更新于：2024-11-01

Adrenocortical Carcinoma

肾上腺皮质癌

更新于：2024-11-01

基本信息

别名

ACC、ADRENAL CARCINOMA、ADRENAL CORTEX CANCER, CARCINOMA

+ [55]

简介

A malignant neoplasm of the ADRENAL CORTEX. Adrenocortical carcinomas are unencapsulated anaplastic (ANAPLASIA) masses sometimes exceeding 20 cm or 200 g. They are more likely to be functional than nonfunctional, and produce ADRENAL CORTEX HORMONES that may result in hypercortisolism (CUSHING SYNDROME); HYPERALDOSTERONISM; and/or VIRILISM.

关联

项与肾上腺皮质癌相关的药物

Dostarlimab-gxly

多塔利单抗

靶点

PD-1

作用机制

PD-1抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

欧盟 [+3]

首次获批日期2021-04-21

Lenvatinib mesylate

甲磺酸仑伐替尼

靶点

FGFR1 x FGFR2 x FGFR3 x FGFR4 x PDGFRα x RET x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit

作用机制

FGFR1拮抗剂 [+9]

在研机构

Merck Sharp & Dohme Corp. [+7]

原研机构

Eisai Co., Ltd.

在研适应症

晚期子宫内膜癌 [+76]

非在研适应症

晚期胃癌 [+27]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2015-02-13

Pembrolizumab

帕博利珠单抗

靶点

PD-1

作用机制

PD-1抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2014-09-04

100

项与肾上腺皮质癌相关的临床试验

NCT06487481 / Not yet recruiting临床1期IIT

A Phase I Dose-escalation Study of Preoperative Radiation Therapy in Participants With Resectable Recurrent Abdominal Adrenocortical Carcinoma

Background:
The eyeGENE(R) program is a research resource for inherited eye conditions which includes genotypic and phenotypic data, imaging, and a corresponding biobank of DNA samples from people with a variety of eye diseases. Since 2007 this registry has been helping researchers learn more about the genetic sources for many inherited eye diseases. These findings helped them create better treatments. Now researchers want to expand eyeGENE(R) to include more people for certain eye diseases.
Objective: To collect information and DNA samples for the study of eye diseases.
Primary objective
-To expand the current eyeGENE(R) data repository with targeted participant accrual
Secondary objectives
* To enhance recruitment for clinical trials and investigations in inherited eye diseases
* To establish genotype-phenotype correlations for rare eye diseases
Eligibility:
People of any age with certain eye diseases. These can include aniridia; Best disease; blue-cone monochromacy; corneal dystrophy; and disorders of pigmentation, such as albinism. Relatives unaffected by the eye disease of interest may also be needed.
Design:
Researchers will select participants based on their diagnosis. The data may include images and test results from eye exams.
Participants will provide a sample of saliva. They will receive a kit with written instructions. They will spit in a tube and mail it to the NIH.
Participants may be asked to provide a blood sample. The blood may be drawn at the NIH or at a local clinic.
The eyeGENE(R) repository will offer researchers data about the participants eye conditions. The data may include pictures of their eyes, results of genetic testing, and history of other diseases. Researchers will be able to see data such as age and gender, but they will not see names, dates of birth, or contact information.

开始日期2024-11-04

申办/合作机构

National Cancer Institute

NCT06587802 / Not yet recruiting临床2期IIT

Phase II Study of PD-1 Antibody Combined with Radiotherapy in Recurrent or Metastatic Adrenal Cortical Carcinoma

