNIVERSITY）YEH, JEN JEN，北卡罗来纳大学教堂山分校（UNIV OF NORTH CAROLINA CHAPEL HILL）PASCA DI MAGLIANO, MARINA，密歇根大学安娜堡分校（UNIVERSITY OF MICHIGAN AT ANN ARBOR）2，基金最多的研究机构JOHNS HOPKINS UNIVERSITY约翰斯·霍普金斯大学UNIVERSITY OF MICHIGAN AT ANN ARBOR密歇根大学安娜堡分校UNIVERSITY OF TX MD ANDERSON CAN CTR德克萨斯大学MD安德森癌症中心UNIVERSITY OF NEBRASKA MEDICAL CENTER内布拉斯加大学医学中心UNIV OF NORTH CAROLINA CHAPEL HILL北卡罗来纳大学教堂山分校二，研究热点研究领域总览（根据关键词）研究大的方向也包括临床试验（Clinical Trials）、代谢（Metabolism）、T细胞（T Cell）、肿瘤生长(Tumor Growth）、生存率（Survival Rate）、免疫检查点（Immune Checkpoint）等。三，借鉴与突破我们也分享在该领域的几项课题摘要，希望对同仁们有所启发。A，Transforming Human Pancreatic Cancer Into An Immunologic DiseasePancreatic ductal adenocarcinoma (PDA) is rising in incidence but remains deadly for most patients. Some progress has occurred in activating immune responses against PDA, however there are unanswered questions that need to be addressed for immunotherapy to have a significant impact on the lives of PDA patients. Our Team will address two critical problems: 1) inefficient generation of high quality T cells targeted against PDA antigens capable of tumor trafficking and killing; and 2) multiple cellular barriers that comprise stromal and myeloid cells that inhibit effector T cell trafficking and function in the PDA tumor microenvironment (TME). Both clinical studies (“science in patients”) and pre-clinical studies (mouse models) will be conducted to address these issues, and to evaluate novel combinatorial therapies that successfully modulate PDA stroma and chronic inflammation to facilitate improved tumor infiltration of high quality and durable cancer targeted T cells. This program is composed of 4 Projects and 4 Cores. The four projects will address the common overarching theme that PDA is composed of multiple cell types and signals that inhibit T cell induction, trafficking into, and function in tumors. Each project will address either the induction of quality T cells or the modulation of suppressive cell populations as major barriers to T cell infiltration and activation, and all will integrate agents that bypass these suppressive mechanisms with optimal T cell therapies. Projects 1, 2, and 4 will combine ongoing preclinical studies aimed at uncovering mechanisms of suppression of different barriers with translational clinical trials that study combination therapy to bypass these suppressive mechanisms. Project 3 will conduct a biomarker heavy clinical trial using a multi-arm Platform design that will add and delete immune modulatory arms based on data from biomarker analysis in this Project and from data that feeds into this Project from the other 3 Projects. Standard procedures will be used across Projects to collect and bank serial biospecimens obtained from patients treated on the clinical trials. The Cores will be critical for conducting the proposed assays and for analysis and integration of the data. A Program database will be developed to allow for integration of data generated from these assays across the entire Program. This will be a unique database that will also bring in data from other sources such as the TCGA database, and will provide the Program Team with the ability to compare results based