更新于：2024-05-01

PMS2

PMS1 homolog 2, mismatch repair system component

更新于：2024-05-01

基本信息

别名

DNA mismatch repair protein PMS2、H_DJ0042M02.9、HNPCC4

+ [7]

简介

Component of the post-replicative DNA mismatch repair system (MMR) (PubMed:30653781, PubMed:35189042). Heterodimerizes with MLH1 to form MutL alpha. DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Possesses an ATPase activity, but in the absence of gross structural changes, ATP hydrolysis may not be necessary for proficient mismatch repair (PubMed:35189042).

关联

项与 PMS2 相关的药物

NP-1867

靶点

PMS2

作用机制

PMS2抑制剂

在研机构

NeoPhore Ltd.初创企业

原研机构

NeoPhore Ltd.初创企业

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PMS2 相关的临床结果

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100 项与 PMS2 相关的转化医学

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0 项与 PMS2 相关的专利（医药）

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2,058

项与 PMS2 相关的文献（医药）

2024-02-16·The Journal of pathology

Integrated analyses of the genetic and clinicopathological features of cholangiolocarcinoma: cholangiolocarcinoma may be characterized by mismatch-repair deficiency.

Article

作者: Kenta Makino ; Takamichi Ishii ; Haruhiko Takeda ; Yoichi Saito ; Yukio Fujiwara ; Masakazu Fujimoto ; Takashi Ito ; Satoshi Wakama ; Ken Kumagai ; Fumiaki Munekage ; Hiroshi Horie ; Katsuhiro Tomofuji ; Yu Oshima ; Elena Yukie Uebayashi ; Takayuki Kawai ; Satoshi Ogiso ; Ken Fukumitsu ; Atsushi Takai ; Hiroshi Seno ; Etsuro Hatano

Cholangiolocarcinoma (CLC) is a primary liver carcinoma that resembles the canals of Hering and that has been reported to be associated with stem cell features. Due to its rarity, the nature of CLC remains unclear, and its pathological classification remains controversial. To clarify the positioning of CLC in primary liver cancers and identify characteristics that could distinguish CLC from other liver cancers, we performed integrated analyses using whole-exome sequencing (WES), immunohistochemistry, and a retrospective review of clinical information on eight CLC cases and two cases of recurrent CLC. WES demonstrated that CLC includes IDH1 and BAP1 mutations, which are characteristic of intrahepatic cholangiocarcinoma (iCCA). A mutational signature analysis showed a pattern similar to that of iCCA, which was different from that of hepatocellular carcinoma (HCC). CLC cells, including CK7, CK19, and EpCAM, were positive for cholangiocytic differentiation markers. However, the hepatocytic differentiation marker AFP and stem cell marker SALL4 were completely negative. The immunostaining patterns of CLC with CD56 and epithelial membrane antigen were similar to those of the noncancerous bile ductules. In contrast, mutational signature cluster analyses revealed that CLC formed a cluster associated with mismatch-repair deficiency (dMMR), which was separate from iCCA. Therefore, to evaluate MMR status, we performed immunostaining of four MMR proteins (PMS2, MSH6, MLH1, and MSH2) and detected dMMR in almost all CLCs. In conclusion, CLC had highly similar characteristics to iCCA but not to HCC. CLC can be categorized as a subtype of iCCA. In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA. © 2024 The Pathological Society of Great Britain and Ireland.

2024-02-13·Clinical cancer research : an official journal of the American Association for Cancer Research

Differential responses to immune checkpoint inhibitors are governed by diverse mismatch repair gene alterations.

Article

作者: Moh'd M Khushman ; Michael D Toboni ; Joanne Xiu ; Upender Manne ; Alex Farrell ; Emil Lou ; Anthony F Shields ; Philip A Philip ; Mohamed E Salem ; Jim Abraham ; David Spetzler ; John Marshall ; Priya Jayachandran ; Michael J Hall ; Heinz-Josef Lenz ; Ibrahim Halil Sahin ; Andreas Seeber ; Matthew A Powell

PURPOSE:

The response to immune checkpoint inhibitors (ICIs) in deficient mismatch repair (dMMR) colorectal cancer (CRC) and endometrial cancer (EC) is variable. Here, we explored the differential response to ICIs according to different MMR alterations.

