NANT Colorectal Cancer (CRC) Vaccine: A Phase 1b/2 Trial of the NANT CRC Vaccine vs Regorafenib in Subjects With Metastatic CRC Who Have Been Previously Treated With Standard-of-Care Therapy

QUILT 3.071 NANT Colorectal Cancer (CRC) Vaccine: This is a Phase 1b/2 study investigating the effect of NANT CRC vaccine vs regorafenib in subjects with CRC who were previously treated with SOC.

开始日期2018-09-28

申办/合作机构

ImmunityBio, Inc.

NCT03554109

/ Withdrawn临床2期

An Open-Label Randomized Phase 2 Trial Of The NANT NEOADJUVANT Triple-Negative Breast Cancer (TNBC) VACCINE VS Standard-Of-Care For The Neoadjuvant Treatment Of Subjects With TNBC

This is a randomized open-label phase 2 study to evaluate the efficacy and safety (as assessed by pCR) of the NANT Neoadjuvant TNBC Vaccine regimen (experimental arm) compared to the SoC dose-dense regimen of doxorubicin/cyclophosphamide followed by paclitaxel (control arm).

开始日期2018-09-01

申办/合作机构

ImmunityBio, Inc.

NCT03169777

/ Withdrawn临床1/2期

NANT Colorectal Cancer (CRC) Vaccine: Combination Immunotherapy in Subjects With Recurrent or Metastatic CRC

This is a phase 1b/2 study to evaluate the safety and efficacy of metronomic combination therapy in subjects with recurrent and metastatic CRC.

开始日期2018-08-01

申办/合作机构

ImmunityBio, Inc.

100 项与 GI-4000 相关的临床结果

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100 项与 GI-4000 相关的转化医学

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100 项与 GI-4000 相关的专利（医药）

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项与 GI-4000 相关的文献（医药）

2021-03-01·Journal of pancreatic cancer

A Phase 2 Randomized Placebo-Controlled Adjuvant Trial of GI-4000, a Recombinant Yeast Expressing Mutated RAS Proteins in Patients with Resected Pancreas Cancer

Article

作者: Roder, Joanna ; Roder, Heinrich ; Harrell, Frank E. ; Coeshott, Claire ; Rosemurgy, Alexander ; Ross, Sharona B. ; Richards, Donald A. ; Mattson, Alicia ; Apelian, David ; McIntyre, Kristi ; Bekaii-Saab, Tanios ; Rodell, Timothy C. ; Cohn, Allen ; Muscarella, Peter ; Fisher, William E. ; Flynn, Patrick J.

Purpose: GI-4000, a series of recombinant yeast expressing four different mutated RAS proteins, was evaluated in subjects with resected ras-mutated pancreas cancer. Methods: Subjects (n = 176) received GI-4000 or placebo plus gemcitabine. Subjects' tumors were genotyped to identify which matched GI-4000 product to administer. Immune responses were measured by interferon-γ (IFNγ) ELISpot assay and by regulatory T cell (Treg) frequencies on treatment. Pretreatment plasma was retrospectively analyzed by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-ToF) mass spectrometry for proteomic signatures predictive of GI-4000 responsiveness. Results: GI-4000 was well tolerated, with comparable safety findings between treatment groups. The GI-4000 group showed a similar pattern of median recurrence-free and overall survival (OS) compared with placebo. For the prospectively defined and stratified R1 resection subgroup, there was a trend in 1 year OS (72% vs. 56%), an improvement in OS (523.5 vs. 443.5 days [hazard ratio (HR) = 1.06 [confidence interval (CI): 0.53-2.13], p = 0.872), and increased frequency of immune responders (40% vs. 8%; p = 0.062) for GI-4000 versus placebo and a 159-day improvement in OS for R1 GI-4000 immune responders versus placebo (p = 0.810). For R0 resection subjects, no increases in IFNγ responses in GI-4000-treated subjects were observed. A higher frequency of R0/R1 subjects with a reduction in Tregs (CD4⁺/CD45RA⁺/Foxp3^low) was observed in GI-4000-treated subjects versus placebo (p = 0.033). A proteomic signature was identified that predicted response to GI-4000/gemcitabine regardless of resection status. Conclusion: These results justify continued investigation of GI-4000 in studies stratified for likely responders or in combination with immune check-point inhibitors or other immunomodulators, which may provide optimal reactivation of antitumor immunity. ClinicalTrials.gov Number: NCT00300950.

2018-04-01·Journal of immunotherapy (Hagerstown, Md. : 1997)4区 · 医学

Whole Recombinant Saccharomyces cerevisiae Yeast Expressing Ras Mutations as Treatment for Patients With Solid Tumors Bearing Ras Mutations: Results From a Phase 1 Trial

4区 · 医学

Article

作者: Bellgrau, Donald ; Coeshott, Claire ; Ferraro, John ; Apelian, David ; Whiting, Samuel ; Morse, Michael A ; Cohn, Allen ; O'Neil, Bert ; Rodell, Timothy C

We are developing whole, heat-killed, recombinant Saccharomyces cerevisiae yeast, engineered to encode target proteins, which stimulate immune responses against malignant cells expressing those targets. This phase 1 trial, enrolling patients with advanced colorectal or pancreas cancer, was designed to evaluate safety, immunogenicity, response, and overall survival of ascending doses of the GI-4000 series of products, which express 3 different forms of mutated Ras proteins. The study enrolled 33 heavily pretreated subjects (14 with pancreas and 19 with colorectal cancer), whose tumors were genotyped before enrollment to identify the specific ras mutation and thereby to identify which GI-4000 product to administer. No dose limiting toxicities were observed and no subject discontinued treatment due to a GI-4000 related adverse event (AE). The majority of AEs and all fatal events were due to underlying disease progression and AE frequencies were not significantly different among dose groups. GI-4000 was immunogenic, as Ras mutation-specific immune responses were detected on treatment in ∼60% of subjects. No objective tumor responses were observed but based on imaging, clinical status and/or biochemical markers, stable disease was observed in 6 subjects (18%) on day 29, while 1 subject had stable disease at days 57 and 85 follow-up visits. The median overall survival was 3.3 months (95% confidence interval, 2.3–5.3 mo), and 5 subjects survived past the 48-week follow-up period. No significant dose-dependent trends for survival were observed. This first clinical trial in humans with GI-4000 demonstrated a favorable safety profile and immunogenicity in the majority of subjects.

2015-04-03·Human vaccines & immunotherapeutics3区 · 医学

Pancreatic cancer, treatment options, and GI-4000

3区 · 医学

Review

作者: Ampie, Leonel ; Hartley, Marion L ; Marshall, John L ; Bade, Najeebah A ; Prins, Petra A

Although pancreatic cancer is but the eleventh most prevalent cancer in the US, it is predicted that of all the patients newly diagnosed with this disease in 2014, only 27% will still be alive at the end of the first year, which is reduced to 6% after 5 years. The choice of chemotherapy in the treatment of pancreatic cancer is dependent on disease stage and patient performance status but, in general, the most widely used approved regimens include 5-fluorouracil (5-FU) combinations and gemcitabine combinations. Recent therapeutic strategies have resulted in an improvement in survival of patients with pancreatic cancer but the magnitude of change is disappointing and vast improvements are still needed. The goal of immunotherapy is to enhance and guide the body's immune system to recognize tumor-specific antigens and mount an attack against the disease. Among newer immune therapies, GI-4000 consists of 4 different targeted molecular immunogens, each containing a different Ras protein (antigen) encoded by the most commonly found mutant RAS genes in solid tumors-RAS mutations exist in over 90% of pancreatic ductal adenocarcinomas. We will review pancreatic cancer epidemiology and its current treatment options, and consider the prospects of immunotherapy, focusing on GI-4000. We discuss the potential mechanism of action of GI-4000, and the performance of this vaccination series thus far in early phase clinical trials.