on the genetics and inflammatory composition of each patient’s tumor and their response to the therapy they received. The final outcomes will include results from a number of therapeutic interventions, approaches to optimize each therapeutic, the potential to further integrate therapies that were tested in one or more projects in future trials, and the ability to develop TME signatures that may further stratify patients for therapeutic interventions. This program will substantially accelerate progress in PDA therapy, and allow otherwise nearly impossible achievements in defining predictors of successful immunological therapeutic intervention for PDAs.B, Preclinical drug development in pancreatic cancerMy laboratory aims to address the unmet medical need for more effective treatments for patients afflicted by pancreas and other solid organ cancers by developing new cancer drugs. Scientific achievements with regard to the pursued drug development projects in the last year include: 1. Identification of a clinically safe dose level of metarrestin, a first-in-class small molecule targeting genome organization in metastatic cancer cells. Metarrestin is a novel, first-in-class small molecule inhibitor with selective activity against the metastatic phenotype of cancer cells. Metarrestin is currently administered to patients with advanced malignancies in escalating doses to determine safety and tolerability of the drug. PK data from the first 28 patients treated with metarrestin identified a safe regimen of a loading dose followed by a maintenance dose as safe, which achieves therapeutic levels in tumoral lesions. A robust population PK (popPK) model has been generated with a near perfect fit between measured and simulated PK. Recent preclinical work has shown that metarrestin inhibits the assembly of the small subunit (SSU) processome, a large ribonucleoprotein particle which organizes the assembly of the small ribosomal subunit by coordinating the folding, cleavage, and modification of nascent pre-ribosomal RNA (rRNA). Metarrestin leads to disruption of the diffuse fibrillar compartment (DFC) of the nucleolus. DFC biomolecular condensate particles with partially processed rRNA species are translocated from the nucleolus to the nucleus where they activate the exosome complex (PM/Scl complex) blocking p53 activation. The lack of p53 activation and induced cell death is a sentinel distinguishing feature of metarrestin to other polymerase I inhibitors and presumed to be related to the favorable clinical safety profile. 2. Preclinical development and clinical translation of innate checkpoint modulators targeting CD206 on tumor associated macrophages (TAMs). Prior work of ours has shown that the mannose receptor CD206 on M2-like TAMs functions as an immune checkpoint. CD206 activation reprograms TAMs from a pro-tumor, immune suppressive to an anti-tumor, inflammatory phenotype and CD206 ligation is able to reinvigorate innate anti-tumor responses via direct cancer cell phagocytosis. Due to its restricted expression, CD206 is an attractive target for novel cancer immunotherapy in immunologically 'cold' cancers which currently do not