更新于：2024-05-01

BRCA2

BRCA2 DNA repair associated

更新于：2024-05-01

基本信息

别名

BRCA2、BRCA2 DNA repair associated、BRCC2

+ [8]

简介

Involved in double-strand break repair and/or homologous recombination. Binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). Acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. Part of a PALB2-scaffolded HR complex containing RAD51C and which is thought to play a role in DNA repair by HR. May participate in S phase checkpoint activation. Binds selectively to ssDNA, and to ssDNA in tailed duplexes and replication fork structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with PALB2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity. In concert with NPM1, regulates centrosome duplication. Interacts with the TREX-2 complex (transcription and export complex 2) subunits PCID2 and SEM1, and is required to prevent R-loop-associated DNA damage and thus transcription-associated genomic instability. Silencing of BRCA2 promotes R-loop accumulation at actively transcribed genes in replicating and non-replicating cells, suggesting that BRCA2 mediates the control of R-loop associated genomic instability, independently of its known role in homologous recombination (PubMed:24896180).

关联

项与 BRCA2 相关的药物

CAM833

靶点-

作用机制

BRCA2 inhibitors [+1]

在研机构

University of Cambridge

原研机构

University of Cambridge

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

AG1-4361

靶点

BRCA2 x PARP1

作用机制

BRCA2调节剂 [+1]

在研机构-

原研机构

Fred Hutchinson Cancer Research Center

在研适应症-

非在研适应症

卵巢癌

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 BRCA2 相关的临床结果

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100 项与 BRCA2 相关的转化医学

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0 项与 BRCA2 相关的专利（医药）

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10,353

项与 BRCA2 相关的文献（医药）

2024-03-01·The Lancet regional health. Western Pacific

Age-specific breast and ovarian cancer risks associated with germline BRCA1 or BRCA2 pathogenic variants - an Asian study of 572 families.

Article

作者: Weang-Kee Ho ; Nur Tiara Hassan ; Sook-Yee Yoon ; Xin Yang ; Joanna M C Lim ; Nur Diana Binte Ishak ; Peh Joo Ho ; Eldarina A Wijaya ; Patsy Pei-Sze Ng ; Craig Luccarini ; Jamie Allen ; Mei-Chee Tai ; Jianbang Chiang ; Zewen Zhang ; Mee-Hoong See ; Meow-Keong Thong ; Yin-Ling Woo ; Alison M Dunning ; Mikael Hartman ; Cheng-Har Yip ; Nur Aishah Mohd Taib ; Douglas F Easton ; Jingmei Li ; Joanne Ngeow ; Antonis C Antoniou ; Soo-Hwang Teo

Background:

Clinical management of Asian BRCA1 and BRCA2 pathogenic variants (PV) carriers remains challenging due to imprecise age-specific breast (BC) and ovarian cancer (OC) risks estimates. We aimed to refine these estimates using six multi-ethnic studies in Asia.

Methods:

Data were collected on 271 BRCA1 and 301 BRCA2 families from Malaysia and Singapore, ascertained through population/hospital-based case-series (88%) and genetic clinics (12%). Age-specific cancer risks were estimated using a modified segregation analysis method, adjusted for ascertainment.

Findings:

BC and OC relative risks (RRs) varied across age groups for both BRCA1 and BRCA2. The age-specific RR estimates were similar across ethnicities and country of residence. For BRCA1 carriers of Malay, Indian and Chinese ancestry born between 1950 and 1959 in Malaysia, the cumulative risk (95% CI) of BC by age 80 was 40% (36%-44%), 49% (44%-53%) and 55% (51%-60%), respectively. The corresponding estimates for BRCA2 were 29% (26-32%), 36% (33%-40%) and 42% (38%-45%). The corresponding cumulative BC risks for Singapore residents from the same birth cohort, where the underlying population cancer incidences are higher compared to Malaysia, were higher, varying by ancestry group between 57 and 61% for BRCA1, and between 43 and 47% for BRCA2 carriers. The cumulative risk of OC by age 80 was 31% (27-36%) for BRCA1 and 12% (10%-15%) for BRCA2 carriers in Malaysia born between 1950 and 1959; and 42% (34-50%) for BRCA1 and 20% (14-27%) for BRCA2 carriers of the same birth cohort in Singapore. There was evidence of increased BC and OC risks for women from >1960 birth cohorts (p-value = 3.6 × 10^-5 for BRCA1 and 0.018 for BRCA2).