项与 GI-4000 相关的新闻（医药）

2025-08-02

·精准药物

【综述】一文带你读懂靶向KRAS的药物研发最新进展

01KRAS突变的生物学特征 No.1KRAS信号激活与突变机制◆ RAS基因家族：RAS基因家族包括HRAS、KRAS、NRAS，均为癌基因，其中KRAS是癌症中突变最频繁的亚型(占RAS突变的81%)，其次为NRAS(15%)和HRAS(4%)。◆ KRAS蛋白：是KRAS基因的产物，属于小GTP酶家族，在活性GTP结合状态(KRAS(ON))和失活GDP结合状态(KRAS(OFF))之间动态转换，调控细胞增殖、生存等信号。图1 KRAS GTPase蛋白序列和结构◆ KRAS激活：上游RTK(如EGFR)通过SOS1促进KRAS-GTP形成，下游激活RAF-MEK-ERK和PI3K-AKT等通路，驱动肿瘤发生。图2 KRAS的激活状态及其对信号通路的影响◆ KRAS突变：KRAS突变占人类癌症的20%以上，通过破坏GTP结合口袋的构象，导致GTP酶活性降低，维持KRAS持续激活状态，驱动肿瘤生长。 No.2KRAS突变类型与表达调控◆ KRAS突变类型与肿瘤分布：KRAS突变中约95%发生在G12位点，其次为G13(3–5%)和Q61(1–2%)。G12突变包括G12C、G12D、G12V、G12R、G12S等，其中G12C、G12D、G12V占所有KRAS突变的60–70%。①G12C：约13%，多见于非小细胞肺癌(12–15%)，在结直肠癌(2–3%)和胰腺癌(<1%)中罕见。②G12D：约26%，是结直肠癌(30–40%)和胰腺癌(40–50%)的最常见突变亚型。③G12V：约21%，在子宫内膜癌、卵巢癌中占比可达15–20%。图3 各种癌症类型的KRAS突变率◆ KRAS突变受非编码RNA的调控①长链非编码RNA(lncRNA)：lncRNA通过调控染色质重塑和转录因子活性，维持KRAS突变细胞的恶性表型。②微小RNA(miRNA)：miRNA通过靶向KRAS的3'UTR或下游通路组件，调节信号传导强度。 No.3KRAS突变对肿瘤微环境与代谢的影响◆ KRAS突变对肿瘤微环境与细胞行为影响①癌相关成纤维细胞(CAFs)重编程：KRAS激活TFCP2，诱导CAFs向脂质富集细胞分化，促进血管生成和肿瘤进展。②免疫微环境抑制：KRAS突变通过分泌TGF-β、IL-6等细胞因子，招募调节性T细胞(Treg)和髓系抑制细胞(MDSCs)，形成免疫抑制微环境，削弱抗肿瘤免疫应答。③癌症干细胞(CSCs)维持：KRAS突变激活CDK1，促进蛋白O-乙酰葡糖胺糖基化修饰，上调CSC标志物SOX2，增强肿瘤干细胞的自我更新和治疗耐药性。④巨胞饮作用(MP)激活：KRAS突变激活MP，增强细胞对营养物质的摄取，支持肿瘤在代谢压力下的生存。⑤细胞竞争与侵袭：KRAS突变激活NF-κB-MMP21通路，促进肿瘤细胞对邻近正常细胞的排斥和扩散浸润，增强肿瘤的侵袭性。图4 靶向致癌KRAS驱动的肿瘤中的代谢途径◆ KRAS突变促进代谢重编程①糖酵解与谷氨酰胺利用增强：KRAS突变上调己糖激酶、谷氨酰胺酶等酶活性，促进有氧糖酵解和谷氨酰胺分解，为肿瘤细胞提供能量和生物合成前体。②天冬氨酸代谢依赖：突变型KRAS激活PCK1、ASS1等酶，增强天冬氨酸和尿素循环代谢，维持核苷酸合成和氧化还原平衡，支持细胞快速增殖。图5 受致癌KRAS突变影响的KRAS蛋白和代谢途径 No.4KRAS突变的常用检测技术与局限◆ 检测方法①直接测序法(如Sanger测序)：敏感性低(需肿瘤细胞占比≥10–25%)，可检测未知突变。②BEAMing技术：敏感性高(可检测<1%突变)，但临床常规应用受成本限制。③焦磷酸测序(Pyrosequencing)：在FIRE-3试验中用于KRAS突变检测，灵敏度1–10%。④Luminex技术：敏感性约1–10%，在RASKET试验中用于KRAS突变分型◆ 临床局限性①样本质量影响：石蜡包埋样本的DNA降解可导致G>A、C>T伪突变，影响结果准确性。②异质性检测：部分KRAS突变呈亚克隆状态，突变等位基因频率低时易漏检。RenyuBio仁域生物02KRASG12C突变 No.1KRASG12C突变的分子特征该突变指KRAS蛋白第12位的甘氨酸被半胱氨酸取代，导致KRAS(OFF)状态积累。这种突变会通过空间位阻阻止GTP酶激活蛋白(GAPs)的相互作用，降低GTP酶活性，进而使活性KRASG12C-GTP蛋白(KRAS(ON))增多。图6 处于失活GDP结合状态的KRASG12C蛋白模型 No.2KRASG12C突变频率与分布◆ 肺癌方面：在非小细胞肺癌(NSCLC)中，KRASG12C突变约占13%-25%，在肺腺癌中更为常见。不同种族和性别存在差异，女性患者的突变率相对较高，且该突变与吸烟密切相关，多见于吸烟者。图7 NSCLC中的热点KRAS突变◆ 结直肠癌方面：在转移性结直肠癌(mCRC)中，KRASG12C突变发生率约为3%。在所有结直肠癌样本中，其突变频率低于G12D、G12V等突变类型，占比约3.4%。 No.3KRASG12C突变的相关临床特征◆ 肺癌临床特征：携带KRASG12C突变的NSCLC患者，肿瘤生长相对迅速，容易发生转移，常见转移部位包括脑等。患者对传统化疗和免疫疗法反应较差，预后不佳，生存期较短。◆ 结直肠癌临床特征：KRASG12C突变的结直肠癌患者，无进展生存期(PFS)较差，接受化疗时，一线化疗的中位PFS为6.4个月，二线为3.9个月，三线为3.0个月。与KRAS非G12C突变患者相比，总生存期(OS)更差。 No.4KRASG12C突变的分子机制与信号通路◆ 突变影响蛋白活性：正常情况下，KRAS蛋白通过结合GTP和GDP在激活和失活状态间转换，调控细胞生长和分化。KRASG12C突变导致第12位氨基酸由甘氨酸突变为半胱氨酸，使KRAS蛋白对GTP的亲和力增强，持续处于激活状态，无法正常调控细胞，促进肿瘤细胞的增殖和存活。◆ 激活下游信号通路：激活态的KRASG12C蛋白可激活下游的MAPK和PI3K-AKT等信号通路。如在MAPK通路中，激活RAF、MEK、ERK等，促进细胞增殖、分化和存活；在PI3K-AKT通路中，激活AKT，抑制细胞凋亡，增强细胞的生存能力。◆ 与其他基因的关系：在肺癌中，KRASG12C突变常与TP53、STK11等基因突变共存，但与EGFR突变、EML4-ALK融合等驱动突变互斥。在结直肠癌中，KRASG12C突变与其他驱动突变大多相互排斥，仅少数病例存在相关共突变。RenyuBio仁域生物03KRASG12D突变 No.1KRASG12D突变的分子特征与临床意义◆ 突变机制：KRASG12D突变指KRAS蛋白第12位甘氨酸被天冬氨酸取代，导致GTP酶活性降低，使KRAS持续处于GTP结合的激活状态，激活下游MAPK(如ERK)和PI3K-AKT信号通路，驱动细胞异常增殖。◆ 信号激活：突变蛋白通过与SOS1(鸟嘌呤核苷酸交换因子)结合，促进GDP向GTP转换，维持信号持续传导；同时，其天冬氨酸(Asp12)可与抑制剂形成盐桥，为药物设计提供靶点。◆ 与其他信号通路的交互①ERBB家族依赖：KRASG12D驱动的肿瘤依赖ERBB受体酪氨酸激酶(如EGFR)激活，抑制ERBB可增强MEK抑制剂疗效。②RhoA/Wnt信号：KRASG12D激活RhoA，抑制Wnt/β-catenin信号，减少肿瘤转移潜能。◆ 临床预后与治疗敏感性①预后争议：部分研究显示KRASG12D突变与更短的无进展生存期(PFS)和总生存期(OS)相关，但也有研究认为其预后影响与其他KRAS亚型无显著差异。②治疗响应：KRASG12D突变患者对贝伐珠单抗敏感性较低，且STK11/KEAP1共突变会削弱免疫治疗效果。 No.2KRASG12D相关信号通路与调控网络◆ 核心信号通路①ERBB-RAS-ERK轴：KRASG12D驱动的肿瘤依赖ERBB家族受体酪氨酸激酶(如EGFR)激活，抑制ERBB可增强MEK抑制剂疗效🔶4-44🔶。②SOS1-KRAS相互作用：SOS1作为鸟嘌呤核苷酸交换因子，促进KRASG12D的GTP结合，其抑制剂(如BI-3406)可阻断KRAS激活。◆ 非经典通路调控①RhoA/Wnt信号：KRASG12D通过抑制Wnt/β-catenin信号，减少肿瘤转移潜能。②NF-κB通路：KRASG12D与IKKα协同激活NF-κB，促进肿瘤生存，其抑制剂硼替佐米在侵袭性黏液腺癌中显示部分活性。RenyuBio仁域生物04不同KRAS突变亚型的差异(G12C vs G12D) No.1分子机制与信号通路差异◆ 构象与结合特性①G12C：突变产生的半胱氨酸可与抑制剂共价结合(如Sotorasib)，锁定KRAS于失活状态。②G12D：天冬氨酸(Asp12)通过盐桥与抑制剂结合(如MRTX1133)，但无法形成共价键，需依赖非共价相互作用。◆ 下游信号通路激活模式①G12C：主要激活RAF/MEK/ERK通路，对RALGDS结合影响较小。②G12D：因Asp12的空间位阻，干扰KRAS同源二聚体形成及RALGDS结合，导致RAL信号未激活。此外，G12D激活PI3K/AKT通路的能力更强，且依赖ERBB家族受体酪氨酸激酶(如EGFR)的上游信号。 No.2共突变模式差异◆ 常见共突变①G12C：常与TP53(17–50%)、KEAP1(6–23%)、STK11(10–28%)共突变。②G12D：合并STK11(15.9%)、TP53(33.6%)、KEAP1(9.4%)突变较多，其中STK11/KEAP1共突变与不良预后相关。◆ 与其他驱动突变的互斥性：均与EGFR突变、EML4-ALK融合互斥，但G12D突变与EGFR共突变率(11.6%)略高于G12C。 No.3药物开发策略差异◆ 抑制剂设计思路①G12C：利用半胱氨酸的共价结合特性开发抑制剂。②G12D：依赖非共价结合(如盐桥、氢键)，需设计与Asp12特异性作用的分子(如MRTX1133的吡啶并嘧啶骨架)。◆ 联合治疗策略：G12D因依赖ERBB信号，需联合EGFR抑制剂(如Erlotinib)增强疗效；而G12C更常与免疫治疗或SHP2抑制剂联用。RenyuBio仁域生物05KRAS靶向治疗进展与药物开发图8 KRAS的直接抑制剂 No.1KRASG12C抑制剂：从突破到局限◆ 作用机制：首款获批的KRASG12C抑制剂(如Sotorasib、Adagrasib)为“OFF状态”抑制剂，通过与KRASG12C(OFF)中突变的半胱氨酸12附近的变构结合口袋(P2口袋)共价结合，阻止GDP向GTP转换，从而抑制RAS-效应器相互作用。尽管KRASG12C突变会导致KRAS(ON)积累，但细胞中仍有25%的KRAS处于GDP结合的失活状态，这为抑制剂发挥作用提供了可能。图9 对OFF状态KRASG12C抑制剂的“靶向”和“脱靶”机制总结◆ 第一代抑制剂的突破与局限①Sotorasib(AMG510)：通过与G12C半胱氨酸共价结合，锁定其于失活状态(KRAS(OFF))。