EXPERIMENTAL DESIGN:

CRC (N=13701) and EC (N=3315) specimens were tested at Caris Life Sciences. Median overall survival (mOS) was estimated using Kaplan-Meier. The prediction of high, intermediate and low affinity epitopes by tumor mutation burden (TMB) values was conducted using R-squared (R2) Results: Compared to mutL (MLH1 and PMS2) co-loss, the mOS was longer in mutS (MSH2 and MSH6) co-loss in all CRC (54.6m vs. 36m; p=0.0.025) and EC (81.5m vs. 48.2m; p<0.001) patients. In ICIs-treated patients, the mOS was longer in mutS co-loss in CRC (not reached (NR) vs. 36m; p=0.011). In EC, the mOS was NR vs. 42.2m; p=0.711). The neoantigen load (NAL) in mutS co-loss compared to mutL co-loss was higher in CRC (high-affinity epitopes: 25.5 vs 19; q=0.017, intermediate: 39 vs. 32; q=0.004, low: 87.5 vs. 73; q<0.001) and EC (high-affinity epitopes: 15 vs. 11; q=0.002, intermediate: 27.5 vs. 19; q<0.001, low: 59 vs. 41; q<0.001) respectively. R2 ranged from 0.25 in mutS co-loss CRC to 0.95 in mutL co-loss EC.

CONCLUSIONS:

Patients with mutS co-loss experienced longer mOS in CRC and EC and better response to ICIs in CRC. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL.

2024-01-31·Diagnostic pathology

Rare germline mutation and MSH2-&MSH6 + expression in a double primary carcinoma of colorectal carcinoma and endometrial carcinoma: a case report.

Article

作者: Tiansong Zhang ; Xiaoqiang Huang ; Wenjie Liu ; Xiulan Ling ; Zhenping Su ; Mengwei Huang ; Shuanlong Che

BACKGROUND:

Multiple primary malignancies are rare in cancer patients, and risk factors may include genetics, viral infection, smoking, radiation, and other environmental factors. Lynch syndrome (LS) is the most prevalent form of hereditary predisposition to double primary colorectal and endometrial cancer in females. LS, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a common autosomal dominant condition. Pathogenic germline variants in the DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, and less frequently, deletions in the 3' end of EPCAM cause LS. It manifested itself as loss of MMR nuclear tumor staining (MMR protein deficient, dMMR).

CASE PRESENTATION:

This case study describes a double primary carcinoma in a 49-year-old female. In June 2022, the patient was diagnosed with highly to moderately differentiated endometrioid adenocarcinoma. The patient's mother died of esophageal cancer at age 50, and the father died of undefined reasons at age 70. Immunohistochemical stainings found ER (++), PR (++), P53 (+), MSH2 (-), MSH6 (+), MLH1 (+), and PMS2 (+). MMR gene sequencing was performed on endometrial tumor and peripheral blood samples from this patient. The patient carried two pathogenic somatic mutations in the endometrial tumor, MSH6 c.3261dupC (p.Phe1088LeufsTer5) and MSH2 c.445_448dup (p.Val150fs), in addition to a rare germline mutation MSH6 c.133G > C (p.Gly45Arg). Two years ago, the patient was diagnosed with moderately differentiated adenocarcinoma in the left-half colon. Immunohistochemical stainings found MSH2(-), MSH6(+), MLH1(+), and PMS2(+) (data not shown).

CONCLUSIONS:

In the case of a patient with double primary EC and CRC, a careful evaluation of the IHC and the genetic data was presented. The patient carried rare compound heterozygous variants, a germline missense mutation, and a somatic frameshift mutation of MSH6, combined with a novel somatic null variant of MSH2. Our study broadened the variant spectrum of double primary cancer and provided insight into the molecular basis for abnormal MSH2 protein loss and double primary carcinoma.