Interpretation:

The absolute age-specific cancer risks of Asian carriers vary depending on the underlying population-specific cancer incidences, and hence should be customised to allow for more accurate cancer risk management.

Funding:

Wellcome Trust [grant no: v203477/Z/16/Z]; CRUK (PPRPGM-Nov20∖100002).

2024-02-23·Free radical research

Brca2^{(p.T1942fs/+)} dissipates ovarian reserve in rats through oxidative stress in follicular granulosa cells.

Article

作者: Hideaki Tanaka ; Yashiro Motooka ; Yuki Maeda ; Reina Sonehara ; Tomoko Nakamura ; Hiroaki Kajiyama ; Tomoji Mashimo ; Shinya Toyokuni

Pathogenic variants of BRCA1/2 constitute hereditary breast and ovarian cancer (HBOC) syndrome, and BRCA1/2 mutant is a risk for various cancers. Whereas the clinical guideline for HBOC patients has been organized for the therapy and prevention of cancer, there is no recommendation on the female reproductive discipline. Indeed, the role of BRCA1/2 pathogenic variants in ovarian reserve has not been established due to the deficiency of appropriate animal models. Here we used a rat model of Brca2^{(p.T1942fs/+)} mutant of Sprague-Dawley strain with CRISPR-Cas9 editing to evaluate ovarian reserve in females. Fertility and ovarian follicles were evaluated and anti-Müllerian hormone (AMH) was measured at 8-32 weeks of age with a comparison between the wild-type and the mutant rats (MUT). MUT revealed a significantly smaller number of deliveries with fewer total pups. Furthermore, MUT showed a significant decrease in primordial follicles at 20 weeks and a low AMH level at 28 weeks. RNA-sequencing of the ovary at 10 weeks detected acceleration of the DNA damage repair pathway, which was accompanied by oxidative stress-induced DNA double-strand breaks, a decrease in PTEN, and an increase in mTOR in follicular granulosa cells. In conclusion, Brca2^{(p.T1942fs/+)} dissipates primordial follicles via early activation of granulosa cells through oxidative stress, leading to earlier termination of fertility.

2024-02-23·The oncologist

A Somatic BRCA2-Mutated Pancreatic Adenocarcinoma With Sustained Exceptional Response to Modified FOLFIRINOX.

Article

作者: Jacob K Jamison ; Michael S May ; Alexander G Raufi ; Lyndon Luk ; Winston Wong ; Prabhjot S Mundi ; Gulam A Manji

Homologous recombination repair (HRR) pathway deficiency opens multiple therapeutic avenues within pancreatic cancer. Patients with HRR deficiency-associated gene mutations such as BRCA1, BRCA2, and PALB2 are more susceptible to platinum-based chemotherapies and in those with somatic BRCA mutations, PARP inhibitor therapy prolongs progression-free survival. The case discussed herein illustrates the therapeutic opportunities offered through the identification of HRR deficiency in pancreatic cancer, as well as the challenges associated with treatment and prevention of central nervous system metastases in long-term survivors of pancreatic cancer.

195

项与 BRCA2 相关的新闻（医药）

2024-04-08

·PRNewswire

Laekna Announces Two Poster Presentations on Internally Discovered Drug Candidates at AACR 2024