在NSCLC中ORR达33.3%，mPFS6.9个月，但在结直肠癌(CRC)中ORR仅约10%，联合Panitumumab在结直肠癌中mPFS达5.6个月。②Adagrasib(MRTX849)：选择性结合KRASG12C-GDP，II期试验显示NSCLC患者ORR为42.9%，联合Cetuximab使结直肠癌ORR提升至34%。③局限性：由于KRAS在GDP和GTP结合状态之间的动态“循环”，使得靶向GDP结合形式无法完全阻断致癌驱动。图10 KRASG12C的耐药机制◆ 第二代抑制剂的优化：提升靶点占有率、延长作用时间，克服第一代抑制剂的耐药问题(如H95D突变)①D-1553：一种新型口服强效KRASG12C抑制剂。I期研究中，NSCLC患者ORR达40.5%，DCR为91.9%，脑转移患者ORR17%(样本量6例)。安全性方面，94.9%的患者出现治疗相关不良事件，38.0%的患者发生3级或4级不良事件，多数不良事件可控。②GDC-6036(Divarasib)：亲和力比Sotorasib高5-20倍，单药ORR29.1%，联合Cetuximab在CRC中ORR达62.5%，mPFS8.1个月。③LY3537982(Olomorasib)：一种强效抑制剂，能实现持续的>90%的靶点占有率，对第一代抑制剂耐药患者仍有效。LOXO-RAS-20001试验显示安全性良好，颅内结果待公布。④FMC-376：能同时结合KRAS-GDP和GTP构象，对“ON”状态KRAS耐药突变的活性比Adagrasib高14-30倍，已进入I/II期临床试验。⑤IBI351：一种不可逆的KRASG12C共价抑制剂。II期研究确认ORR为46.6%，DCR为90.5%，脑转移患者疗效未单报。⑥D3S-001：快速靶标结合动力学，30分钟内实现>95%靶标占有率，对Sotorasib耐药模型有效，I期试验显示持久响应。表1 KRASG12 抑制剂在非小细胞肺癌中的应用◆ 联合治疗策略①EGFR抑制剂联用：Sotorasib联合EGFR抑制剂(如Erlotinib)在小鼠模型中可克服CRC中的EGFR反馈激活，使联合治疗ORR提升至43%，显著高于单药22%。②免疫治疗联合：Sotorasib可重塑肿瘤微环境为促炎状态，与PD-(L)1抑制剂联用在肺癌模型中增强疗效，但CRC中因免疫抑制微环境需进一步验证。图11 临床研究中增强KRASG12C系列抑制剂疗效的组合策略 No.2KRASG12D抑制剂：非共价结合的新探索◆ KRASG12D非共价小分子抑制剂①MRTX1133：非共价结合SwitchII口袋，抑制SOS1催化的核苷酸交换，阻断KRAS-GTP形成。临床前模型中抑制胰腺癌和结直肠癌细胞增殖，I/II期试验正在评估，但因药代动力学问题已终止。②TH-Z816/TH-Z827/TH-Z835：以G12C抑制剂MRTX22为骨架，引入烷基胺基团与Asp12形成盐桥，选择性结合KRASG12D-GDP/GTP，阻断KRAS-RAF相互作用，抑制MAPK和PI3K/mTOR通路。◆ KRASG12D抑制性肽类(KS-58、NKTP-3)①NKTP-3：双靶点环肽，先结合癌细胞膜NRP1，再进入细胞与KRASG12D结合，抑制AKT和ERK磷酸化，在A427细胞异种移植模型中显著抗肿瘤，无明显毒性。②KS-58：KRpep-2d衍生物，通过双环结构阻断KRAS-SOS1和KRAS-BRAF相互作用，选择性抑制KRASG12D阳性细胞(如A427、PANC-1)增殖，体内模型中肿瘤缩小但药代动力学需优化。表2 KRASG12D抑制剂临床试验◆ 联合EGFR抑制剂的协同效应：CRC中KRASG12D突变依赖EGFR上游信号，MRTX1133联合西妥昔单抗可阻断反馈激活，在细胞模型中抑制PI3K/AKT和ERK磷酸化，延缓耐药发生。 No.3泛KRAS与通路靶向药物：突破突变亚型限制◆ 泛KRAS抑制剂①BI-2865：非共价结合KRAS非激活态，抑制G12D/V突变细胞增殖，通过阻止核苷酸交换发挥作用，但可能因激活其他RAS亚型(如HRAS/NRAS)导致耐药，对抑制作用较弱。②ADT-007：新型泛RAS抑制剂，在CRC小鼠模型中诱导肿瘤凋亡，机制为靶向RAS效应器结构域，对G12C/D/V突变均有效。 No.4新型疗法：从降解剂到免疫干预◆ KRAS(ON)抑制剂：靶向激活态KRAS通过“分子胶水”技术结合KRAS激活态(GTP-bound)，诱导其与免疫亲和素CyclophilinA(CYPA)形成稳定三元复合物，阻断KRAS与下游效应蛋白(如RAF)的相互作用，抑制下游信号传导。区别于KRAS(OFF)抑制剂(如Sotorasib)，KRAS(ON)抑制剂可靶向多种突变亚型(如G12D、G12V)，且不依赖KRAS的GDP结合状态。代表药物RMC-6236(G12C/D/V等突变)、RMC-9805(G12D)、RMC-6291、BBO-8520等。◆ PROTAC降解剂：诱导KRAS蛋白降解双功能分子通过E3泛素连接酶配体(如VHL)与KRAS结合域连接，招募E3酶标记KRAS蛋白，经蛋白酶体降解，实现靶向敲低。代表药物ASP3082(G12D)、XX4–88、ACBI3、LC-2等。◆ 抗RAS疫苗(GI-4000、TG02)①GI-4000：热灭活重组酵母表达KRAS突变肽，PhaseI试验显示可诱导T细胞应答，与PD-1抑制剂联用治疗KRAS突变型CRC的安全性已验证。②mRNA疫苗(mRNA-5671)：编码KRAS突变新抗原，刺激CD8+T细胞应答，正进行PhaseI试验评估联合pembrolizumab的疗效。◆ 核酸药物：剪接调控与ASO利用反义寡核苷酸(ASO)靶向KRAS突变转录本，或通过剪接调控诱导突变型KRAS降解。例如，针对KRASQ61K突变的剪接调节剂可选择性杀伤突变细胞，避免野生型KRAS抑制毒性。图12 KRAS抑制剂目前临床试验总结 No.5靶向KRAS信号通路的间接策略图13 靶向KRAS信号通路的间接策略◆ SOS1抑制剂①BI-3406：结合SOS1催化域，阻止其与KRAS相互作用，减少GTP-KRAS形成，对G12D/E/V突变肿瘤有效，与MEK抑制剂联用可增强疗效。②BAY-293：靶向SOS1表面口袋，阻断KRAS-SOS1复合物形成，与KRASG12D共价抑制剂联用有协同效应。◆ MEK抑制剂：单药疗效有限，但与免疫治疗(如抗PD-L1)联合可增强肿瘤微环境T细胞浸润。图14 RAS抑制剂表现出不同的作用机制◆ SHP2抑制剂①RMC-4550/SHP099：变构抑制SHP2，阻断SOS1介导的KRAS激活，降低RAS-ERK信号，对KRASG12D突变细胞敏感。②RMC-4630/TN0155：变构抑制SHP2，阻断RTK介导的KRAS激活，与KRASG12C抑制剂联用可降低RAS-ERK信号，克服反馈耐药，PhaseI/II试验正在进行中。◆ GRP78/HSP90抑制剂①HA15/YuW70：靶向ER分子伴侣GRP78，减少KRASG12D蛋白成熟，同时抑制PI3K、TGF-β等通路，诱导ER应激和细胞凋亡，对KRAS突变型CRC细胞具选择性毒性。图15 RAS抑制剂的临床阶段表3 靶向KRAS信号通路的间接策略RenyuBio仁域生物06KRAS耐药机制分类与联合治疗 No.1原发性耐药与KEAP1、SMARCA4、CDKN2A等基因突变相关，这些突变会导致患者对KRAS抑制剂治疗的临床结局更差，疾病早期进展风险升高。 No.2获得性耐药◆ “靶向”耐药机制(KRAS自身突变)①KRAS基因二次突变：KRASG12基因发生二次突变(如G12D、G12V)，或KRAS其他位点突变(如R68S、H95D)，阻止抑制剂结合或激活下游通路。②KRAS拷贝数扩增：突变型KRAS基因扩增或拷贝数增加，会增强信号输出，降低抑制剂的相对作用效率。◆ “非靶向”机制(旁路激活)①上游受体酪氨酸激酶(RTK)基因：如EGFR、MET，扩增或突变，激活KRAS非依赖的信号通路。②下游通路基因：如NRAS、BRAF、PI3KCA，激活突变，或抑癌基因(如PTEN)失活突变，绕过KRAS调控。③其他：基因融合(如EML4-ALK)或MET扩增，通过HGF/MET通路激活AKT和ERK。图16 KRAS抑制期间结直肠癌的耐药机制 No.3非遗传机制耐药◆ 生长因子受体(GFR)上游再激活：EGFR、HER2等RTK快速激活，增加KRAS突变型蛋白输出并激活野生型KRAS/NRAS，恢复MAPK信号。如Sotorasib治疗后48小时内可观察到ERK和RSK磷酸化升高。◆ 上皮-间质转化(EMT)：KRAS抑制剂诱导EMT，通过TGF-β信号增强肿瘤细胞迁移能力，同时激活PI3K/AKT通路，形成耐药微环境。◆ Wnt/β-catenin通路：Wnt/β-catenin通路与KRAS突变协同激活，促进肿瘤细胞存活。例如，β-catenin与突变KRAS结合可增强其稳定性，削弱抑制剂效果。◆ 血脑屏障(BBB)：BBB限制药物进入中枢神经系统(CNS)，导致脑转移灶药物浓度不足，形成局部耐药。◆ 肿瘤微环境(TME)：KRAS突变肿瘤的TME具有免疫抑制性，RAS抑制可短暂降低免疫抑制，增强免疫治疗敏感性，但具体耐药机制尚不明确。 No.4联合治疗策略为应对耐药问题，联合治疗策略不断发展，包括RTK抑制(如联合EGFR抑制剂)、SHP2抑制(联合SHP2抑制剂阻断RTK-RAS信号)、免疫与代谢靶向联合(如联合PD-1抑制剂重塑肿瘤微环境，或联合代谢调节剂诱导突变细胞能量危机)等。表4 临床试验中当前RAS抑制剂的单一和联合疗法RenyuBio仁域生物07挑战与未来方向 No.1当前瓶颈◆ 耐药机制复杂：KRAS抑制剂治疗后可出现H95/Y96突变、PI3K通路激活或YAP/TEAD核转位，需联合多靶点抑制。◆ 器官特异性差异：CRC中KRAS突变依赖EGFR反馈激活，而肺癌更依赖免疫微环境，需开发适配CRC生物学特征的联合方案。 No.2未来策略◆ 共价KRASG12D抑制剂开发：借鉴G12C抑制剂思路，设计与Asp12共价结合的分子，提升结合稳定性。◆ 液体活检动态监测：通过ctDNA追踪KRAS突变克隆演变，如治疗中出现G12D二次突变，及时切换至MRTX1133联合方案。◆ 代谢靶向联合：针对KRAS突变细胞的谷氨酰胺依赖，联用谷氨酰胺酶抑制剂(如CB-839)与KRAS抑制剂，诱导能量危机。RenyuBio仁域生物抗体发现服务 & 产品01羊驼免疫&骆驼免疫—自建现代化养殖农场02万亿级天然抗体库产品—轻松DIY科研抗体03配套产品—助您轻松搭建基因工程抗体平台参考文献Jiang M, Ma S, Xuan Y, Chen K. 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2025-08-02