项与 PMS2 相关的新闻（医药）

2024-03-09

·精准药物

【综述】合成致死研发进展

——诺华“合成致死”新靶点创新产品进展——2024年1月26日，CDE官网公示，诺华在研创新产品HRO761获得临床试验默示许可，拟开发治疗晚期不可切除或转移性MSI-H/dMMR型实体瘤。截图来源：CDE官网HRO761为WRN抑制剂。Werner综合征RecQ解旋酶（WRN）是近年来发现的“合成致死”新靶点，对MSI-H肿瘤具有“合成致死”作用，是该赛道的潜力创新产品。但纵观诺华近年来在创新药品领域，进展多遭受坎坷。布局风险性极大的“合成致死”赛道，又是新靶点，着实风险和机遇并存。我们来回顾下该赛道目前的研究进展情况。——合成致死里程碑产品PARPi适应证撤销——PARP抑制剂（PARPi）是首款根据合成致死原理研发的抗癌药，自2014年奥拉帕利问世以来，全球已上市六款PARP抑制剂，分别是奥拉帕利、鲁卡帕尼、尼拉帕利、他拉唑帕利、氟唑帕利和帕米帕利。深刻改变了卵巢癌治疗格局，同时，也先后获得乳腺癌、胰腺癌和前列腺癌的适应症。逐步引起国际制药巨头纷纷押注合成致死赛道。但随着FDA近期对PARPi适应症的撤销，又为合成致死赛道蒙上了阴影。PARP抑制剂（PARPi）的问世，深刻改变了既往治疗手段有限的卵巢癌的治疗格局，但是，随着相应临床试验随访时间的延长，临床数据显示卵巢癌患者使用鲁卡帕尼、奥拉帕利和尼拉帕利的死亡风险有所增加，所以在2022年FDA接连撤回奥拉帕利和鲁卡帕尼末线治疗卵巢癌的适应症以及尼拉帕利末线治疗卵巢癌、输卵管癌或原发性腹膜癌的适应症。让外界对于以PARPi为代表的合成致死赛道前景充满担忧。既往时刻，诸多国际制药巨头已经纷纷押注合成致死赛道，未来是否真的如预期中的一路坦途呢？——合成致死赛道频繁BD——2022年3月22日，Volastra Therapeutics宣布，与百时美施贵宝达成研发合作，利用Volastra基于探索染色体不稳定性（chromosomal instability, CIN）的药物发现平台，发现与染色体不稳定性相关的合成致死药物靶点。合成致死是一种已经得到验证的靶点发现策略，它通过探索肿瘤细胞的弱点，在杀死肿瘤细胞的同时避免伤害健康细胞。根据合作协议，Volastra将负责针对未公开的靶点进行一系列研发活动，直至选定开发候选疗法。百时美施贵宝将负责后续开发、监管和商业化活动。Volastra将获得3000万美元的前期付款，并有资格获得高达11亿美元的里程碑付款。2022年6月1日，RepareTherapeutics宣布，与罗氏制药集团就拆monsertib（RP-3500）的开发和商业化达成全球许可和合作协议。Repare将收到1.25亿美元的预付款，并有资格获得高达12亿美元的潜在开发、监管、商业和销售里程碑，以及全球净产品销售的特许权使用费。Camonsertib是一种选择性ATR（共济失调毛细血管扩张突变基因Rad3相关激酶）口服小分子抑制剂，用于治疗具有特定合成致死基因组改变的肿瘤，包括 ATM（共济失调-毛细血管扩张突变）基因。让大众的视线再次聚焦到合成致死赛道上。在具体回顾基本概念前，我们先讲解下ATR抑制剂的作用机制。——ATR抑制剂作用机制——内源性（DNA双链断裂）和外源性（紫外线辐射和化学毒性等）的因素，引起细胞DNA的损伤，为了维持基因组的完整性，细胞进化出DNA损伤应答机制DDR（DNAdamageresponse）可以检测DNA损伤并修复，与细胞周期的检查点相互作用以控制细胞增殖。