SHANGHAI and WARREN, N.J., April 7, 2024 /PRNewswire/ -- Laekna (2105.HK) announced that the company has presented two internally-discovered preclinical candidates, in addition to a poster presentation on a clinical trial, at the 2024 Annual Meeting of the American Association for Cancer Research (AACR) in San Diego, California. The presentations featured preclinical data of two novel selective inhibitors, LAE119, a novel PARP1 selective inhibitor and trapper, and LAE120, a novel selective USP1 inhibitor. "After advancing LAE102, our internally discovered antibody against ActRIIA, into IND stage, Laekna continues to strengthen our internal discovery efforts, with new drug candidates emerging", said Dr. Justin Gu, Chief Scientific Officer of Laekna. "The MOA of LAE119 and LAE120 is synthetic lethality, both exhibit strong anti-tumor efficacy and good safety in preclinical models. LAE 119 is a PARP1-selective inhibitor with the strongest DNA-trapping activity among all the PARP inhibitors tested. It shows good activity even in tumor cells with low PARP1 protein level. LAE120 is a novel USP1 inhibitor currently at IND-enabling studies stage. It has a unique chemical scaffold differentiated from all the other disclosed USP1 inhibitors and is expected to induce a different conformational change in USP1. The quick advance of these two projects into PCC stage demonstrates the effectiveness of the close collaboration among Med Chem, Biology and AIDD (AI-driven Drug Discovery) teams. Laekna will continue our internal effort of discovery novel drug candidates to provide more options for patients." Laekna's internal discovery focuses on innovation, scarcity, and differentiation, covering three areas: cancer, metabolic diseases，and liver fibrosis. The company has internally discovered 14 drug candidates, among which seven have been optimized and advanced to PCC (pre-clinical candidate) stage. The company plans to have one drug candidate entering the clinical stage each year. The Annual Meeting of AACR is set for April 05 to 10, 2024 at the San Diego Convention Center, California, USA. It is the focal point of the cancer research community, where scientists, clinicians, other health care professionals, survivors, patients, and advocates gather to share the latest advances in cancer science and medicine. [1] Presentation details are as follows: Title: Preclinical characterization of LAE119, a novel PARP1 selective inhibitor and trapper Authors: Ming Li, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Justin Gu Session Category: Experimental and Molecular Therapeutics Session Title: DNA Damage and Repair Session Date and Time: Wednesday, Apr 10, 2024 9:00 AM- 12:30 PM (PT) Location: Poster Section 22 Poster Board Number: 27 Abstract Highlights: LAE119 is a potent and selective PARP1 inhibitor and PARP1-DNA trapper. It demonstrates more than 1000-fold selectivity for PARP1 DNA trapping activity over PARP2. In comparison to most PARP inhibitors including AZD5305, LAE119 exhibits extremely long residence time on PARP1 in both biochemical and cellular assays and shows good activity even in tumor cells with low PARP1 protein level. It demonstrates robust anti-tumor effect in BRCA2-/- DLD-1 and MDA-MB-436 Xenograft models and has minimal effects on hematologic parameters. Full texts of the abstracts are available here. Title: Preclinical candidate LAE120, a novel selective USP1 inhibitor shows effective anticancer and combination activity with PARP inhibitors Authors: Jintao Wang, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Chaojun Cai, Minhua Zhang, Ming Li, Justin