·靶点圈

一文带你读懂KRAS从“不可成药”到靶向突破的成功奥秘

01KRAS突变的生物学特征 No.1KRAS信号激活与突变机制◆ RAS基因家族：RAS基因家族包括HRAS、KRAS、NRAS，均为癌基因，其中KRAS是癌症中突变最频繁的亚型(占RAS突变的81%)，其次为NRAS(15%)和HRAS(4%)。◆ KRAS蛋白：是KRAS基因的产物，属于小GTP酶家族，在活性GTP结合状态(KRAS(ON))和失活GDP结合状态(KRAS(OFF))之间动态转换，调控细胞增殖、生存等信号。图1 KRAS GTPase蛋白序列和结构◆ KRAS激活：上游RTK(如EGFR)通过SOS1促进KRAS-GTP形成，下游激活RAF-MEK-ERK和PI3K-AKT等通路，驱动肿瘤发生。图2 KRAS的激活状态及其对信号通路的影响◆ KRAS突变：KRAS突变占人类癌症的20%以上，通过破坏GTP结合口袋的构象，导致GTP酶活性降低，维持KRAS持续激活状态，驱动肿瘤生长。 No.2KRAS突变类型与表达调控◆ KRAS突变类型与肿瘤分布：KRAS突变中约95%发生在G12位点，其次为G13(3–5%)和Q61(1–2%)。G12突变包括G12C、G12D、G12V、G12R、G12S等，其中G12C、G12D、G12V占所有KRAS突变的60–70%。①G12C：约13%，多见于非小细胞肺癌(12–15%)，在结直肠癌(2–3%)和胰腺癌(<1%)中罕见。②G12D：约26%，是结直肠癌(30–40%)和胰腺癌(40–50%)的最常见突变亚型。③G12V：约21%，在子宫内膜癌、卵巢癌中占比可达15–20%。图3 各种癌症类型的KRAS突变率◆ KRAS突变受非编码RNA的调控①长链非编码RNA(lncRNA)：lncRNA通过调控染色质重塑和转录因子活性，维持KRAS突变细胞的恶性表型。②微小RNA(miRNA)：miRNA通过靶向KRAS的3'UTR或下游通路组件，调节信号传导强度。 No.3KRAS突变对肿瘤微环境与代谢的影响◆ KRAS突变对肿瘤微环境与细胞行为影响①癌相关成纤维细胞(CAFs)重编程：KRAS激活TFCP2，诱导CAFs向脂质富集细胞分化，促进血管生成和肿瘤进展。②免疫微环境抑制：KRAS突变通过分泌TGF-β、IL-6等细胞因子，招募调节性T细胞(Treg)和髓系抑制细胞(MDSCs)，形成免疫抑制微环境，削弱抗肿瘤免疫应答。③癌症干细胞(CSCs)维持：KRAS突变激活CDK1，促进蛋白O-乙酰葡糖胺糖基化修饰，上调CSC标志物SOX2，增强肿瘤干细胞的自我更新和治疗耐药性。④巨胞饮作用(MP)激活：KRAS突变激活MP，增强细胞对营养物质的摄取，支持肿瘤在代谢压力下的生存。⑤细胞竞争与侵袭：KRAS突变激活NF-κB-MMP21通路，促进肿瘤细胞对邻近正常细胞的排斥和扩散浸润，增强肿瘤的侵袭性。图4 靶向致癌KRAS驱动的肿瘤中的代谢途径◆ KRAS突变促进代谢重编程①糖酵解与谷氨酰胺利用增强：KRAS突变上调己糖激酶、谷氨酰胺酶等酶活性，促进有氧糖酵解和谷氨酰胺分解，为肿瘤细胞提供能量和生物合成前体。②天冬氨酸代谢依赖：突变型KRAS激活PCK1、ASS1等酶，增强天冬氨酸和尿素循环代谢，维持核苷酸合成和氧化还原平衡，支持细胞快速增殖。图5 受致癌KRAS突变影响的KRAS蛋白和代谢途径 No.4KRAS突变的常用检测技术与局限◆ 检测方法①直接测序法(如Sanger测序)：敏感性低(需肿瘤细胞占比≥10–25%)，可检测未知突变。②BEAMing技术：敏感性高(可检测<1%突变)，但临床常规应用受成本限制。③焦磷酸测序(Pyrosequencing)：在FIRE-3试验中用于KRAS突变检测，灵敏度1–10%。④Luminex技术：敏感性约1–10%，在RASKET试验中用于KRAS突变分型◆ 临床局限性①样本质量影响：石蜡包埋样本的DNA降解可导致G>A、C>T伪突变，影响结果准确性。②异质性检测：部分KRAS突变呈亚克隆状态，突变等位基因频率低时易漏检。RenyuBio仁域生物02KRASG12C突变 No.1KRASG12C突变的分子特征该突变指KRAS蛋白第12位的甘氨酸被半胱氨酸取代，导致KRAS(OFF)状态积累。这种突变会通过空间位阻阻止GTP酶激活蛋白(GAPs)的相互作用，降低GTP酶活性，进而使活性KRASG12C-GTP蛋白(KRAS(ON))增多。图6 处于失活GDP结合状态的KRASG12C蛋白模型 No.2KRASG12C突变频率与分布◆ 肺癌方面：在非小细胞肺癌(NSCLC)中，KRASG12C突变约占13%-25%，在肺腺癌中更为常见。不同种族和性别存在差异，女性患者的突变率相对较高，且该突变与吸烟密切相关，多见于吸烟者。图7 NSCLC中的热点KRAS突变◆ 结直肠癌方面：在转移性结直肠癌(mCRC)中，KRASG12C突变发生率约为3%。在所有结直肠癌样本中，其突变频率低于G12D、G12V等突变类型，占比约3.4%。 No.3KRASG12C突变的相关临床特征◆ 肺癌临床特征：携带KRASG12C突变的NSCLC患者，肿瘤生长相对迅速，容易发生转移，常见转移部位包括脑等。患者对传统化疗和免疫疗法反应较差，预后不佳，生存期较短。◆ 结直肠癌临床特征：KRASG12C突变的结直肠癌患者，无进展生存期(PFS)较差，接受化疗时，一线化疗的中位PFS为6.4个月，二线为3.9个月，三线为3.0个月。与KRAS非G12C突变患者相比，总生存期(OS)更差。 No.4KRASG12C突变的分子机制与信号通路◆ 突变影响蛋白活性：正常情况下，KRAS蛋白通过结合GTP和GDP在激活和失活状态间转换，调控细胞生长和分化。KRASG12C突变导致第12位氨基酸由甘氨酸突变为半胱氨酸，使KRAS蛋白对GTP的亲和力增强，持续处于激活状态，无法正常调控细胞，促进肿瘤细胞的增殖和存活。◆ 激活下游信号通路：激活态的KRASG12C蛋白可激活下游的MAPK和PI3K-AKT等信号通路。如在MAPK通路中，激活RAF、MEK、ERK等，促进细胞增殖、分化和存活；在PI3K-AKT通路中，激活AKT，抑制细胞凋亡，增强细胞的生存能力。◆ 与其他基因的关系：在肺癌中，KRASG12C突变常与TP53、STK11等基因突变共存，但与EGFR突变、EML4-ALK融合等驱动突变互斥。在结直肠癌中，KRASG12C突变与其他驱动突变大多相互排斥，仅少数病例存在相关共突变。RenyuBio仁域生物03KRASG12D突变 No.1KRASG12D突变的分子特征与临床意义◆ 突变机制：KRASG12D突变指KRAS蛋白第12位甘氨酸被天冬氨酸取代，导致GTP酶活性降低，使KRAS持续处于GTP结合的激活状态，激活下游MAPK(如ERK)和PI3K-AKT信号通路，驱动细胞异常增殖。◆ 信号激活：突变蛋白通过与SOS1(鸟嘌呤核苷酸交换因子)结合，促进GDP向GTP转换，维持信号持续传导；同时，其天冬氨酸(Asp12)可与抑制剂形成盐桥，为药物设计提供靶点。◆ 与其他信号通路的交互①ERBB家族依赖：KRASG12D驱动的肿瘤依赖ERBB受体酪氨酸激酶(如EGFR)激活，抑制ERBB可增强MEK抑制剂疗效。②RhoA/Wnt信号：KRASG12D激活RhoA，抑制Wnt/β-catenin信号，减少肿瘤转移潜能。◆ 临床预后与治疗敏感性①预后争议：部分研究显示KRASG12D突变与更短的无进展生存期(PFS)和总生存期(OS)相关，但也有研究认为其预后影响与其他KRAS亚型无显著差异。②治疗响应：KRASG12D突变患者对贝伐珠单抗敏感性较低，且STK11/KEAP1共突变会削弱免疫治疗效果。 No.2KRASG12D相关信号通路与调控网络◆ 核心信号通路①ERBB-RAS-ERK轴：KRASG12D驱动的肿瘤依赖ERBB家族受体酪氨酸激酶(如EGFR)激活，抑制ERBB可增强MEK抑制剂疗效🔶4-44🔶。②SOS1-KRAS相互作用：SOS1作为鸟嘌呤核苷酸交换因子，促进KRASG12D的GTP结合，其抑制剂(如BI-3406)可阻断KRAS激活。