DDR的核心激酶是3种结构独特的丝氨酸/苏氨酸激酶成分的中枢调控因子：共济失调性毛细血管扩张突变蛋白（ATM）、Rad3相关蛋白ATR、DNA依赖性蛋白激酶(DNA-PK)。ATM和DNA-PK主要在双链断裂修复中被激活；而ATR主要在单链断裂修复中被激活。DNA损伤累积并阻碍DNA复制的过程就会发生RS，在RS下，DNA链的损伤可导致复制减慢或停止，如果损坏未修复可能会崩溃，导致细胞死亡，ATR在协调RS中起着至关重要的作用。复制蛋白A（RPA）在损伤位点与单链DNA结合，所得复合物结合可引发ATR募集到DNA损伤位点。当ATR被复制蛋白A（RPA）激活后，会磷酸化CHK1，后者又磷酸化CDC25A，最终通过抑制周期蛋白依赖性激酶（CDK）的活性介导G2～M期和S期检测点的活化，来减少RS并触发适当的DNA修复途径。而ATR抑制剂可以干扰DNA修复，这样癌细胞的DNA就有可能产生一堆错误而且得不到修复，然后凋亡。正常细胞有很多蛋白质负责DNA修复（比如MMR相关的就有4个，MSH2、MSH6、MLH1、PMS2；此外，BRCA以及POLE等蛋白），单独阻断ATR，并不会对DNA修复有影响。综上可知，ATR抑制剂也属于合成致死理论的明日之星。——合成致死理论——合成致死（Synthetic lethality）理论由来已久，通俗来讲，指两个非致死基因同时失活将导致细胞死亡的现象。概念最早可以追溯到1992年，美国科学家卡尔文在果蝇的研究中发现，具有pd和 Pdr双基因突变的果蝇不能存活，而这其中任何一个基因单独突变都不会导致果蝇死亡。1946年，西奥多·多布赞斯基正式提出“合成致死“概念，用来描述这种不同基因之间的互补性致死作用。科学家们很容易将果蝇中发现的这种现像与肿瘤治疗理论相结合，如果发现肿瘤细胞中存在特定基因A失活，那么用药物抑制它的合成致死搭档基因B，使两者都失活，而健康的体细胞因为有正常的基因A，能够保证正常的生理功能的表达，不会受到药物的伤害，从而只特异性的杀死该类肿瘤细胞。基于合成致死原理的肿瘤治疗原理很简单，但难点相信大家也能想得到。没有技术的突破，你很难找到合适的成对存在的合成致死基因。犹如好的逗哏必须得有好的捧哏才能合演一场成功的相声。突破在于PARP与BRCA这对黄金搭档的世纪相遇，促进了PARP抑制剂的成功商业化上市，并在卵巢癌领域获得巨大成功，由此开启了基于“合成致死”理论进行药物开发的热潮。最成功的产品当然是PARP抑制剂。——PARP抑制剂——PARP（聚腺苷二磷酸核糖聚合酶）在DNA单链碱基切除、修复过程中发挥着关键作用。BRCA是重要的抑癌基因与肿瘤易感基因，包括BRCA1及BRCA2。BRCA基因突变会导致基因组不稳定性显著增加，从而显著提高女性罹患乳腺癌、卵巢癌以及其他癌症（胰腺癌、子宫内膜癌、腹膜癌及宫颈癌等）的风险。在人体内，BRCA可与PARP共同作用于同源重组（HR）修复通路，这种双保险组合，可以有效保证体内DNA复制的正确性。但部分癌细胞，BRCA基因会突变，此时，人类如若开发出能够抑制PARP的药物，通过抑制肿瘤细胞DNA损伤修复、促进肿瘤细胞发生凋亡，从而可增强放疗以及烷化剂和铂类药物化疗的疗效。特别是对于携带BRCA突变的肿瘤细胞，理论上对PARP抑制剂的敏感度会更高。 