更新于：2024-11-01

Brain metastases

脑转移瘤

更新于：2024-11-01

基本信息

别名

BRAIN METASTASES、BRAIN METASTASIS、BRAIN TUMOR METASTATIC

+ [53]

简介

A malignant neoplasm that has spread to the brain from another anatomic site or system. The majority are carcinomas (usually lung or breast carcinomas).

关联

175

项与脑转移瘤相关的药物

Pegulicianine

靶点

组织蛋白酶

作用机制

组织蛋白酶抑制剂 [+1]

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2024-04-17

Elacestrant hydrochloride

艾拉司群

靶点

ERα

作用机制

ERα拮抗剂

在研机构

A. Menarini Industrie Farmaceutiche Riunite SRL [+5]

原研机构

Eisai Co., Ltd.

在研适应症

晚期乳腺癌 [+9]

非在研适应症

HR阳性乳腺腺癌 [+3]

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2023-01-27

Olutasidenib

靶点

IDH1

作用机制

IDH1抑制剂

在研机构

FORMA Therapeutics, Inc. [+2]

原研机构

Forma Therapeutics Holdings, Inc.

在研适应症

IDH1突变急性髓性白血病 [+15]

非在研适应症

晚期恶性实体瘤 [+5]

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2022-12-01

1,029

项与脑转移瘤相关的临床试验

NCT06649058 / Not yet recruiting临床2期IIT

EXCLAIM: Exploring Combined Local and Systemic Approaches In Brain Metastasis: a Multi-cohort Randomized Phase II Study Evaluating Initial Response to Systemic Therapy and Subsequent Integration of Stereotactic Radiosurgery in Patients With Low-risk Brain Metastases and Central Nervous System-active Systemic Therapy Options

To learn if consolidative stereotactic radiosurgery (cSRS) can help to control central nervous system (CNS) disease in patients who have brain metastases and have a partial response or stable brain metastases after systemic therapy.
To learn if using SRS to treat all brain metastases that do not respond to systemic therapy versus treating only metastases that are getting worse can help to control CNS disease in patients whose disease gets worse after systemic therapy.

开始日期2025-04-01

申办/合作机构

The University of Texas MD Anderson Cancer Center

NCT06611306 / Not yet recruitingN/AIIT

BEAT-Breast - Improving Outcomes for Breast Cancer Patients With Brain Metastases: a Pilot Nonrandomised Single Arm Phase 2 Clinical Trial in Patients With Primary Breast Cancer With Brain Metastases Who Are Not Suitable for Stereotactic Radiotherapy

The aim of this study is to demonstrate if it is possible to delivering a novel and modern radiotherapy approach (Dose Escalated internal PTV (DE-iPTV)) and to collect health related quality of life in patients whose breast cancer has spread to the brain (brain metastases) at 8 weeks post enrolling into the study.
The main questions that have been set out to to answer are:
* Is it possible to deliver the novel radiotherapy approach, DE-iPTV?
* Is it possible to measure health -related quality of life?
* What impact does the novel radiotherapy approach have on: patient's quality of life, control of the brain metastasis (control of the lesion) and steroid use?
Participants will:
* Receive 5 doses of radiotherapy
* Complete weekly quality of life (EQ-5D) assessments and medication (steroid) diaries (via telephone/ postal) until 12 weeks post enrolment
* Be reviewed in clinic with up-to-date MRI scans at 8, 12 and 24 weeks post-enrolment
* Complete a more detailed HRQoL panel of assessments will be assessed at baseline, 8 weeks, 12 weeks and 24 weeks post enrolment.

开始日期2025-01-06

申办/合作机构

Imperial College London

[+5]

NCT06620380 / Not yet recruiting临床2期IIT

Ex Vivo Drug Response Evaluation for Next Generation Care of Brain Metastases

Pharmacoscopy refers to an ex vivo real-time drug sensitivity profiling platform that has been shown to be of value in the treatment of leukemia (Snijder et al. 2017) (Kornauth et al. 2022) and may help to identify novel treatment opportunities for brain tumors as well (Lee et al. 2022). The rationale for pharmacoscopy-based drug sensitivity testing on real-time patient biopsies or surgery material is multiple: measuring drug response and sensitivity directly in real-time patient material, overcomes the problem of limited molecular biomarkers for established targeted therapeutic options and can identify effective drugs even for non-targeted therapies such as chemotherapy. It can also identify hitherto unknown specific vulnerabilities of cancer cells. Furthermore, testing directly on patient material overcomes the limitations of patient-derived cell cultures, organoids, and patient xenografts, as their prolonged culture times risk cellular adaptations and clonal selection that alter drug sensitivity. Pharmacoscopy maintains the tumor cell composition, including bystander cells or tumor microenvironment, and limits cell culture to max 48 hours. Furthermore, pharmacoscopy measures drug responses on a single-cell and on a high-content level, uniquely allowing to measure the drug sensitivity of tumor cells, and allowing to compare it to the drug cytotoxicity on healthy cells from the same patient. This relative readout has previously been shown to be essential for the correct prediction of a clinical response in haematological malignancies (Snijder et al. 2017) (Kornauth et al. 2022).
The aim of this study is to generate preliminary data regarding superiority of the personalized pharmacoscopy-guided approach compared to a standard non-pharmacoscopy-guided approach, in patients with brain metastases with an indication for surgery, and limited therapeutic systemic options according to the treating physician.