◆ 非经典通路调控①RhoA/Wnt信号：KRASG12D通过抑制Wnt/β-catenin信号，减少肿瘤转移潜能。②NF-κB通路：KRASG12D与IKKα协同激活NF-κB，促进肿瘤生存，其抑制剂硼替佐米在侵袭性黏液腺癌中显示部分活性。RenyuBio仁域生物04不同KRAS突变亚型的差异(G12C vs G12D) No.1分子机制与信号通路差异◆ 构象与结合特性①G12C：突变产生的半胱氨酸可与抑制剂共价结合(如Sotorasib)，锁定KRAS于失活状态。②G12D：天冬氨酸(Asp12)通过盐桥与抑制剂结合(如MRTX1133)，但无法形成共价键，需依赖非共价相互作用。◆ 下游信号通路激活模式①G12C：主要激活RAF/MEK/ERK通路，对RALGDS结合影响较小。②G12D：因Asp12的空间位阻，干扰KRAS同源二聚体形成及RALGDS结合，导致RAL信号未激活。此外，G12D激活PI3K/AKT通路的能力更强，且依赖ERBB家族受体酪氨酸激酶(如EGFR)的上游信号。 No.2共突变模式差异◆ 常见共突变①G12C：常与TP53(17–50%)、KEAP1(6–23%)、STK11(10–28%)共突变。②G12D：合并STK11(15.9%)、TP53(33.6%)、KEAP1(9.4%)突变较多，其中STK11/KEAP1共突变与不良预后相关。◆ 与其他驱动突变的互斥性：均与EGFR突变、EML4-ALK融合互斥，但G12D突变与EGFR共突变率(11.6%)略高于G12C。 No.3药物开发策略差异◆ 抑制剂设计思路①G12C：利用半胱氨酸的共价结合特性开发抑制剂。②G12D：依赖非共价结合(如盐桥、氢键)，需设计与Asp12特异性作用的分子(如MRTX1133的吡啶并嘧啶骨架)。◆ 联合治疗策略：G12D因依赖ERBB信号，需联合EGFR抑制剂(如Erlotinib)增强疗效；而G12C更常与免疫治疗或SHP2抑制剂联用。RenyuBio仁域生物05KRAS靶向治疗进展与药物开发图8 KRAS的直接抑制剂 No.1KRASG12C抑制剂：从突破到局限◆ 作用机制：首款获批的KRASG12C抑制剂(如Sotorasib、Adagrasib)为“OFF状态”抑制剂，通过与KRASG12C(OFF)中突变的半胱氨酸12附近的变构结合口袋(P2口袋)共价结合，阻止GDP向GTP转换，从而抑制RAS-效应器相互作用。尽管KRASG12C突变会导致KRAS(ON)积累，但细胞中仍有25%的KRAS处于GDP结合的失活状态，这为抑制剂发挥作用提供了可能。图9 对OFF状态KRASG12C抑制剂的“靶向”和“脱靶”机制总结◆ 第一代抑制剂的突破与局限①Sotorasib(AMG510)：通过与G12C半胱氨酸共价结合，锁定其于失活状态(KRAS(OFF))。在NSCLC中ORR达33.3%，mPFS6.9个月，但在结直肠癌(CRC)中ORR仅约10%，联合Panitumumab在结直肠癌中mPFS达5.6个月。②Adagrasib(MRTX849)：选择性结合KRASG12C-GDP，II期试验显示NSCLC患者ORR为42.9%，联合Cetuximab使结直肠癌ORR提升至34%。③局限性：由于KRAS在GDP和GTP结合状态之间的动态“循环”，使得靶向GDP结合形式无法完全阻断致癌驱动。图10 KRASG12C的耐药机制◆ 第二代抑制剂的优化：提升靶点占有率、延长作用时间，克服第一代抑制剂的耐药问题(如H95D突变)①D-1553：一种新型口服强效KRASG12C抑制剂。I期研究中，NSCLC患者ORR达40.5%，DCR为91.9%，脑转移患者ORR17%(样本量6例)。安全性方面，94.9%的患者出现治疗相关不良事件，38.0%的患者发生3级或4级不良事件，多数不良事件可控。②GDC-6036(Divarasib)：亲和力比Sotorasib高5-20倍，单药ORR29.1%，联合Cetuximab在CRC中ORR达62.5%，mPFS8.1个月。③LY3537982(Olomorasib)：一种强效抑制剂，能实现持续的>90%的靶点占有率，对第一代抑制剂耐药患者仍有效。LOXO-RAS-20001试验显示安全性良好，颅内结果待公布。④FMC-376：能同时结合KRAS-GDP和GTP构象，对“ON”状态KRAS耐药突变的活性比Adagrasib高14-30倍，已进入I/II期临床试验。⑤IBI351：一种不可逆的KRASG12C共价抑制剂。II期研究确认ORR为46.6%，DCR为90.5%，脑转移患者疗效未单报。⑥D3S-001：快速靶标结合动力学，30分钟内实现>95%靶标占有率，对Sotorasib耐药模型有效，I期试验显示持久响应。表1 KRASG12 抑制剂在非小细胞肺癌中的应用◆ 联合治疗策略①EGFR抑制剂联用：Sotorasib联合EGFR抑制剂(如Erlotinib)在小鼠模型中可克服CRC中的EGFR反馈激活，使联合治疗ORR提升至43%，显著高于单药22%。②免疫治疗联合：Sotorasib可重塑肿瘤微环境为促炎状态，与PD-(L)1抑制剂联用在肺癌模型中增强疗效，但CRC中因免疫抑制微环境需进一步验证。图11 临床研究中增强KRASG12C系列抑制剂疗效的组合策略 No.2KRASG12D抑制剂：非共价结合的新探索◆ KRASG12D非共价小分子抑制剂①MRTX1133：非共价结合SwitchII口袋，抑制SOS1催化的核苷酸交换，阻断KRAS-GTP形成。临床前模型中抑制胰腺癌和结直肠癌细胞增殖，I/II期试验正在评估，但因药代动力学问题已终止。②TH-Z816/TH-Z827/TH-Z835：以G12C抑制剂MRTX22为骨架，引入烷基胺基团与Asp12形成盐桥，选择性结合KRASG12D-GDP/GTP，阻断KRAS-RAF相互作用，抑制MAPK和PI3K/mTOR通路。◆ KRASG12D抑制性肽类(KS-58、NKTP-3)①NKTP-3：双靶点环肽，先结合癌细胞膜NRP1，再进入细胞与KRASG12D结合，抑制AKT和ERK磷酸化，在A427细胞异种移植模型中显著抗肿瘤，无明显毒性。②KS-58：KRpep-2d衍生物，通过双环结构阻断KRAS-SOS1和KRAS-BRAF相互作用，选择性抑制KRASG12D阳性细胞(如A427、PANC-1)增殖，体内模型中肿瘤缩小但药代动力学需优化。表2 KRASG12D抑制剂临床试验◆ 联合EGFR抑制剂的协同效应：CRC中KRASG12D突变依赖EGFR上游信号，MRTX1133联合西妥昔单抗可阻断反馈激活，在细胞模型中抑制PI3K/AKT和ERK磷酸化，延缓耐药发生。 No.3泛KRAS与通路靶向药物：突破突变亚型限制◆ 泛KRAS抑制剂①BI-2865：非共价结合KRAS非激活态，抑制G12D/V突变细胞增殖，通过阻止核苷酸交换发挥作用，但可能因激活其他RAS亚型(如HRAS/NRAS)导致耐药，对抑制作用较弱。②ADT-007：新型泛RAS抑制剂，在CRC小鼠模型中诱导肿瘤凋亡，机制为靶向RAS效应器结构域，对G12C/D/V突变均有效。 No.4新型疗法：从降解剂到免疫干预◆ KRAS(ON)抑制剂：靶向激活态KRAS通过“分子胶水”技术结合KRAS激活态(GTP-bound)，诱导其与免疫亲和素CyclophilinA(CYPA)形成稳定三元复合物，阻断KRAS与下游效应蛋白(如RAF)的相互作用，抑制下游信号传导。区别于KRAS(OFF)抑制剂(如Sotorasib)，KRAS(ON)抑制剂可靶向多种突变亚型(如G12D、G12V)，且不依赖KRAS的GDP结合状态。代表药物RMC-6236(G12C/D/V等突变)、RMC-9805(G12D)、RMC-6291、BBO-8520等。◆ PROTAC降解剂：诱导KRAS蛋白降解双功能分子通过E3泛素连接酶配体(如VHL)与KRAS结合域连接，招募E3酶标记KRAS蛋白，经蛋白酶体降解，实现靶向敲低。代表药物ASP3082(G12D)、XX4–88、ACBI3、LC-2等。