Adrenal cortical cancer is an extremely rare and highly aggressive malignancy with an incidence of 0.7-2 per million people · year and a 5-year overall survival rate of 15-44%, among which the 5-year survival rate of stage IV cortical cancer is only 13% and the prognosis is poor. Complete surgical resection is one of the most important ways to cure cortical cancer, but the surgical trauma is large, the complications are high, the postoperative recovery of patients is slow, and the tumor is difficult to achieve complete resection, and the postoperative recurrence and metastasis rate of patients is high, even for localized cortical cancer (stage I-III), the recurrence and metastasis rate is still close to 60%.
Recurrent or metastatic cortical cancer is mainly treated with drugs. However, the current first-line drug therapy is only 22.3% effective, the tumor progression-free time is 5.6 months, and the serious adverse reaction rate is as high as 58.1%.
The effective rate of second-line treatment with chemotherapy and targeted drugs was less than 10%, and the tumor progression-free time was only 2.8 months.
The Phase II study of PD-1 monoclonal antibody in the treatment of cortical cancer showed that the treatment effective rate was 23%, and the tumor progression-free survival time was 2.1 months, which was comparable to the first-line regimen, and has been approved by the guidelines for advanced cortical cancer.
Radiation therapy has high efficiency and local control rate, small side effects, and can inhibit tumor growth, relieve local pressure and pain. However, it only has a good effect on the irradiated site, and it is difficult to inhibit the progression of non-radiotherapy lesions and the generation of other new lesions.
The synergistic effect of immunotherapy combined with radiation therapy for metastatic stoves has been confirmed in many solid tumors such as kidney cancer, which can improve the local control rate of solid tumors and prolong the time of tumor progressive-free.
In the early stage, this research team applied PD-1 monoclonal antibody combined with radiotherapy to treat recurrent or metastatic adrenal cortical cancer in many cases after receiving first-line drug therapy regimen, which not only achieved local control of the radiotherapy focus, but also inhibited the progression of other metastases, and achieved longer disease control effect.

开始日期2024-09-30

申办/合作机构

中山大学

ChiCTR2400089134 / Suspended临床2期IIT

Phase II clinical study of PD-1 monoclonal antibody combined with radiotherapy in the treatment of recurrent or metastatic adrenal cortical carcinoma

开始日期2024-09-15

申办/合作机构

中山大学肿瘤防治中心

100 项与肾上腺皮质癌相关的临床结果

登录后查看更多信息

100 项与肾上腺皮质癌相关的转化医学

登录后查看更多信息

0 项与肾上腺皮质癌相关的专利（医药）

登录后查看更多信息

5,609

项与肾上腺皮质癌相关的文献（医药）

2025-01-01·The American Journal of Surgery

Survival impact of treatment utilization and margin status after resection of adrenocortical carcinoma

Article

作者: Abou Azar, Sara ; Vaghaiwalla, Tanaz M. ; Afolaranmi, Oluwasegun ; Vaghaiwalla, Tanaz M ; Memeh, Kelvin

BACKGROUNDThis study examines the combined impact of margin status and adjuvant therapy utilization on overall survival (OS) for adrenocortical carcinoma (ACC) patients undergoing surgery with curative intent.METHODSThe 2004-2020 National Cancer Database (NCDB) was queried for ACC patients ≥18yrs undergoing curative surgery (no debulking), subdivided into R0 and R1/R2-groups, and analyzed using inverse-probability-weighted Cox Proportional Hazard-model.RESULTSOf 5023 ACC patients, 3193 underwent curative surgery, 2213 (69 %) had R0 margins. Compared to the R0, the R1/R2 group had a decreased OS by 15.6 months (HR = 1.89, p = 0.002). While there has been no significant improvement in margin status over the years studied (2008-2017), there has been an overall increase in the proportion of patients receiving adjuvant therapy regardless of margin status, and the adverse impact of a positive margin on survival has decreased [HR 2.20 vs 1.76] CONCLUSIONS: R1/R2 margins are associated with decreased OS. The adverse impact of R1/R2 margins on OS decreased over time while adjuvant therapy utilization increased for all patients.

2024-12-18·Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences

[Clinical treatment and prognosis of adrenocortical carcinoma with venous tumor thrombus].

Article

作者: Hou, Xiaofei ; Liu, Shuai ; Zhang, Shudong ; Zhang, Fan ; Zhao, Lei ; Liu, Zhuo ; Wang, Guoliang ; Liu, Lei ; Tian, Xiaojun ; Ma, Lulin