Gu Session Category: Experimental and Molecular Therapeutics Session Title: Novel Antitumor Agents 2 Session Date and Time: Sunday, Apr 7, 2024 1:30 PM- 5:00 PM (PT) Location: Poster Section 27 Poster Board Number: 16 Abstract Highlights: LAE120 is a novel, allosteric and highly potent USP1 inhibitor, displaying monotherapy potency and combination activity with PARP inhibitor in HRD (homologous recombination deficiency) cancers. It has a unique chemical structure differentiated from all the other disclosed USP1 inhibitors and is expected to induce a different conformational change in USP1. LAE120 shows robust tumor inhibitory activity in MDA-MB-436 and K562 xenograft models as a single agent and exhibits synergistic effect in combination with PARP inhibitors. LAE120 demonstrates good therapeutic window in DRF study and is currently at IND-enabling stage. Full texts of the abstracts are available here. About Laekna Founded in 2016, Laekna is a science-driven, clinical-stage biotechnology company committed to bringing novel therapies to cancer, metabolic diseases and liver fibrosis patients worldwide. As of December 31, 2023, we have initiated six clinical trials for Afuresertib (LAE002), LAE001 and LAE005 for the treatment of breast cancer, prostate cancer, ovarian cancer and PD-1/ PD-L1 drug-resistant solid tumors to address the unmet medical needs. Among the six clinical trials, three are multi-regional clinical trials (MRCTs). Afuresertib is a potent AKT inhibitor that inhibits all three AKT isoforms (AKT1, AKT2 and AKT3) as well as one of the only two AKT inhibitors in or completed the pivotal-stage clinical development for anti-cancer treatment globally. Laekna's internal drug discovery platform has discovered 14 drug candidates. LAE102 is our internally discovered antibody against ActRIIA. We've submitted IND applications to CDE and FDA respectively for LAE102 in relation to obesity in the first quarter of 2024. Blocking Activin-ActRII pathway could promote skeletal muscle regeneration and decrease fat mass. Laekna team has accumulated tremendous experiences and deep knowhow in this specific field and is developing more drug candidates (LAE103 and LAE123) to maximize the value of targeting ActRII receptors. Laekna, Inc. was listed on the Main Board of The Stock Exchange of Hong Kong Limited (the "Hong Kong Stock Exchange") on June 29, 2023, with the stock code 2105.HK. For more information, please visit: or Forward Looking Statements This press release may contain certain "forward-looking statements" which are not historical facts, but instead are predictions about future events based on Laekna's current beliefs, assumptions, and expectations, commonly identified by words such as "would", "may", "expects", "believes", "plans", "intends", "projects" and other terms with similar meaning. Although we believe that our predictions are reasonable, future events are inherently uncertain and our actual future results or performance may be materially different from what we expect. Accordingly, you are strongly cautioned that reliance on any forward-looking statements is subject to significant known and unknown risks and uncertainties. All forward-looking statements contained herein are qualified by reference to the cautionary statements set forth in this section. All information provided in this press release is as of the date of this press release and are based on assumptions that we believe to be reasonable as of this date, and we do not undertake any obligation to update any forward-looking statement, except as required under applicable law. SOURCE Laekna