BRCA和PARP的合成致死示意图目前，已经有四种PARP抑制剂在中国获批上市，分别是奥拉帕利、尼拉帕利、氟唑帕利以及帕米帕利，将这几款PARPi在卵巢癌领域获得FDA和NMPA批准的适应症总结如下：来源：NMPA、FDA、各公司官网（未更新最新追踪结果）——开发PARP抑制剂新策略——随着临床上PARPi不断涌现，耐药现象同样限制了PARPi的进一步运用。PARPi的耐药性的主要原因是BRCA1/2突变癌细胞HR修复活性的恢复。详细地说，BRCA1/2中的继发突变与原始突变导致的链终止子/移码的废除有关，导致全长 BRCA1/2 开放阅读框的恢复。因此，活性BRCA1/BRCA2蛋白表达被恢复，从而重新启动功能齐全的HR途径。除了BRCA1/2中其他突变介导的耐药性外，还提出了BRCA1启动子甲基化的减少/丧失，从而恢复了BRCA1的表达而导致对PARPi的耐药性。为了克服耐药性，一方面进一步对PARP抑制剂进行修饰开发以发现下一代PARP抑制剂，另一方面采取联合用药，如2023年3月，强生旗下杨森（Janssen）公司则宣布向FDA递交了将PARP抑制剂尼拉帕利和醋酸阿比特龙（abiraterone acetate）以双效片剂（DAT）形式的新药申请（NDA），联合强的松（prednisone）共同用于治疗BRCA阳性的转移性去势抵抗性前列腺癌（mCRPC）患者，或者双靶点抑制剂，如进入临床II期的Stenoparib，同时抑制PARP1/2和TNKS1/2，还有很多临床前在研的靶向PARP和其它靶点如HDAC、TOPO、BRD4、PI3K、HSP90、AChE和PD-L1等的抑制剂。与此同时也在开展其它靶向PARP新策略，如PARP的PROTAC和PARP抑制剂的前药。除了在PARPi升级改造下苦功夫以外，也期望能够在其他的靶点上，如WEE1和TP53，重塑PARPi的辉煌。——WEE1与TP53——PRMT5/MAT2A抑制剂、WEE1抑制剂，都是潜在的合成致死赛道的黑马，本文主要介绍尚在临床早期的WEE1抑制剂的相关知识。与 WEE1 形成合成致死基因搭档的，则是大名鼎鼎的抑癌基因 TP53。 TP53 与 WEE1合成致死效应 TP53 是人类非常重要的抑癌基因，在正常细胞中低表达，在恶性肿瘤中高表达。TP53 基因翻译的 P53 蛋白是细胞生长、增殖和损伤修复的重要调节因子。细胞的 DNA 受损时，P53 蛋白阻止细胞增殖而停止于 G1/S 期，把损伤修复好后才能进入 G2 期，如不能修复则促进细胞凋亡。在所有恶性肿瘤中，50% 以上会出现该基因的突变，从而导致大多数恶性肿瘤细胞于 G1/S 期检查点存在修复缺陷，复制出错的细胞就会轻松通过 G1 关卡，进入到 G2 期。 WEE1在 G2/M 检查点中作用的示意图目前，直接针对抑癌基因 TP53 的药物研发，比直接针对原癌基因，如 EGFR、ALK 的靶向药物研发要艰难的多。现在针对抑癌基因的药物研发，更多的是在信号通路的上下游想办法，找相应的药物靶点，进行抑制。而 WEE1 就是合理的与 TP53 相搭配的合成致死靶点。WEE1 是 DNA 损伤修复（DDR）通路相关的一个重要激酶。WEE1 激酶能磷酸化细胞分裂周期基因 (cell division cycle，CDC2)，下调其活性，进而可以调控细胞 G 2 到 M 期的转变并调节细胞有丝分裂。