OBJECTIVETo analyze the clinicopathological features, prognostic value and surgical treatment experience in patients with adrenocortical carcinoma with venous tumor thrombus.METHODSWe collected relevant data of the patients with adrenocortical carcinoma who had undergone surgery in Peking University Third Hospital from 2018 to 2023. The patients were divided into venous tumor thrombus group and non-tumor thrombus group. The Wilcoxon rank sum test was used to compare the quantitative variables. The chi-squared test and Fisher's exact test were used to compare the categorical variables. The Kaplan-Meier method was used to estimate the survival rate.RESULTSA total of 27 patients with adrenocortical carcinoma were included, of whom 11 cases (40.7%) had venous tumor thrombus. In the patients with venous tumor thrombus, 8 patients were female and 3 were male. The median age was 49 (36, 58) years. The median body mass index was 26.0 (24.1, 30.4) kg/m². Seven patients presented with symptoms at their initial visit. Six patients had a history of hypertension. Elevated levels of cortisol were observed in 2 cases. Three tumors were found on the left side, while 8 were found on the right side. Median tumor diameter was 9.4 (6.5, 12.5) cm. On the left, there was a case of tumor thrombus limited to the central vein of the left adrenal gland without invasion into the left renal vein, and two cases of tumor thrombus growth extending into the inferior vena cava below the liver. One case of tumor thrombus on the right adrenal central vein did not invade the inferior vena cava. Four cases of tumor thrombus invaded the inferior vena cava below the liver and three cases extended to the posterior of the liver. Ten patients were in European Network for the Study of Adrenal Tumors (ENSAT) stage Ⅲ and one was in ENSAT stage Ⅳ. Open surgery was performed in 6 cases, laparoscopic surgery alone in 4 cases and robot-assisted laparoscopic surgery in 1 case. Two patients underwent ipsilateral kidney resection. Median operative time was 332 (261, 440) min. Median intraoperative bleeding was 900 (700, 2 200) mL. Median hospital stay was 9 (5, 10) days. Median survival time for the patients with tumor thrombus was 24.0 months and median time to recurrence was 7.0 months. The median survival and recurrence time of 16 patients without tumor thrombus were not reached. The patients with tumor thrombus had worse 3-year overall survival (OS) rate (40.9% vs. 71.4%; Log-rank, P=0.038) and 2-year recurrence-free survival (RFS) (9.1% vs.53.7%; Log-rank, P=0.015) rates compared with the patients with non-tumor thrombus.CONCLUSIONPatients with adrenocortical carcinoma with venous tumor thrombus have poor prognosis. Different adrenal tumor resections and venous tumor thrombus removal procedures based on different tumor thrombus locations are safe and effective in treating this disease.

2024-12-01·Molecular and Cellular Endocrinology

Analysis of miR-483-3p and miR-630 expression profile in pediatric adrenocortical tumors and the effect of their modulation on adrenal tumorigenesis in vitro

Article

作者: Lira, Régia Caroline Peixoto ; Antonini, Sonir Roberto Rauber ; Silva, Keteryne Rodrigues da ; Corrêa, Carolina Alves Pereira ; Andrade, Augusto Faria ; Brandalise, Silvia Regina ; Veronez, Luciana Chain ; de Paula Gomes Queiroz, Rosane ; Chagas, Pablo Shimaoka ; Suazo, Veridiana Kill ; Scrideli, Carlos Alberto ; Queiroz, Rosane de Paula Gomes ; Tone, Luiz Gonzaga ; da Silva, Keteryne Rodrigues ; Molina, Carlos Augusto Fernandes ; Baroni, Mirella ; Yunes, José Andres ; Valera, Elvis Terci

Pediatric adrenocortical tumors (ACT) are rare aggressive neoplasms with heterogeneous prognosis. MicroRNA (miRNA) signatures have been associated with cancer diagnosis, treatment response, and outcomes of several types of cancer. However, the role played by miRNAs in pediatric ACT has been poorly explored. In this study, we have evaluated the expression of miR-483-3p and miR-630 in 67 pediatric ACT and 19 non-neoplastic adrenal samples, the effects of the modulations of these miRNAs, and their relationship with the TGF-β pathway in the H295R and H295A cell lines. Deregulation of both miRNAs was related to survival and disease advanced stages and hence to patients' prognosis. Moreover, modified miR-483-3p and miR-630 in vitro expression decreased cell viability and colony formation capacity, changed how some genes of the TGF-β pathway, such as TGFBR1, TGFBR2, and SMAD7, are expressed, and altered Smad3, pSmad3, Smad 2/3, N-cadherin, and Vimentin protein expression. Besides that, when inhibition of the TGF-β pathway was combined with miR-630 overexpression or miR-483-3p silencing, cell viability and colony formation capacity decreased, and protein expression in the TGF-β pathway changed. Together, the data indicate that both miRNAs participate in the TGF-β pathway and are therefore potential markers for predicting the prognosis of patients with pediatric ACT.