◆ 抗RAS疫苗(GI-4000、TG02)①GI-4000：热灭活重组酵母表达KRAS突变肽，PhaseI试验显示可诱导T细胞应答，与PD-1抑制剂联用治疗KRAS突变型CRC的安全性已验证。②mRNA疫苗(mRNA-5671)：编码KRAS突变新抗原，刺激CD8+T细胞应答，正进行PhaseI试验评估联合pembrolizumab的疗效。◆ 核酸药物：剪接调控与ASO利用反义寡核苷酸(ASO)靶向KRAS突变转录本，或通过剪接调控诱导突变型KRAS降解。例如，针对KRASQ61K突变的剪接调节剂可选择性杀伤突变细胞，避免野生型KRAS抑制毒性。图12 KRAS抑制剂目前临床试验总结 No.5靶向KRAS信号通路的间接策略图13 靶向KRAS信号通路的间接策略◆ SOS1抑制剂①BI-3406：结合SOS1催化域，阻止其与KRAS相互作用，减少GTP-KRAS形成，对G12D/E/V突变肿瘤有效，与MEK抑制剂联用可增强疗效。②BAY-293：靶向SOS1表面口袋，阻断KRAS-SOS1复合物形成，与KRASG12D共价抑制剂联用有协同效应。◆ MEK抑制剂：单药疗效有限，但与免疫治疗(如抗PD-L1)联合可增强肿瘤微环境T细胞浸润。图14 RAS抑制剂表现出不同的作用机制◆ SHP2抑制剂①RMC-4550/SHP099：变构抑制SHP2，阻断SOS1介导的KRAS激活，降低RAS-ERK信号，对KRASG12D突变细胞敏感。②RMC-4630/TN0155：变构抑制SHP2，阻断RTK介导的KRAS激活，与KRASG12C抑制剂联用可降低RAS-ERK信号，克服反馈耐药，PhaseI/II试验正在进行中。◆ GRP78/HSP90抑制剂①HA15/YuW70：靶向ER分子伴侣GRP78，减少KRASG12D蛋白成熟，同时抑制PI3K、TGF-β等通路，诱导ER应激和细胞凋亡，对KRAS突变型CRC细胞具选择性毒性。图15 RAS抑制剂的临床阶段表3 靶向KRAS信号通路的间接策略RenyuBio仁域生物06KRAS耐药机制分类与联合治疗 No.1原发性耐药与KEAP1、SMARCA4、CDKN2A等基因突变相关，这些突变会导致患者对KRAS抑制剂治疗的临床结局更差，疾病早期进展风险升高。 No.2获得性耐药◆ “靶向”耐药机制(KRAS自身突变)①KRAS基因二次突变：KRASG12基因发生二次突变(如G12D、G12V)，或KRAS其他位点突变(如R68S、H95D)，阻止抑制剂结合或激活下游通路。②KRAS拷贝数扩增：突变型KRAS基因扩增或拷贝数增加，会增强信号输出，降低抑制剂的相对作用效率。◆ “非靶向”机制(旁路激活)①上游受体酪氨酸激酶(RTK)基因：如EGFR、MET，扩增或突变，激活KRAS非依赖的信号通路。②下游通路基因：如NRAS、BRAF、PI3KCA，激活突变，或抑癌基因(如PTEN)失活突变，绕过KRAS调控。③其他：基因融合(如EML4-ALK)或MET扩增，通过HGF/MET通路激活AKT和ERK。图16 KRAS抑制期间结直肠癌的耐药机制 No.3非遗传机制耐药◆ 生长因子受体(GFR)上游再激活：EGFR、HER2等RTK快速激活，增加KRAS突变型蛋白输出并激活野生型KRAS/NRAS，恢复MAPK信号。如Sotorasib治疗后48小时内可观察到ERK和RSK磷酸化升高。◆ 上皮-间质转化(EMT)：KRAS抑制剂诱导EMT，通过TGF-β信号增强肿瘤细胞迁移能力，同时激活PI3K/AKT通路，形成耐药微环境。◆ Wnt/β-catenin通路：Wnt/β-catenin通路与KRAS突变协同激活，促进肿瘤细胞存活。例如，β-catenin与突变KRAS结合可增强其稳定性，削弱抑制剂效果。◆ 血脑屏障(BBB)：BBB限制药物进入中枢神经系统(CNS)，导致脑转移灶药物浓度不足，形成局部耐药。◆ 肿瘤微环境(TME)：KRAS突变肿瘤的TME具有免疫抑制性，RAS抑制可短暂降低免疫抑制，增强免疫治疗敏感性，但具体耐药机制尚不明确。 No.4联合治疗策略为应对耐药问题，联合治疗策略不断发展，包括RTK抑制(如联合EGFR抑制剂)、SHP2抑制(联合SHP2抑制剂阻断RTK-RAS信号)、免疫与代谢靶向联合(如联合PD-1抑制剂重塑肿瘤微环境，或联合代谢调节剂诱导突变细胞能量危机)等。表4 临床试验中当前RAS抑制剂的单一和联合疗法RenyuBio仁域生物07挑战与未来方向 No.1当前瓶颈◆ 耐药机制复杂：KRAS抑制剂治疗后可出现H95/Y96突变、PI3K通路激活或YAP/TEAD核转位，需联合多靶点抑制。◆ 器官特异性差异：CRC中KRAS突变依赖EGFR反馈激活，而肺癌更依赖免疫微环境，需开发适配CRC生物学特征的联合方案。 No.2未来策略◆ 共价KRASG12D抑制剂开发：借鉴G12C抑制剂思路，设计与Asp12共价结合的分子，提升结合稳定性。◆ 液体活检动态监测：通过ctDNA追踪KRAS突变克隆演变，如治疗中出现G12D二次突变，及时切换至MRTX1133联合方案。◆ 代谢靶向联合：针对KRAS突变细胞的谷氨酰胺依赖，联用谷氨酰胺酶抑制剂(如CB-839)与KRAS抑制剂，诱导能量危机。RenyuBio仁域生物抗体发现服务 & 产品01羊驼免疫&骆驼免疫—自建现代化养殖农场02万亿级天然抗体库产品—轻松DIY科研抗体03配套产品—助您轻松搭建基因工程抗体平台仁域生物成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！protocol 获取 / 产品咨询邮箱｜find@renyubio.com电话｜19136178673地址｜成都市经开区科技产业孵化园关注我们，持续更新相关内容参考文献Jiang M, Ma S, Xuan Y, Chen K. Synthetic approaches and clinical application of KRAS inhibitors for cancer therapy. Eur J Med Chem. 2025 Jul 5;291:117626.Dong P, Ni J, Zheng X, Wang M, Yang M, Han H. Small molecules for Kirsten rat sarcoma viral oncogene homolog mutant cancers: Past, present, and future. Eur J Pharmacol. 2025 Jun 5;996:177428. Isermann T, Sers C, Der CJ, Papke B. KRAS inhibitors: resistance drivers and combinatorial strategies. Trends Cancer. 2025 Feb;11(2):91-116. Takeda M, Yoshida S, Inoue T, Sekido Y, Hata T, Hamabe A, Ogino T, Miyoshi N, Uemura M, Yamamoto H, Doki Y, Eguchi H. The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives. Cancers (Basel). 2025 Jan 27;17(3):428. Shi Y, Zheng H, Wang T, Zhou S, Zhao S, Li M, Cao B. Targeting KRAS: from metabolic regulation to cancer treatment. Mol Cancer. 2025 Jan 11;24(1):9. Liguori L, Salomone F, Viggiano A, Sabbatino F, Pepe S, Formisano L, Bianco R, Servetto A. 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2022-06-17