AACR会议临床申请

2024-04-07

·生物探索

Circulation | 扬州大学龚开政等团队合作发现维持肺血管稳态的调控新机制

引言BRCC3 (BRCA1/BRCA2-containing complex亚基3)在特发性肺动脉高压患者和实验性肺动脉高压动物的肺组织中表达降低。激活素受体样激酶2 (ALK2)的BRCC3去泛素化激活了肺血管平滑肌细胞中TGF-β(转化生长因子-β)信号的BMP(骨形态发生蛋白)臂。BRCC3功能获得可能降低人类肺动脉高压易感性。2024年4月2日，扬州大学龚开政、加州大学圣地亚哥分校John Y.-J. Shyy及 Jason X.-J. Yuan共同通讯在Circulation（IF 38）在线发表题为“BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension”的研究论文，该研究发现BRCC3通过维持BMP信号(即ALK2-Smad1/5-PPARγ轴)的完整性，同时抑制PASMCs中TGF-β信号，在维持肺血管稳态中起关键作用。在PAH患者和实验性肺动脉高压动物的pasmc中，BRCC3显著下调。BRCC3通过在Lys-472和Lys-475位点去泛素化ALK2，激活受体调控的Smad1/5/9 (Smad1/5/9)，从而导致BMP调控的PPARγ、p53和Id1的转录激活。BRCC3过表达也通过下调TGF-β表达和抑制Smad3磷酸化来减弱TGF-β信号传导。体外实验表明，BRCC3或去泛素样ALK2-K472/475R的过表达可减弱PASMC的增殖和迁移，增强PASMC的凋亡。在SM22α-BRCC3-Tg小鼠中，由于PASMCs中ALK2-Smad1/5-PPARγ轴的激活，肺动脉高压得到改善。相比之下，Brcc3-/-小鼠由于抑制ALK2-Smad1/5信号通路，对实验性肺动脉高压的易感性增加。总之，这些结果表明，BRCC3通过维持BMP信号(即ALK2-Smad1/5-PPARγ轴)的完整性，同时抑制PASMCs中TGF-β信号，在维持肺血管稳态中起关键作用。这种BMP/TGF-β通路的再平衡对于PAH的缓解具有重要的临床转化意义。BMPR2(骨形态发生蛋白2型受体)的突变和功能障碍与特发性和遗传性肺动脉高压(PAH)的发展有关。BMPR2在缺乏遗传原因的PAH患者中趋于下调，可能是由于炎症或环境影响。在BMP(骨形态发生蛋白)结合后，BMPR2结合并磷酸化其同源I型受体ALK2 (激活素受体样激酶-2；也被称为激活素A受体，I型)来激活BMP-BMPR2-Smad1/5/9信号级联。磷酸化的(p) Smad1/5/9易位进入细胞核，导致典型转录因子如Id1和非典型转录因子包括PPARγ和p53的激活，这些转录因子对肺动脉平滑肌细胞(PASMCs)发挥抗增殖和促凋亡作用。TGF-β(转化生长因子-β)或激活素-A结合后，TGF-β受体通过磷酸化Smad2/3发出信号，对肺血管细胞产生促增殖作用。然而，BMP和TGF-β臂对血管细胞的增殖、肥大、分化和存活有不同的影响，这取决于谱系和生物学背景。TGF-β家族受体(包括BMPR2/ALK2和TGF-β r2 /R1)和受体调节(R) Smads (Smad1/5/9或Smad2/3)的翻译后修饰(如磷酸化和泛素化)显著影响其活性，从而调节靶细胞命运。与K48相关的蛋白质泛素化通常与其蛋白酶体降解有关，而与K63相关的泛素化则参与多种细胞事件，包括DNA修复、细胞内蛋白质运输和激酶信号传导。SMURF1 (Smad泛素化调节因子1)作为HECT (E6AP C端同源)型E3泛素连接酶的成员，泛素化R-Smads (Smad1/5)进行蛋白酶体降解，从而阻断BMP信号传导。此外，SMURF1通过I-Smads对BMPRI和Smad1/5的降解，下调BMP信号。在实验性肺动脉高压(PH)啮齿动物中，SMURF1显著升高。然而，SMURF1是否介导多环芳烃肺血管中BMP成分蛋白的泛素化以及任何再平衡机制目前尚不清楚。BRCC3在PAH减轻中的保护作用示意图（Credit: Circulation）PASMCs向高增殖状态的表型变化与肺血管重构和小动脉肌肉化的发展有关。在PAH患者和实验性PH动物的PASMCs中，抗增殖BMP信号下调，而TGF-β、激活素和GDFs(生长分化因子)诱导的促增殖信号增强。事实上，ActRIIA(一种激活素受体IIA的融合蛋白配体陷阱)能够抑制促增殖TGF-β信号，降低肺血管阻力，提高PAH患者的生存率(PulSAR和STELLAR试验)。该研究表明，BRCC3水平在人类多环芳烃疾病和啮齿动物PH模型中较低。BRCC3通过在PASMCs中去泛素化ALK2激活ALK2-Smad1/5/9-PPAR γ轴。因此，BRCC3似乎在疾病发病机制中拮抗SMURF1，上调和激活BRCC3可能是PAH/PH的一种新的治疗策略。原文链接https://doi.org/10.1161/CIRCULATIONAHA.123.066430责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