项与肾上腺皮质癌相关的新闻（医药）

2024-10-16

·PRNewswire

Remix Therapeutics™ to Present Preclinical Data Demonstrating Tumor Regressions Induced by REM-422 in Adenoid Cystic Carcinoma Patient-Derived Xenograft Models at the 2024 EORTC-NCI-AACR Symposium

REM-422, a first-in-class MYB mRNA degrader, induces regression across multiple preclinical models of ACC WATERTOWN, Mass., Oct. 16, 2024 /PRNewswire/ -- Remix Therapeutics (Remix), a clinical-stage biotechnology company developing small molecule therapies to modulate RNA processing and address underlying drivers of disease, will deliver a poster presentation demonstrating the therapeutic potential of REM-422, a potent, selective, oral small molecule MYB mRNA degrader for the treatment of acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC), at the upcoming 2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics being held on October 23-25, 2024 in Barcelona, Spain. MYB is an oncogenic transcription factor that is dysregulated in human malignancies including ACC, where the majority of tumors contain a hallmark t(6:9) rearrangement resulting in a MYB::NFIB fusion oncogene. The poster presentation will include preclinical data from biophysical and cellular assays that demonstrate the mechanism of action of REM-422 in suppressing MYB mRNA and protein expression by promoting inclusion of a poison exon into the MYB mRNA transcript. In vivo studies in ACC patient-derived xenograft (PDX) mouse models harboring the MYB::NFIB fusion demonstrates that REM-422 induces tumor regressions, including in models that harbor co-occurring mutations in the Notch pathway, a profile that represents especially aggressive clinical cases of ACC. Anti-tumor activity of REM-422 in these models is associated with a reversal of gene transcriptional programs that are associated with ACC, as assessed by genome-wide RNAseq experiments. "We've built an exciting package of preclinical data across various models that reinforces the therapeutic potential of REM-422 for the treatment of ACC and other MYB-dysregulated cancers," said Peter Smith, Ph.D., Co-Founder and Chief Executive Officer of Remix Therapeutics. "The preclinical data demonstrated that REM-422 monotherapy treatment leads to tumor regressions in PDX models of ACC and support clinical development in ACC patients." REM-422 is currently being investigated as a potential treatment for adenoid cystic carcinoma (ACC) and AML/HR-MDS (High-Risk Myelodysplastic Syndromes) in two, phase 1 clinical trials. Details for the poster presentation are as follows: Title: REM-422, a potent, selective, oral small molecule mRNA degrader of the MYB oncogene, induces regressions in mouse patient-derived xenograft models of adenoid cystic carcinoma Authors: M. Cameron1, S. Levin-Furtney1, A. Harney1, M. Thomas1, J. Maag1, B. Dunyak1, M. Shan1, S. Prajapati1, Y.A. Siu1, D. Nguyen1, S. Buonamici1, M. Seiler1, F. Vaillancourt1, P. Smith1, D. Reynolds1, C. Kung1. 1Remix Therapeutics, Research, Watertown, USA. Abstract Number: ENA24-0468 Session Date and Time: Wednesday, October 23, 2024 (11:00 AM – 8:00 PM) Session Location: CCIB Exhibition Hall poster area, Barcelona, Spain About REM-422 REM-422 is a first-in-class, potent, selective, and oral small molecule mRNA degrader that induces the reduction of MYB mRNA and subsequent protein expression. REM-422 functions by facilitating the incorporation of poison exons within the mRNA transcript, leading to nonsense-mediated decay (NMD) of the transcript. REM-422 addresses MYB dysregulation, a driver of oncogenesis, upstream of protein expression. About ACC Adenoid cystic carcinoma (ACC) is a rare cancer that commonly develops in glandular tissues in the head and neck. It is caused by genetic mutations, likely developed over a patient's lifetime, with the majority of ACC cases linked to an overexpression of the MYB protein. Current treatment solutions include surgery, radiation therapy, and chemotherapy. About AML/HR-MDS Acute myeloid leukemia (AML), a rare cancer of the blood and bone marrow, is the most common type of acute leukemia in adults. AML is caused by genetic mutations within bone marrow cells, which in turn causes the production of leukemic white blood cells that crowd out healthy blood cells. This may cause problems with bleeding, infection, and anemia. Myelodysplastic Syndromes (MDS) are disorders of blood-forming units in the bone marrow. High-risk (HR)-MDS patients have a higher percentage of blast cells in the bone marrow and that, in many cases, progresses to AML. There are several approved agents to treat AML, however, many patients relapse after achieving a response, underscoring the need for new therapies. About Remix Therapeutics Remix Therapeutics is a clinical-stage biotechnology company developing novel small molecule therapies designed to reprogram RNA processing and treat disease. The REMaster™ technology platform facilitates RNA processing pattern identification, leveraging these learnings to modulate gene expression. Remix's innovative therapeutic approach has the potential to alter the way genes are read from the genome, to correct, enhance, or eliminate the gene message, thereby addressing disease drivers at their origin. For more information visit . SOURCE Remix Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床1期AACR会议