·PRNewswire

Biologic Therapy Market Information: By Product and Geography - Global Forecast till 2025

NEW YORK, June 17, 2022 /PRNewswire/ -- One of the key factors driving the Biologic Therapy Market growth is the strong R&D pipeline. The efficiency of biologics in the treatment of severe infections, malignancies, and immunological and hormonal disorders is encouraging manufacturers to invest in R&D for the development of biologics. For instance, monoclonal antibodies constitute one of the fastest-growing segments amongst biological therapies. To date, 88 monoclonal antibodies have been approved for different indications. Some of the examples are ICT-107 for glioblastoma, VGX-3100 for cervical cancer, NeuVax for breast cancer, NexVax2 for celiac disease, CRS-207 for pancreatic cancer, PEV7 for recurrent vulvovaginal candidiasis, and GI-4000 for pancreatic cancer. Similar is the case of biologics meant to be used as vaccines and therapeutic proteins, the pipeline of vendors like AbbVie, Amgen, Johnson & Johnson, and F. Hoffmann-La Roche clearly indicate huge investments in R&D. Apart from manufacturers that are actively involved in research on biologics, many research institutes are also engaged in developing novel biologics through industrial collaborations. Technavio has announced its latest market research report titled Biologic Therapeutics Market by Product and Geography - Forecast and Analysis 2021-2025 Get more information on Macro & Micro Economic Factor Analysis, Statistical Tools, and Trend Projection at Affordable Pricing options. Learn More The Biologic Therapy Market value is set to grow by USD 226.61 billion, progressing at a CAGR of 11% from 2020 to 2025, as per the latest report by Technavio. Moreover, the market is segmented by product (antibody therapeutics, vaccines, cell therapy, gene therapy, and other therapies) and geography (North America, Europe, Asia, and ROW). Biologic Therapy Market 2021-2025: Segmentation Product Antibody Therapeutics Vaccines Cell Therapy Gene Therapy Other Therapies The biologic therapy market share growth by antibody therapeutics will be significant during the forecast period. Monoclonal antibodies are amongst the most widely sold biologics and are even referred to as the future of medicine. Monoclonal antibodies are cloned from single-parent cells and are designed to recognize and bind to specific receptors on the surface of the cells. This specificity in action makes monoclonal antibodies more effective than conventional treatments for immunological and chronic ailments like cancer. Owing to these factors, it is expected that the global biologic therapy market will grow during the forecast period. Geography North America Europe Asia ROW 57% of the market's growth will originate from North America during the forecast period. The US is the key market for biologic therapy in North America. Market growth in this region will be slower than the growth of the market in the Asia region. One of the reasons for market growth in the Americas is the increased incidence of chronic diseases. The rise in the prevalence of major health disorders is mainly due to lifestyle changes and increased consumption of alcohol and tobacco in the US. However, market growth is expected to be only gradual due to the patent expiry of major biologics present in the market. Biologic Therapy Market 2021-2025: Scope Biologic Therapy Market size Biologic Therapy Market trends Biologic Therapy Market analysis High cost of biologics is one of the key challenges hindering the biologic therapy market growth. Biologics can be used for the treatment of several types of malignancies, hormonal imbalances, and autoimmune conditions, but they are expensive, which makes them beyond the reach of the economically underprivileged. The total manufacturing costs, which include the costs related to the clinical trials associated with biologics, account for vendors offering these products at high costs. The development of a biological molecule requires a separate living organism. Though bacterial production is not that costly, the production of therapeutic agents like monoclonal antibodies and vaccines becomes costly as they involve animal handling. The immunization of the animal and other procedures related to the production of antibodies and vaccines increases the cost of that product. Due to the high price of biologic therapy, many patients are unable to access this effective therapy, and this will remain a major challenge for the market during the forecast period. Biologic Therapy Market 2021-2025: Vendor Analysis The report analyzes the market's competitive landscape and offers information on several market vendors, including: AbbVie Inc. AstraZeneca Plc Bristol-Myers Squibb Co. F. Hoffmann-La Roche Ltd. GlaxoSmithKline Plc Johnson and Johnson Inc. Merck and Co. Inc. Novartis AG Pfizer Inc. Sanofi SA The biologic therapy market is concentrated and the vendors are deploying growth strategies such as partnering with research organizations and hospitals for R&D to compete in the market. Biologic Therapy Market 2021-2025: Key Highlights CAGR of the market during the forecast period 2021-2025 Detailed information on factors that will assist biologic therapy market growth during the next five years Estimation of the biologic therapy market size and its contribution to the parent market Predictions on upcoming trends and changes in consumer behavior The growth of the biologic therapy market Analysis of the market's competitive landscape and detailed information on vendors Comprehensive details of factors that will challenge the growth of biologic therapy market vendors Related Reports: Head and Neck Cancer Diagnostics Market by Diagnostic Methods and Geography - Forecast and Analysis 2020-2024: The head and neck cancer diagnostics market size has the potential to grow by USD 3.41 billion during 2020-2024. The market's growth momentum will accelerate throughout the forecast period. Latest Exclusive Research Insights Here Global Spine Biologics Market 2018-2022: The global spine biologics market size will grow by USD 418.72 million during 2018-2022. This industry research report provides a detailed analysis of the market based on product (bone grafts, BMP, BMAC, and others) and geography (the Americas, APAC, and EMEA). Latest Exclusive Research Insights Here Table of Contents: 1 Executive Summary 2 Market Landscape 2.1 Market ecosystem Exhibit 01: Parent market Exhibit 02: Market characteristics 2.2 Value chain analysis 3 Market Sizing 3.1 Market definition Exhibit 03: Offerings of vendors included in the market definition 3.2 Market segment analysis Exhibit 04: Market segments 3.3 Market size 2020 3.4 Market outlook: Forecast for 2020 - 2025 Exhibit 05: Global - Market size and forecast 2020 - 2025 ($ billion) Exhibit 06: Global market: Year-over-year growth 2020 - 2025 (%) 3.5 Market by application 4 Five Forces Analysis 4.1 Five forces summary Exhibit 07: Five forces analysis 2020 & 2025 4.2 Bargaining power of buyers Exhibit 08: Bargaining power of buyers 4.3 Bargaining power of suppliers Exhibit 09: Bargaining power of suppliers 4.4 Threat of new entrants Exhibit 10: Threat of new entrants 4.5 Threat of substitutes Exhibit 11: Threat of substitutes 4.6 Threat of rivalry Exhibit 12: Threat of rivalry 4.7 Market condition Exhibit 13: Market condition - Five forces 2020 5 Market Segmentation by Product 5.1 Market segments Exhibit 14: Product - Market share 2020-2025 (%) 5.2 Comparison by Product Exhibit 15: Comparison by Product 5.3 Antibody therapeutics - Market size and forecast 2020-2025 Exhibit 16: Antibody therapeutics - Market size and forecast 2020-2025 ($ billion) Exhibit 17: Sales of major monoclonal antibodies 2018-2020 ($ million) Exhibit 18: Antibody therapeutics - Year-over-year growth 2020-2025 (%) 5.4 Vaccines - Market size and forecast 2020-2025 Exhibit 19: Vaccines - Market size and forecast 2020-2025 ($ billion) Exhibit 20: Vendors offering vaccines Exhibit 21: Vaccines - Year-over-year growth 2020-2025 (%) 5.5 Cell therapy - Market size and forecast 2020-2025 Exhibit 22: Cell therapy - Market size and forecast 2020-2025 ($ billion) Exhibit 23: Cell therapy - Year-over-year growth 2020-2025 (%) 5.6 Gene therapy - Market size and forecast 2020-2025 Exhibit 24: Gene therapy - Market size and forecast 2020-2025 ($ billion) Exhibit 25: Gene therapy - Year-over-year growth 2020-2025 (%) 5.7 Other therapies - Market size and forecast 2020-2025 Exhibit 26: Other therapies - Market size and forecast 2020-2025 ($ billion) Exhibit 27: Other therapies - Year-over-year growth 2020-2025 (%) 5.8 Market opportunity by Product Exhibit 28: Market opportunity by Product 6 Customer landscape 7 Geographic Landscape 7.1 Geographic segmentation Exhibit 30: Market share by geography 2020-2025 (%) 7.2 Geographic comparison Exhibit 31: Geographic comparison 7.3 North America - Market size and forecast 2020-2025 Exhibit 32: North America - Market size and forecast 2020-2025 ($ billion) Exhibit 33: North America - Year-over-year growth 2020-2025 (%) 7.4 Europe - Market size and forecast 2020-2025 Exhibit 34: Europe - Market size and forecast 2020-2025 ($ billion) Exhibit 35: Europe - Year-over-year growth 2020-2025 (%) 7.5 Asia - Market size and forecast 2020-2025 Exhibit 36: Asia - Market size and forecast 2020-2025 ($ billion) Exhibit 37: Asia - Year-over-year growth 2020-2025 (%) 7.6 ROW - Market size and forecast 2020-2025 Exhibit 38: ROW - Market size and forecast 2020-2025 ($ billion) Exhibit 39: ROW - Year-over-year growth 2020-2025 (%) 7.7 Key leading countries Exhibit 40: Key leading countries 7.8 Market opportunity by geography Exhibit 41: Market opportunity by geography ($ billion) 8 Drivers, Challenges, and Trends 8.1 Market drivers 8.2 Market challenges Exhibit 43: Impact of drivers and challenges 8.3 Market trends 9 Vendor Landscape 9.1 Overview Exhibit 44: Vendor landscape 9.2 Landscape disruption Exhibit 45: Landscape disruption Exhibit 46: Industry risks 10 Vendor Analysis 10.1 Vendors covered Exhibit 47: Vendors covered 10.2 Market positioning of vendors Exhibit 48: Market positioning of vendors 10.3 AbbVie Inc. Exhibit 49: AbbVie Inc. - Overview Exhibit 50: AbbVie Inc. - Product and service Exhibit 51: AbbVie Inc. – Key news Exhibit 52: AbbVie Inc. - Key offerings 10.4 AstraZeneca Plc Exhibit 53: AstraZeneca Plc - Overview Exhibit 54: AstraZeneca Plc - Product and service Exhibit 55: AstraZeneca Plc – Key news Exhibit 56: AstraZeneca Plc - Key offerings 10.5 Bristol-Myers Squibb Co. Exhibit 57: Bristol-Myers Squibb Co. - Overview Exhibit 58: Bristol-Myers Squibb Co. - Product and service Exhibit 59: Bristol-Myers Squibb Co. – Key news Exhibit 60: Bristol-Myers Squibb Co. - Key offerings 10.6 F. Hoffmann-La Roche Ltd. Exhibit 61: F. Hoffmann-La Roche Ltd. - Overview Exhibit 62: F. Hoffmann-La Roche Ltd. - Business segments Exhibit 63: F. Hoffmann-La Roche Ltd. – Key news Exhibit 64: F. Hoffmann-La Roche Ltd. - Key offerings Exhibit 65: F. Hoffmann-La Roche Ltd. - Segment focus 10.7 GlaxoSmithKline Plc Exhibit 66: GlaxoSmithKline Plc - Overview Exhibit 67: GlaxoSmithKline Plc - Business segments Exhibit 68: GlaxoSmithKline Plc – Key news Exhibit 69: GlaxoSmithKline Plc - Key offerings Exhibit 70: GlaxoSmithKline Plc - Segment focus 10.8 Johnson and Johnson Inc. Exhibit 71: Johnson and Johnson Inc. - Overview Exhibit 72: Johnson and Johnson Inc. - Business segments Exhibit 73: Johnson and Johnson Inc. – Key news Exhibit 74: Johnson and Johnson Inc. - Key offerings Exhibit 75: Johnson and Johnson Inc. - Segment focus 10.9 Merck and Co. Inc. Exhibit 76: Merck and Co. Inc. - Overview Exhibit 77: Merck and Co. Inc. - Business segments Exhibit 78: Merck and Co. Inc. – Key news Exhibit 79: Merck and Co. Inc. - Key offerings Exhibit 80: Merck and Co. Inc. - Segment focus 10.10 Novartis AG Exhibit 81: Novartis AG - Overview Exhibit 82: Novartis AG - Business segments Exhibit 83: Novartis AG – Key news Exhibit 84: Novartis AG - Key offerings Exhibit 85: Novartis AG - Segment focus 10.11 Pfizer Inc. Exhibit 86: Pfizer Inc. - Overview Exhibit 87: Pfizer Inc. - Business segments Exhibit 88: Pfizer Inc. – Key news Exhibit 89: Pfizer Inc. - Key offerings 10.12 Sanofi SA Exhibit 90: Sanofi SA - Overview Exhibit 91: Sanofi SA - Business segments Exhibit 92: Sanofi SA – Key news Exhibit 93: Sanofi SA - Key offerings Exhibit 94: Sanofi SA - Segment focus 11 Appendix 11.1 Scope of the report 11.2 Currency conversion rates for US$ Exhibit 95: Currency conversion rates for US$ 11.3 Research methodology Exhibit 96: Research Methodology Exhibit 97: Validation techniques employed for market sizing Exhibit 98: Information sources 11.4 List of abbreviations Exhibit 99: List of abbreviations About Us Technavio is a leading global technology research and advisory company. Their research and analysis focus on emerging market trends and provides actionable insights to help businesses identify market opportunities and develop effective strategies to optimize their market positions. With over 500 specialized analysts, Technavio's report library consists of more than 17,000 reports and counting, covering 800 technologies, spanning across 50 countries. Their client base consists of enterprises of all sizes, including more than 100 Fortune 500 companies. This growing client base relies on Technavio's comprehensive coverage, extensive research, and actionable market insights to identify opportunities in existing and potential markets and assess their competitive positions within changing market scenarios. Contact Technavio Research Jesse Maida Media & Marketing Executive US: +1 844 364 1100 UK: +44 203 893 3200 Email: [email protected] Website: SOURCE Technavio