它在染色体浓缩延迟和组蛋白合成中也起到关键作用，与 TP53基因突变存在一定的合成致死效应。 ——WEE1抑制剂在研项目汇总—— PARPi和WEE1抑制剂与化疗的增敏探索目前，临床有多款 WEE1 抑制剂在研，且各种 WEE1 抑制剂与 DNA 损伤 (化疗或放射治疗) 相结合的联合治疗方式已取得了很多进展，如进展最快的 Adavosertib（AZD1775），已在全球布局50余项临床试验，多为联合用药方案。基于此，WEE1 逐渐成为肿瘤治疗中的一个重要靶点。来源：医药魔方巧合的是，与 PARPi 在卵巢癌领域所获得的巨大成就相比，作为临床进展最快的 WEE1抑制剂—Adavosertib，在妇瘤领域中的浆液性子宫癌（USC）中也有着不俗的表现。 USC非化疗药物数据对比普通化疗对USC疗效较差，近年来，Her-2靶向治疗，抗血管生成药，酪氨酸激酶抑制剂与免疫检查点抑制剂的结合，以及我们今天所介绍的WEE1细胞周期调节剂，在USC领域取得了不错的ORR和PFS数据。然而 Adavosertib 单药或联合用药均出现频率较高的不良事件，主要为腹泻、呕吐等胃肠道相关及贫血等血液方面不良事件, 对于Adavosertib 进一步的拓展蒙上了阴影。国内一众企业，在“合成致死“肿瘤治疗领域，多聚焦于已经商业化运作成功的PARPi的研发，鲜有突破创新者。不过值得一提的是，专注于”合成致死“作用机制药物研发的英派药业，是国内该领域鲜有的突破创新者，利用自主研发的 DNA损伤修复通路平台，开始探索PARP、WEE1等合成致死靶点的药物研发。在研产品包括PARP抑制剂（IMP4297）、WEE1抑制剂（IMP7068）、Hedgehog通路抑制剂（IMP5471）等。此次施贵宝重金布局合成致死领域，会更加吸引大众视野。——PRMT5与MTAP的初识探索——有企业全力押注PARPi的研发，自然也有企业想弯道超车，基于PARPi的成功，能否寻找到堪比PARP/BRCA的下一对“合成致死“黄金搭档呢？答案是有的， PRMT5/MTAP正是这种潜在的组合。PRMT5在基因表达、剪接和DDR中的作用模型PRMT（蛋白质精氨酸甲基转移酶）能够使多种蛋白甲基化，并在基因表达、剪接和DNA损伤修复等生物学过程中发挥重要作用。目前，已发现了11种PRMT家族的成员，主要的研究热点集中在PEMT5上。 MTAP（methylthioadenosine phosphorylase，甲硫腺苷磷酸化酶）常与体内常见的抑癌基因CDKN2A发生共缺失现象，这种共缺失现象在肿瘤中的比例可达9%~15%。 PRMT5和MTAP是合成致死组合2016年的两篇背靠背《Science》文章首次报道了抑制PRMT5在MTAP缺失肿瘤中的合成致死效应。另外，有研究证明，MTAP缺失的癌细胞对蛋氨酸腺苷转移酶2A（MAT2A）也敏感。因此，PRMT5抑制剂和MAT2A抑制剂有望成为治疗MTAP缺失肿瘤的新一代靶向药物。在研PRMT5/MAT2A抑制剂项目汇总目前，有多款PRMT5/MAT2A抑制剂正在临床试验中，其中不乏GSK、辉瑞等大药企的身影，也有Agios这类新兴生物制药公司。让我们期待在肿瘤靶向药物治疗领域，“合成致死“理论能够再下一城。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