2024-10-15

·精准药物

通过ClickRNA-PROTAC实现肿瘤选择性蛋白靶向降解和治疗

今天分享一篇JACS上的文章“ClickRNA-PROTAC for Tumor-Selective Protein Degradation and Targeted Cancer Therapy”，通讯作者是来自清华大学化学系的李景虹院士。蛋白降解靶向嵌合体PROTAC是一种基于泛素蛋白酶体系统的新型治疗策略，它通过粘合目标蛋白和E3泛素连接酶实现对目标蛋白的降解，从而发挥治疗效果。在这项策略发展的过程中，研究者们注意到E3泛素连接酶在肿瘤中的分布存在差异，同时PROTAC分子的的肿瘤特异性较低，这些因素限制了PROTAC的进一步应用。目前已有基于共价自标记标签如HaloTag、SNAPTag等改进PROTAC方法可以实现对更多类型的蛋白的靶向降解，但是只能应用于外源表达的蛋白上。而本文作者则注意到了一种由RNA特异性腺苷脱氨酶（ADAR）介导的mRNA碱基编辑策略，据此可以设计出肿瘤细胞特异性的方式诱导终止密码子UAG的A-to-I碱基编辑，从而激活下游蛋白质的翻译。在本文中，作者基于这一技术和SNAPTag开发了ClickRNA-PROTAC技术，能够实现肿瘤细胞特异性的内源目标蛋白的降解。 ClickRNA-PROTAC系统依赖于一个由脂质纳米颗粒递送的mRNA，这条mRNA的5’端感应区可以和肿瘤特异性mRNA形成A-C不匹配的双链RNA，激活ADAR介导的终止密码子UAG的A-to-I碱基编辑，使得后续3’端SNAPTag-E3 ligase的翻译得以继续，最终翻译出的融合蛋白会在中间T2A自裂解肽的作用下被释放并发挥后续功能。由于递送的mRNA上感应区序列仅能和肿瘤细胞特异性mRNA进行互补，正常细胞中SNAPTAg-E3 ligase无法被翻译出来发挥作用，从而实现较好的肿瘤细胞特异性。之后通过添加叠氮基团衍生的目标蛋白共价配体以及DBCO基团衍生的SNAPTag配体，可以实现对肿瘤细胞中内源目标蛋白的降解。在方法的构建中，作者首先测试了不同共价标签和不同E3连接酶的融合表达效果、对BRD4模型蛋白的降解效果，以及在这一模型中BRD4配体和叠氮基团之间连接器结构，从而确定了一组在多种细胞中都有很好降解效果的SIAH1-SN融合蛋白、靶向BRD4的JQ1-N3-C10配体和靶向SNAPTag的BG-DBCO组合。作者也尝试替换靶向不同蛋白如KRAS、p65等的小分子结构以及替换其他类型的E3连接酶，发现这些组合也有一定的降解效果，说明ClickRNA-PROTAC能够拓展到不同的应用场景中进行应用。之后，在肿瘤特异性mRNA响应序列的设计上，作者主要针对肾上腺皮质癌（ACC）进行了序列筛选和优化。他们针对三个ACC特异性高表达转录物设计了15条序列，在其5’端加入mCherry序列、在3’端加入自裂解肽和NanoLuc序列，通过最终mCherry和NanoLuc的信号比值来确定最合适的序列。IGF2-4是效果最好的一条序列，能够特异性地诱导mRNA在癌细胞SW-13中的翻译，而不会在正常细胞HACC中诱导翻译。利用这一序列和之前优化得到的融合蛋白组合，作者成功实现了在SW-13细胞中对ACC中高表达的BRD4蛋白的降解，而在HACC中的BRD4则没有被降解。最后，作者在移植ACC的小鼠模型上验证ClickRNA-PROTAC的治疗效果，发现ClickRNA-PROTAC表现出比传统的PROTAC小分子更好的抗肿瘤效果，同时没有明显的器官组织损伤等副作用，说明了ClickRNA-PROTAC未来被用于ACC临床治疗中的潜力。总之，本文发展了ClickRNA-PROTAC方法，能够实现肿瘤特异性的内源蛋白靶向降解，有潜力用于肿瘤治疗之中。内容来源于网络，如有侵权，请联系删除。