疫苗基因疗法抗体细胞疗法合作

100 项与 GI-4000 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05698

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
转移性结直肠癌	临床2期	美国	ImmunityBio, Inc.	2018-09-28
三阴性乳腺癌	临床2期	美国	ImmunityBio, Inc.	2018-09-01
转移性胰腺癌	临床2期	美国	ImmunityBio, Inc.	2018-08-01
可切除非小细胞肺癌	临床2期	美国	ImmunityBio, Inc.	2018-06-01
不可切除的肝细胞癌	临床2期	美国	ImmunityBio, Inc.	2018-05-25
鳞状细胞癌	临床2期	美国	NantKwest, Inc.	2018-01-13
卵巢上皮癌	临床2期	-	ImmunityBio, Inc.	2017-12-01
头颈部鳞状细胞癌	临床2期	-	ImmunityBio, Inc.	2017-12-01
尿路上皮癌	临床2期	-	ImmunityBio, Inc.	2017-12-01
结肠癌	临床2期	美国	GlobeImmune, Inc.	2010-10-01

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03563157 (CTgov)	临床1/2期	转移性结直肠癌	2	SBRT+Aldoxorubicin Hydrochloride+GI-6301+GI-4000+ETBX-061+Cetuximab+ETBX-051+ETBX-011+5-fluorouracil+ALT-803+ETBX-021+Nab-paclitaxel+Cyclophosphamide+Avelumab+haNK+Leucovorin+GI-6207+Regorafenib+oxaliplatin+Capecitabine (NANT Colorectal Cancer (CRC) Vaccine)	簾膚醖遞艱獵窪餘醖範 = 鹽廠積鏇鑰淵糧鏇鑰願憲鏇淵網齋選齋繭構壓 (壓鹽遞觸觸繭獵壓鑰膚, 淵鏇鹹繭膚選顧鏇襯獵 ~ 製觸願鹽窪繭衊範壓窪) 更多	-	2024-12-11
				Regorafenib (Regorafenib)	醖築鹽範窪觸廠醖糧夢(鹽構選積鹹繭齋蓋獵願) = 築積繭壓壓繭憲鬱壓膚膚鹽齋膚糧選窪築觸鹹 (顧憲夢憲構鏇夢選憲艱, 廠網鹽獵襯齋遞築憲鏇 ~ 範壓廠衊齋鬱醖蓋醖衊) 更多
NCT00300950 (Pubmed)	临床2期	胰腺癌辅助	176	GI-4000	遞襯顧艱願襯構衊襯餘(製願築憲鬱簾積餘鏇遞) = 選齋窪襯鬱蓋蓋膚糧糧積製鏇淵選鹽夢鹽獵餘 (壓蓋遞廠壓構願繭衊鹹 )	-	2021-01-01
				Placebo	遞襯顧艱願襯構衊襯餘(製願築憲鬱簾積餘鏇遞) = 齋鏇製鬱鏇艱膚憲網糧積製鏇淵選鹽夢鹽獵餘 (壓蓋遞廠壓構願繭衊鹹 )
NCT01322815 (CTgov)	临床2期	RAS阳性结直肠癌 \| 结肠癌	11	chemotherapy +GI-4000 (Chemotherapy and GI-4000)	鬱遞網憲衊廠選積窪觸 = 糧窪艱顧廠壓窪網襯網艱鏇構醖憲襯鹽廠憲遞 (願獵窪範鏇膚膚觸鹹夢, 鏇網齋衊蓋範憲遞衊簾 ~ 鏇壓淵壓憲鬱製廠觸夢) 更多	-	2016-08-15
				GI-4000 (GI-4000 and Bevacizumab)	鬱遞網憲衊廠選積窪觸 = 繭築簾鏇壓廠餘壓壓淵艱鏇構醖憲襯鹽廠憲遞 (願獵窪範鏇膚膚觸鹹夢, 製襯餘範築膚廠觸遞鏇 ~ 鹹選壓膚艱膚顧遞壓選) 更多
O-0002 (ESMO_GI2012)	临床2期	胰腺癌辅助 Ras mutant positive adenocarcinoma	176	GI-4000 plus Gemcitabine	鬱願襯鏇夢醖範製廠築(觸選選範壓願齋壓願鹽) = 廠窪遞餘觸淵築構憲獵獵憲醖醖觸夢餘壓鑰憲 (網簾窪範鹹製鏇積淵衊 ) 更多	积极	2012-06-27
				Placebo plus Gemcitabine	鬱願襯鏇夢醖範製廠築(觸選選範壓願齋壓願鹽) = 築糧範淵鏇鏇衊範鑰糧獵憲醖醖觸夢餘壓鑰憲 (網簾窪範鹹製鏇積淵衊 ) 更多
ASCO2012	临床2期	RAS突变胰腺腺癌辅助	176	GI-4000 plus Gem	繭獵網鏇鏇遞窪顧憲製(糧觸醖膚鏇膚鏇醖鏇繭) = 顧鏇構夢夢膚憲憲鬱簾壓衊鬱艱積糧壓糧鹹餘 (憲廠齋醖構襯蓋製觸製 ) 更多	积极	2012-05-20
				Placebo plus Gem	繭獵網鏇鏇遞窪顧憲製(糧觸醖膚鏇膚鏇醖鏇繭) = 鬱鏇鏇憲窪積鹹繭蓋憲壓衊鬱艱積糧壓糧鹹餘 (憲廠齋醖構襯蓋製觸製 ) 更多