引进/卖出申请上市

2024-02-01

·Pharmaceutical Technology

NeoPhore adds $12.2m in Series B extension for immuno-oncology pipeline

NeoPhore is developing a pipeline of drugs targeting proteins along the DNA mismatch repair (MMR) pathway. Image credit: Shutterstock/Billion Photos. NeoPhore has raised £9.6m ($12.2m) in a Series B financing extension, bringing the round’s total to £31.1m. Sixth Element Capital, which is currently managing the CRT Pioneer Fund (CPF), led the round, with participation from existing backers and three new investors, as per a 1 February press release. The UK-based company, which spun out of the University of Turin and the UK-based PhoreMost, extended the round with a £6m extension in January 2023. The CPF is a joint initiative between Cancer Research Technology (CRT) and the European Investment Fund (EIF). NeoPhore is developing a pipeline of drugs targeting proteins along the DNA mismatch repair (MMR) pathway. MMR deficiency is where errors in DNA base pairing are not corrected. Cells that do not have these routine corrections can have many mutations, which could lead to cancer. NeoPhore says that this tumour suppressor pathway is lost in up to 40% of sporadic cancers. The company announced its lead compound, NP1867, which targets the MMR protein PMS2, at AACR-NCI-EORTC, held in Boston, US, from 7 to 10 October 2023. NeoPhore said the funding would help advance its lead oral programme. See Also: Gilead and Arcus Biosciences expand oncology partnership deal Synnovation launches with $102m to advance therapy pipeline The UK-based biotech is homing in on raising tumour mutational burdens. Deficient MMR can result in a high-frequency microsatellite instability MSI (MSI-H) phenotype. Higher MSI status is linked with the creation of neoantigens – substrates that help mediate immune activation. Neoantigens are already being explored in cancer vaccines, such as BioNTech ’s highly anticipated RNA vaccine for pancreatic cancer. NeoPhore is developing small molecule MMR inhibitors that induce neoantigen expression intending to increase immunogenicity in solid tumours. This would make cancer patients more responsive to immunotherapy. NeoPhore says that the combination of immune checkpoint inhibitors such as PD-1 inhibitors, together with an increased neoantigen repertoire could elicit more efficacious tumour treatment. MSD’s blockbuster Keytruda is the best-selling PD-1 inhibitor, and one of the top-selling drugs worldwide – generating $20.9bn in sales in 2022. The drug is approved for patients with unresectable or metastatic MSI-H or MMR-deficient solid tumours, amongst others. NeoPhore’s CEO Dr Matthew Baker said: “With the support of our committed and new investors, along with our research collaborations with academic institutions that are in place, we remain on track to deliver a candidate drug for our lead PMS2 program by early 2025.”