蛋白降解靶向嵌合体信使RNA

2024-10-12

·AIDD Pro

靶向癌症治疗新策略：ClickRNA-PROTAC技术

9月25日，清华大学李景虹院士研究团队在《Journal of the American Chemical Society》期刊上发表了重要研究成果，该研究团队开发了一种ClickRNA-PROTAC系统，该系统通过mRNA转染表达E3泛素连接酶SIAH1和SNAPTag的融合蛋白，并使用生物正交点击化学招募靶蛋白（POI）。该策略只需更换弹头分子，即可有效降解BRD4、KRAS、NF-κB等多种蛋白质。ClickRNA-PROTAC克服了不同肿瘤之间E3酶表达水平差异的限制，拓展了PROTAC技术的应用范围（图1）。目前，临床阶段的PROTAC药物主要通过招募E3泛素连接酶VHL和CRBN来介导靶蛋白的泛素化，从而实现蛋白降解。然而，由于不同肿瘤中E3泛素连接酶的表达水平存在差异（图2），这限制了PROTAC药物在癌症治疗中的应用范围和疗效。此外，PROTAC分子缺乏对肿瘤的特异性，可能会在正常细胞中引起靶蛋白的降解，从而对正常细胞造成损害，并可能产生不良副作用。因此，迫切需要开发不依赖内源性E3连接酶的肿瘤选择性PROTAC药物。共价自标记标签（Self-labeling protein tags, SLPs）是一种蛋白质工程技术，它允许特定的蛋白质在活细胞中被标记，用于生物成像、蛋白质纯化和功能探究等。这些标签通过与目标蛋白质融合表达，并通过特定的配体小分子共价结合，实现对目标蛋白质的标记。目前，已经发展出多种共价自标记标签系统，如HaloTag、SNAP-tag和CLIP-tag等。这些标签系统各有特色，例如：HaloTag基于细菌脱卤酶的突变体，通过亲核的天冬氨酸残基与标记的氯烷烃配体形成稳定的共价键，SNAP-tag可以特异性识别并与苄基鸟嘌呤（BG）反应，形成稳定的共价键，而CLIP-tag可以与SNAP-tag互补使用，特异性识别苄基胞嘧啶（BC）并与之反应，适用于双重标记。共价自标记标签可以通过基因编码的标记蛋白选择性地调节细胞内蛋白之间的相互作用，与PROTACs的原理非常吻合。 2015年，Crews教授团队报道了HaloPROTACs，研究人员将HaloTag技术引入到PROTAC的研究中，建立了HaloPROTAC系统（图3）。HaloPROTAC利用E3连接酶配体与氯烷结合来介导融合蛋白的降解。目前，已有多种类型的基于VHL E3配体以及cIAP配体的HaloPROTAC被广泛用于各种融合靶蛋白的降解。然而，目前报道的方法旨在调节外源蛋白的表达和降解，而不是靶向降解肿瘤相关蛋白，肿瘤选择性PROTAC药物的研发市场仍是一片空白。 mRNA疗法是一种革命性的技术，它通过利用mRNA来指导细胞产生治疗性蛋白，展现出治疗多种疾病的潜力。自从mRNA新冠疫苗成功应用于临床以来，mRNA技术在疫苗开发和疾病治疗方面取得了显著进展（图4）。在疫苗开发方面，mRNA技术正在被用于开发针对流感、巨细胞病毒（CMV）和呼吸道合胞病毒（RSV）的疫苗。mRNA疫苗的优势在于它们可以快速设计和生产，以应对快速变异的病原体。在疾病治疗方面，研究人员正在探索使用mRNA表达治疗性蛋白来治疗遗传性疾病、心血管疾病等。例如，mRNA可以被用来表达血管内皮生长因子（VEGF）来治疗心力衰竭。此外，mRNA也被用于CRISPR-Cas9等基因编辑技术，以治疗遗传性疾病。 CRISPR/Cas9系统可以由Cas9蛋白和单链导向RNA（sgRNA）组成，通过sgRNA的导向作用在特定靶部位切割靶基因，实现基因编辑。在肿瘤靶向治疗方面，研究人员正在开发以细胞类型特异性方式调节mRNA编码蛋白翻译的方法。例如，合成的内含子可以被肿瘤细胞中的剪接因子突变激活，导致肿瘤细胞靶向剪接和mRNA的表达。此外，由腺苷脱氨酶RNA特异性（ADAR）介导的mRNA碱基编辑策略，称为CellREADR，可以以细胞特异性的方式诱导Ato-I对停止密码子UAG进行碱基编辑，从而激活下游蛋白的翻译。然而，这些方法尚未用于肿瘤靶向mRNA治疗的开发。 9月25日，清华大学李景虹院士研究团队开发了一种新型蛋白质降解技术ClickRNA-PROTAC，它结合了mRNA转染和PROTAC技术。