respond to T cell activation via immune checkpoint inhibition. Our group has via in silico screening of large chemical libraries identified a phenyl-imidoazo[2,3] pyrazine-based small molecule drug candidate, NCGC72, which has recently been selected for IND enabling studies and clinical translation by the Therapeutic Development Branch (TDB), NCATS. NCGC72 induces tumor regressions across murine and human preclinical cancer models. NCGC72 has no discernable off-target activity and showed a large therapeutic window in preclinical safety and toxicity studies due to remarkable selectivity for tumoral CD206 isoforms. The selectivity for CD206 expressed on TAMs is due to its unique glycosylation state which is characterized by decreased sialylation of select amino acid residues in the vicinity of the binding region of NCGC72 interfering with access of the small molecule to the receptor. The lack of activation of immune cells residing in normal organs is a distinguishing a feature to immune checkpoint inhibition with PD-1/PD-L1 or CTLA-4 blockade. NCGC72 is currently evaluated in a dedicated phase I/II study for safety, tolerability, and efficacy in sarcoma-bearing dogs. After acceptance of NCGC72 as a clinical candidate by the TDB, NCATS, manufacturing of GMP drug substance for both GLP safety and toxicokinetic studies and clinical grade product for human phase I testing has been completed with IND filing estimated in 2025 and start of clinical testing in 2026. Additional preclinical work has shown that NCGC72's reprogramming of CD206high, M2-like TAMs towards a proinflammatory phenotype via the induction of an interferon type I response is the main anti-tumor mechanism as blockade of NCGC72-mediated M2-like cell killing recruits TAMs towards enhanced cancer cell phagocytosis and tumor control. Current work expanding on these findings is studying (1) rationale designed drug combinations of immune-oncology agents with NCGC72, and (2) molecular markers to select tumors most likely to respond to NCGC72. Spurned by recent reports that CD206 positive macrophages mediate disease-causing processes in non-malignant conditions like eye disease or type II diabetes, we evaluated NCGC72 in a preclinical model of proliferative diabetic retinopathy. NCGC72 substantially reduced sub-retinal fibrosis and vitriol hemorrhages, causes of blindness in diabetic retinopathy and we are currently evaluating NCGC72 in a preclinical model of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis.天下科研，唯快不破。看了上述检索结果，对您有什么启发？赶快行动吧。如果您需要HS提供类似的选题大数据分析，可阅读下面的推文：应用这个“外挂”，他的选题思路源源不断、文章不断发表！关键词： #美国基金解析；#Hanson临床科研；#Healsan医路成长作者：Amber Wang，助理：ChatGPT美国Healsan(恒祥医学)，专长于Healsan™医学大数据分析、基于大数据的HansonCR™临床科研支持，以及MedEditing™的医学编辑服务。主要为医院科研处、生物制药公司和医生科学家提供数据分析和SCI报告，成为诸多机构的“临床科研外挂”。网址：https://healsan.com/