免疫疗法疫苗上市批准AACR会议

2024-01-03

·奇点网

高通量测序技术的逐渐普及，帮助更多患者得到适合的治疗。

*仅供医学专业人士阅读参考对于具有错配修复缺陷（MMR-D）的癌症患者而言，免疫检查点抑制剂治疗是一种非常有效的治疗方法。准确评估MMR状态对于治疗决策至关重要，因为假阴性会限制免疫检查点抑制剂的使用，从而降低患者的临床获益。近日，美国布列根和妇女医院的Amin H. Nassar及其同事们发表在《癌细胞》期刊上的论文[1]，揪出了当前指南中MMR标准检测方法的漏洞，并提供了能够帮助更多乳腺癌患者从免疫治疗中获益的方法。他们结合下一代测序技术（NGS）的检测结果发现，采用当前推荐的免疫组化染色（IHC）方法检测MMR-D时，有5.9%的子宫内膜癌患者和1%的结直肠癌患者被漏诊，而NGS可以识别出这些患者并帮助其接受更为有效的免疫治疗。据估计，如果采用NGS进行MMR检测，可额外识别出5000多名被IHC漏诊的美国结直肠癌或子宫内膜癌患者。这项研究结果支持重新评估指南中以IHC作为MMR标准检测方法的建议，并提出采用更加灵敏的NGS在诊断早期阶段进行MMR检测。论文首页截图DNA错配修复系统（MMR）在细胞中负责识别和修复DNA复制过程中产生的错误，维持遗传稳定性。当发生错配修复缺陷（MMR-D）时，常常引起DNA中的短串联重复序列长度改变，即微卫星不稳定性（MSI），并且与多种癌症的发展有关，特别是与结直肠癌和子宫内膜癌的关系最为密切。MMR的常用检测方法为两种，一种是通过免疫组化染色（IHC）检测肿瘤组织中MMR蛋白（MLH1、MSH2、MSH6、PMS2）的异常表达，另一种是通过聚合酶链反应（PCR）检测MSI。目前，美国病理学会（CAP）、美国临床肿瘤协会（ASCO）、欧洲肿瘤医学学会（ESMO）推荐，将IHC作为结直肠癌或子宫内膜癌患者进行MMR检测的首选方法[2,3]。ESMO推荐在不同癌症类型和免疫治疗疗程中进行MSI检测[3]下一代测序（NGS）又称高通量测序技术，能够快速、全面地检测和分析MMR-D所导致的MSI。此次研究共纳入1655名结直肠癌或子宫内膜癌患者，这些患者的MMR状态由IHC和NGS进行检测。对比两种方式，Amin H. Nassar等人发现，5.9%的子宫内膜癌患者和1%的结直肠癌患者，其IHC的检测结果为错配修复功能正常，而NGS检测结果为MMR-D。进一步分析结果显示，这些被IHC漏诊、而被NGS检测为MMR-D的患者，对免疫治疗的反应比其它全身治疗明显更好，具有更长的生存期。另外，与NGS和IHC结果一致为错配修复功能正常的患者相比，这些患者接受免疫检查点治疗的中位总生存期和治疗失败时间显著延长（中位OS：NR[95%CI 10个月-NR] vs 14.9个月[95%CI 7.3-25]，p=0.003）（中位TTF：44.4个月[95%CI 10-NR] vs 5.0个月[95%CI 3.2-7.3],p=0.001），而与NGS、IHC检测结果一致为MMR-D的患者免疫检查点抑制剂疗效相近。这意味着，NGS可以更灵敏地检测MMR状态，并使具有MMR-D的结直肠癌患者或子宫内膜癌者不会错过对其更为有效的免疫治疗。据统计，2022年美国新发结直肠癌和新发子宫内膜癌分别达到151030例和65950例。按此推断，仅以IHC作为检测方法，其中共有5401名具有MMR-D的患者被漏诊，而NGS检测可以识破IHC的假阴性结果。“我们不想错过这些患者，否则可能会剥夺他们获得长期治疗益处的机会，”Amin H. Nassar表示[4]。“此外，我们也希望能够为不同患者提供适合的治疗方式，避开毒性更大或效果较差的疗法。”随着NGS技术已经越来越多地被用于日常临床护理中，研究者们建议在诊断早期阶段采用NGS进行MMR检测，以及早识别漏诊的MMR-D患者，指导其采取适当的临床决策。接下来，他们将在更大队列中验证这一结论，并探索基于NGS的MMR检测方法是否同样有助于指导其它癌症类型患者的治疗。参考文献：[1]https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00420-8[2]Vikas, P., Messersmith, H., Compton, C.,Sholl, L., Broaddus, R.R., Davis, A., EstevezDiz, M., Garje, R., Konstantinopoulos, P.A.,Leiser, A., et al. (2023). Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of College of American Pathologists Guideline. J. Clin. Oncol. 41, 1943–1948.[3]Luchini, C., Bibeau, F., Ligtenberg, M.J.L., Singh, N., Nottegar, A., Bosse, T., Miller, R., Riaz, N., Douillard, J.Y., Andre, F., and Scarpa, A. (2019). ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann. Oncol. 30, 1232–1243.[4]https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4618本文作者丨张艾迪

ASCO会议免疫疗法临床研究临床结果