临床结果临床研究临床终止

2024-04-05

·CPHI制药在线

攻克gBRCA突变/HER2-乳腺癌，PARP抑制剂有望再出新组合

关注并星标CPHI制药在线日前，恒瑞医药的「氟唑帕利胶囊」和「甲磺酸阿帕替尼片」被CDE拟纳入突破性治疗品种，适应症为：两者联合治疗gBRCA突变的HER2阴性乳腺癌。氟唑帕利（艾瑞颐®）是恒瑞医药自主研发的一款PARP抑制剂，已在国内获批两项适应症：既往经二线及以上化疗的伴有胚系BRCA突变(gBRCAm)的铂敏感复发性卵巢癌、输卵管癌或原发性腹膜癌（2020.12）；铂敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者在含铂化疗达到完全缓解或部分缓解后的维持治疗（2021.06）。此外，氟唑帕利单药或联合阿帕替尼用于晚期上皮性卵巢癌、输卵管癌或原发性腹膜癌患者在一线含铂化疗达到完全缓解或部分缓解后的维持治疗的上市申请正在国内接受审查（相关受理号为：CXHS2300070）。甲磺酸阿帕替尼（艾坦®）是恒瑞自主研发的小分子抗血管生成靶向药（作用靶点为VEGFR-2），目前已在国内获批三项适应症：既往至少接受过2种系统化疗后进展或复发的晚期胃腺癌或胃-食管结合部腺癌（2014.10）；既往接受过至少一线系统性治疗后失败或不可耐受的晚期肝细胞癌（HCC）（2020.12）；联合PD-1抑制剂卡瑞利珠单抗一线治疗晚期肝细胞癌（2023.01）。氟唑帕利联合阿帕替尼被开发用于治疗gBRCA突变、HER2-乳腺癌是有理论和临床研究支持的。研究发现，抗血管生成药物可以引起肿瘤微环境缺氧，导致遗传不稳定性和BRCA1/2的下调，从而增强对PARP抑制剂的敏感性。既往研究也表明PARP抑制剂来联合抗血管生成药物可改善患者PFS。《BMC Medicine》上发表的氟唑帕利联合阿帕替尼治疗晚期卵巢癌和三阴性乳腺癌的1期研究结果显示：最高剂量下，即氟唑帕利100mg联合阿帕替尼500mg治疗组的客观缓解率（ORR）为50%，其中gBRCA突变的患者ORR和中位无进展生存期（PFS）均优于gBRCA野生型患者。而且，氟唑帕利联合阿帕替尼治疗晚期卵巢癌或三阴性乳腺癌患者安全性良好。期待氟唑帕利联合阿帕替尼可以早日攻克gBRCA突变、HER2-乳腺癌。 gBRCA突变、HER2-乳腺癌治疗现状据WHO最新数据，乳腺癌已取代肺癌成为全球第一大恶性肿瘤，2020年全球新增病例达226万。BRCA1/2基因是目前已知最主要的乳腺癌易感基因，约5%-10%的乳腺癌患者携带BRCA基因突变。携带BRCA1/2基因突变的乳腺癌在临床上表现出更强的侵袭性，预后相对较差。 BRCA是人体内重要的抑癌基因，主要通过同源重组修复（HRR）途径参与DNA双链断裂修复，来“医治”细胞内因突变而造成的遗传物质的损伤，防治细胞癌变。BRCA突变包括胚系BRCA（gBRCA）突变和体细胞BRCA（sBRCA）突变，其中gBRCA突变来源于生殖细胞（卵子/精子），在三阴性乳腺癌（TNBC，ER-/PR-/HRE2-）和HR+/HER2-型乳腺癌患者中发生率较高。 PARP（多聚腺苷二磷酸核糖聚合酶）主要作用于DNA单链损伤修复，当双链断裂修复过程中的BRCA1、BRCA2和PALB2等蛋白所在的DNA同源重组修复（HRR）通路失效时，PARP就能接替HRR工作继续进行DNA修复。基于“合成致死”原理，理论上PARP抑制剂可用于治疗BRCA突变肿瘤。目前，全球获批治疗gBRCA突变、HER2阴性乳腺癌的疗法有限。其中阿斯利康与默沙东合作开发的PARP抑制剂奥拉帕利（Lynparza）于2018年1月被FDA批准用于治疗携带gBRCA基因突变、HER2-转移性乳腺癌。此外，该药还于2022年3月被FDA批准单药或联合内分泌治疗用于既往接受过新辅助或辅助化疗的gBRCA1/2突变的HER2-早期高危乳腺癌成人患者的辅助治疗。