个人学习整理，所有信息均来源于网络，可能会存在疏漏KRAS是肿瘤学中最重要的致癌基因之一，长期以来被视为“不可成药”的靶点。2021年，安进的Sotorasib（AMG-510）获得FDA批准，打破了这一僵局，标志着KRAS靶向治疗元年的开启。目前，竞争焦点主要集中在G12C突变上，但针对其他突变（如G12D, G12V）和联合疗法的探索是未来的核心战场。赛道已从“从0到1”的验证，进入“从1到N”的优化与差异化竞争阶段，吸引了众多跨国药企和生物技术公司加入，竞争日趋激烈。 靶点布局 1. KRAS G12C 生物学特征：第12位甘氨酸（Gly）被半胱氨酸（Cys）取代，创造了共价抑制剂的结合位点。主要见于肺癌、结直肠癌和部分胰腺癌。 竞争格局：最成熟、最内卷的赛道，已有多款药物上市（安进、BMS、信达/劲方、益方、加科思），多家企业进入临床后期。 G12C赛道已从单药竞争转向联合疗法和前线治疗的竞争2. KRAS G12D 生物学特征：第12位甘氨酸（Gly）被天冬氨酸（Asp）取代。这是最常见的KRAS突变，尤其是胰腺导管腺癌（~40%）、结直肠癌（~13%） 的主要驱动突变。由于不含半胱氨酸，无法用传统的共价策略靶向，开发难度更大。 竞争格局：公认的“圣杯”，一旦攻克市场空间巨大。目前尚无药物上市，竞争处于早期但极其激烈。成功的G12D抑制剂有望彻底改变胰腺癌的治疗范式，成为比G12C抑制剂更大的重磅炸弹。3. Pan-KRAS 生物学特征：旨在开发一种药物覆盖多种甚至所有常见的KRAS突变体（如G12C, G12D, G12V, G13D等），同时避免影响野生型KRAS。 竞争格局：下一代技术的终极竞争，是解决KRAS异质性和耐药性的潜在方案。RMC-6236/daraxonrasib是目前该领域的明星分子，是一种口服的三复合物抑制剂，可强效抑制G12X突变（包括D, C, V等），已在早期临床中在多种肿瘤（尤其是胰腺癌）中显示出令人振奋的活性。4. 关于Pan-KRAS和RAS(ON)概念的澄清 Pan-KRAS 像是一把万能钥匙，经过特殊设计，能打开许多种不同牌子的锁（各种KRAS突变），但它开锁的方式都是把锁芯拨回原始位置（锁定在OFF状态）。 RAS(ON) 抑制剂则像是一罐超级强力胶水。不管是什么牌子的锁（KRAS, NRAS, HRAS突变），只要它处于“打开”状态（ON状态），就把胶水喷进去，再把一个巨大的障碍物粘在锁眼里，让钥匙（效应蛋白）根本无法插进去转动，同时这个被胶水粘住的锁本身也会被管理员（细胞）当成垃圾扔掉（降解）。 RMC-6236 本质上是一个Pan-KRAS 抑制剂，但它实现“泛”抑制的机制，依赖于其能够靶向并抑制 RAS(ON) 信号通路的独特能力。简单来说：它的身份是Pan-KRAS，但其作用机制的核心是干扰RAS(ON)。适应症格局1. NSCLC 既治人群：G12C已具备稳定商业化基础 美国：sotorasib（Lumakras/Lumykras，安进，2021获批）；adagrasib（Krazati，BMS/原Mirati，2022获批） 中国：fulzerasib（GFH-925/IBI351，劲方/信达，2024-08获批）；garsorasib（D-1553，益方，2024-11获批）；Glecirasib (JAB-21822，加科思，2025-05获批) 一线：聚焦与PD-1/PD-L1或化疗联用（divarasib、olomorasib正推进）。2. mCRC 单药G12C疗效受限； 与EGFR抗体联用成为主流与注册路径。 美国：adagrasib+cetuximab，2024-06 获批；sotorasib+panitumumab，2025-01获批；divarasib+cetuximab早期ORR达到~62% 中国：尚无获批3. PDAC KRAS突变率高（~90%）； RAS(ON)与G12D抑制剂目前成为最活跃方向；daraxonrasib获BTD并入III期，媒体与学术均广泛关注其为PDAC带来的“首批可见的分子靶向希望”。典型公司与资产1. 安进（sotorasib） 持续经营；mCRC联用获批（2025-01-16）；但NSCLC全部门类完全转正面临OS证据挑战。2. BMS/原Mirati（adagrasib） mCRC联用2024-06获批，与并购整合提速。3. 罗氏（divarasib） KRASCENDO III期推进；CRC联用数据领跑同类。4. 礼来（olomorasib/LY4066434） olomorasib 主要攻克一线NSCLC，联合K药用于一线治疗经 FDA 批准的检测方法确定为 PD-L1 表达 ≥ 50% 且 KRAS G12C 突变的不可切除的晚期或转移性非小细胞肺癌（NSCLC）患者获得FDA突破性疗法认定； LY4066434是pan-KRAS，曾在AACR 2025会议上展示。 5. Revolution Medicines（RMC-6236 / RMC-9805） RMC-9805：通过选择性结合 KRAS G12D 的活性构象（RAS-GTP状态），阻断其与下游效应蛋白（如 RAF）结合，从而抑制 MAPK/ERK 信号通路。2025 年发表于 Science 的早期临床数据（I/II期）显示，在PDAC患者中取得了约30%的ORR，DCR超过 80%。 RMC-6236/daraxonrasib：是一种针对多种 KRAS 突变的“广谱RAS(ON)抑制剂”，已在 PDAC 显示出前所未有的疗效（ORR ~30%），并快速推进至 III期，被视为最有希望改变 KRAS 靶向治疗格局的药物之一。 6. 劲方/信达（fulzerasib/IBI351） 2024-08中国获批。7. 益方（garsorasib） 2024-11中国获批；CRC（±cetuximab）开放获取论文显示“可观活性+可管理安全”。8. 加科思/艾力斯（Glecirasib/JAB-21822） 2025年5月中国获批。竞争格局一览表 SOC for KRAS-Related NSCLC/mCRC/PDAC1. NSCLC1L SOC（无 KRAS 特异药物）免疫联合化疗（PD-1/PD-L1 抗体 + 铂类化疗）；如：Pembrolizumab+Carboplatin+PemetrexedPD-L1 高表达（TPS ≥ 50%）：免疫单药可选注意：KRAS 靶向药物尚未进入 1L SOC（但有多个III期在研：divarasib、olomorasib）2L SOC（KRAS G12C特异）KRAS G12C抑制剂单药：Sotorasib（Lumakras）；Adagrasib（Krazati），已获 FDA & EMA 批准，适用于既治 KRAS G12C NSCLC。2. mCRC1L SOC（无 KRAS 特异药物）化疗为 backbone：FOLFOX / FOLFIRI ± Bevacizumab；若 RAS 野生型且左半结肠 → 可用 Cetuximab / PanitumumabKRAS 突变患者：EGFR抗体无效，SOC 以化疗 ± 抗VEGF为主。2L SOC（KRAS G12C特异）KRAS G12C 抑制剂 + EGFR抗体：Adagrasib + Cetuximab（FDA加速批准2024-06）；Sotorasib + Panitumumab（FDA 批准2025-01）已成为 KRAS G12C 突变 mCRC 的标准方案。3. PDAC1L SOC（无 KRAS 特异药物）化疗方案：FOLFIRINOX；Gemcitabine + Nab-paclitaxelKRAS 靶向药物尚无获批。2L SOC（无 KRAS 特异药物）化疗为主：5-FU + 纳米白蛋白紫杉醇 / liposomal irinotecan探索中：RMC-6236（多 RAS 抑制剂，III期）；RMC-9805、MRTX1133（KRAS G12D 抑制剂，早期） SOC一览表总结 END 免责声明：本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。 OTC2025论坛深度聚焦类器官与疾病建模、新药发现/研发、3D细胞培养、类器官培养及质控。OTC2026合作热线：王晨180 1628 8769