该技术通过转染mRNA在活细胞中表达共价标签的E3泛素连接酶融合蛋白，并通过二苯基环辛炔（DBCO）修饰的配体使融合蛋白功能化，再利用点击化学将叠氮化合物偶联的POI配体连接到融合蛋白上，诱导POIs泛素化并降解。为了实现肿瘤特异性，该技术采用了基于UAG终止密码子的AI碱基编辑策略，调控mRNA的翻译。合成的mRNA由5′传感区和3′蛋白编码区组成，中间有一个UAG终止密码子，以防止初始状态下3′蛋白编码区翻译。在肿瘤细胞中，5′传感区与肿瘤特异性mRNA杂交，激活ADAR介导的A到I碱基编辑，使得原本的终止密码子UAG变为可翻译的UIG密码子，从而重新激活3′蛋白质编码区的翻译。研究人员构建了52种不同的Tag-E3融合蛋白，并在HEK293FT细胞中验证了它们的表达水平。其中，SIAH1-SN、VHL-HC和PARKIN-HN等16种融合蛋白表达良好，能有效降解BRD4蛋白（图5）。 ClickRNA-PROTAC系统通过mRNA形式递送，能有效降解KRAS和p65蛋白，且具有剂量依赖性。此外，该技术还能特异性激活肾上腺皮质癌效应蛋白的翻译，而不影响正常细胞。在裸鼠肿瘤模型中，ClickRNA-PROTAC显著抑制了肿瘤生长，且与传统的PROTAC相比，具有更优越的抗肿瘤效果（图6）。治疗后小鼠的主要脏器未发现明显组织损伤，表明ClickRNA-PROTAC具有较好的安全性和选择性。 ClickRNA-PROTAC技术展现了高效降解靶蛋白的能力，并且具备几大显著优势：它不依赖于细胞内源的E3泛素连接酶，能够实现肿瘤细胞的选择性作用，并且具有高度的可编程性。这些特性为PROTAC药物的研发和其在临床上的潜在应用开辟了新的道路。总体而言，ClickRNA-PROTAC技术代表了一种治疗肿瘤的创新策略，它通过精确降解肿瘤细胞内的特定蛋白质靶标，有潜力发展成为一个有效的临床治疗方案。 Ref.[1] Mo J, Chen J, Shi Y, Sun J, Wu Y, Liu T, Zhang J, Zheng Y, Li Y, Chen Z. Third-Generation Covalent TMP-Tag for Fast Labeling and Multiplexed Imaging of Cellular Proteins. Angew Chem Int Ed Engl. 2022 Sep 5;61(36):e202207905. doi: 10.1002/anie.202207905.[2] Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL, Smith IE, Miah AH, Harling JD, Crews CM. HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins. ACS Chem Biol. 2015 Aug 21;10(8):1831-7. doi: 10.1021/acschembio.5b00442.[3] Sasso JM, Ambrose BJB, Tenchov R, Datta RS, Basel MT, DeLong RK, Zhou QA. The Progress and Promise of RNA Medicine─An Arsenal of Targeted Treatments. J Med Chem. 2022 May 26;65(10):6975-7015. doi: 10.1021/acs.jmedchem.2c00024.[4] Teng X, Zhao X, Dai Y, Zhang X, Zhang Q, Wu Y, Hu D, Li J. ClickRNA-PROTAC for Tumor-Selective Protein Degradation and Targeted Cancer Therapy. J Am Chem Soc. 2024 Sep 25. doi: 10.1021/jacs.4c06402. 内容来源于网络，如有侵权，请联系删除。

蛋白降解靶向嵌合体信使RNA