辉瑞PARP抑制剂他拉唑帕利（Talzenna）于2018年10月被FDA批准用于治疗gBRCA突变、HER2-局部晚期或转移性乳腺癌。遗憾的是，上述两款药物均未在国内获批治疗gBRCA突变、HER2-乳腺癌。不过奥拉帕利单药或联合内分泌疗法用于既往接受过新辅助或辅助化疗的gBRCA1/2突变、HER2-早期高危乳腺癌成人患者辅助治疗的上市申请正在国内接受优先审查。此外，国内还有多款PARP抑制剂被开发用于治疗gBRCA突变、HER2-乳腺癌，如天士力的TSL-1502、百济神州的帕米帕利、上海药物研究所的希明哌瑞。其中TSL-1502是天士力帝益药业开发的一款PARP抑制剂，对多种BRCA1/2突变的人肿瘤裸小鼠皮下移植模型有明显疗效，并且对BRCA野生型肿瘤明显增效其他细胞毒药物（卡铂、伊立替康）的抗肿瘤作用。而且，TSL-1502体内、体外活性总体上与奥拉帕利相当。目前，TSL-1502针对gBRCA突变、HER2-局部晚期或转移性乳腺癌的临床试验已进入2期。帕米帕利是一种PARP1和PARP2的强效、选择性抑制剂，已于2021年5月在国内被批准用于治疗既往经过二线及以上化疗的伴gBRCA突变的复发性晚期卵巢癌、输卵管癌或原发性腹膜癌。已公布的帕米帕利治疗携带gBRCA突变晚期或转移性TNBC和HR+/HER2-乳腺癌的开放标签、单臂2期临床研究BGB-290-201数据显示：TNBC队列中，独立评审委员会(IRC)评估的客观反应率（ORR）为38.2%，中位缓解持续时间(mDoR)为7.0个月，中位无进展生存期(mPFS)为5.5个月，中位总生存期(mOS)为17.1个月；HR+/HER2-队列中，IRC评估的ORR为61.9%，mDoR为7.5个月，mPFS为9.2个月，mOS未达到。而且，TNBC的ORR亚组分析显示，既往接受化疗线数较少的患者ORR更高：帕米帕利一线治疗患者的ORR达到66.7%；帕米帕利二线治疗患者ORR的为34.5%；帕米帕利三线治疗患者的ORR为9.1%。同时，与使用过铂类患者相比，未使用过铂类患者有更高的ORR：既往未接受铂治疗的患者ORR达到50.0%，既往接受铂治疗的患者ORR为24.0%。安全性方面，帕米帕利治疗乳腺癌最常见的≥3级治疗相关TEAE是血液学不良事件，包括贫血、白细胞计数水平下降和中性粒细胞计数水平下降等，发生率与其他PARP抑制剂相一致，整体安全可控。 BGB-290-201研究是首个公布PARP抑制剂专门针对中国乳腺癌患者疗效和安全性数据的临床研究，已公布的数据也算积极，帕米帕利未来或成为我国携带gBRCA突变晚期或转移性TNBC和HR+/HER2-乳腺癌患者的新选择。不过笔者疑惑的是，自2021年该研究数据公布后，帕米帕利在该适应症上未再公布新进展。总结随着下一代测序技术（NGS）的发展，BRCA基因检测更加便捷和准确。乳腺癌NCCN指南2022.v4版推荐对所有复发或转移性乳腺癌患者行胚系BRCA1/2突变评估，以确定适合接受PARP抑制剂治疗的患者。目前，全球获批治疗携带gBRCA基因突变、HER2-乳腺癌的PARP抑制剂仅有奥拉帕利和他拉唑帕利。目前，国内还未有PARP抑制剂获批治疗携带gBRCA突变、HER2-乳腺癌，该领域还存在很大未满足的市场需求。从目前相关药物进度来看，阿斯利康的奥拉帕利有望在国内率先获批。恒瑞医药开发氟唑帕利联合阿帕替尼治疗携带gBRCA基因突变、HER2-乳腺癌有望给药企在该领域开发性药物组合带来新思路。目前全球已有多款CDK4/6抑制剂被开发用于治疗HR+/HER-乳腺癌、Trop-2靶向ADC、PD-1/L单抗被批准用于治疗TNBC，或许PARP抑制剂可以联合更多类型药物治疗携带gBRCA突变、HER2-乳腺癌。【智药研习社近期课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

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