开始日期2025-01-01

申办/合作机构

University of Zurich

100 项与脑转移瘤相关的临床结果

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100 项与脑转移瘤相关的转化医学

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0 项与脑转移瘤相关的专利（医药）

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23,425

项与脑转移瘤相关的文献（医药）

2025-01-01·Current Cancer Drug Targets

Twenty-four-month Progression-free Survival in HER2-amplified Advanced Gastric Cancer with Brain Metastases after Trastuzumab Deruxtecan Treatment: A Case Report and Literature Review

作者: Zhang, Haibo ; Xu, Min

Background:Trastuzumab deruxtecan (T-DXd) has shown promising outcomes as a second or subsequent-line treatment for human epidermal growth factor-2 (HER2)-positive advanced gastric or gastroesophageal junction cancer.Case Presentation:We reported a 49-year-old male patient with stage IV HER2-amplified gastric cancer. Despite extensive pretreatments, including first-line trastuzumab plus FOLFOX, second-- line trastuzumab plus FOLFOX, followed by traditional Chinese medicine, third-line nivolumab plus trastuzumab, fourth-line pyrotinib plus paclitaxel and five hepatic arterial chemoembolization procedures, and fifth-line pembrolizumab plus nab-paclitaxel and thoracic radiotherapy, the patient experienced disease progression. In April 2021, T-DXd was initiated as the sixth-line therapy in combination with radiotherapy for brain metastases. After one treatment cycle, the patient achieved a partial response. T-DXd was discontinued in August 2022 due to recurrent anemia attributed to cardiac stenosis-related bleeding.Conclusion:The condition of the patient remained stable until May 2023, indicating a progression- free survival of over 24 months. This case suggests that T-DXd may offer long-term clinical benefits in patients with HER2-amplified advanced gastric cancer with brain metastases.

2025-01-01·Journal of Proteomics

4-plex quantitative glycoproteomics using glycan/protein-stable isotope labeling in cell culture

Article

作者: Hakim, Md Abdul ; Jiang, Peilin ; Li, Yunxiang ; Delkhosh, Arvin Saffarian ; Ahmadi, Parisa ; Mechref, Yehia

Alterations in glycoprotein abundance and glycan structures are closely linked to numerous diseases. The quantitative exploration of glycoproteomics is pivotal for biomarker discovery, but comprehensive analysis within biological samples remains challenging due to low abundance, complexity, and lack of universal technology. We developed a multiplex glycoproteomic approach using an LC-ESI-MS platform for direct comparison of glycoproteomic quantitation. Glycopeptides were isotopically labeled during cell culture, achieving high labeling efficiency (≥ 95 %) for both glycans and peptides. Quantitation was validated by mixing the same cell line in a 1:1:1:1 ratio, with mathematical correction applied to deconvolute the ratios. This method proved reliable and was applied to a comparative glycoproteomic study of three breast cancer cell lines (HTB22, MDA-MB-231, MDA-MB-231BR) and one brain cancer cell line (CRL-1620), quantifying glycopeptides from three replicates. The expression of glycopeptides was relatively quantified, and up/down-regulation between cell lines was investigated. This approach provided insights into glycosylation microheterogeneity, crucial for breast cancer brain metastasis research. Benefits include eliminating fluctuations from nano electrospray ionization and reducing analysis time, enabling up to 4-plex profiling in a single injection. Metabolic labeling introduced mass differences at the MS1 level, ensuring increased sensitivity and higher resolution for accurate quantitation. SIGNIFICANCE: Alternations in glycoprotein abundance, changes in glycosylation levels, and variations in glycan structures are closely linked to numerous diseases. The quantitative exploration of glycoproteomics has emerged as a popular area of research for biomarker discovery. However, conducting a comprehensive quantitative analysis of the glycoproteome within biological samples remains challenging due to low abundance, inherent complexities, and the absence of universal quantitative technology. Here, we developed a multiplex glycoproteomic approach using an LC-ESI-MS platform to facilitate direct comparison of glycoproteomic quantitation and enhance throughput. This approach offers benefits such as eliminating quantitative fluctuations arising from nano electrospray ionization (ESI) and reducing analysis time, enabling up to 4-plex glycoproteomic profiling in a single injection. Glycopeptides were stable isotopic labeled during cell culture procedure, attaching to monosaccharides, amino acids, or both. We achieved a high labeling efficiency (≥ 95 %) for both glycans and peptides. Quantitation validation was tested on glycopeptides by mixing the same cell line with 1:1:1:1 ratio. Due to the overlapped isotopes, a mathematical correction was applied to deconvolute the ratio of 4-plex glycopeptides. This method demonstrated quantitative reliability and was successfully applied to a comparative glycoproteomic study of three breast cancer cells (HTB22, MDA-MB-231, and MDA-MB-231BR) and one brain cancer cell (CRL-1620), identifying a total of 264 glycopeptides from three replicates. The expression of glycopeptides among these four cells was relatively quantified and up/down-regulation between two cell lines was investigated. The exploration of glycosylation microheterogeneity through glycopeptide quantification may offer valuable insights for further investigation into breast cancer brain metastasis. Conclusion: The primary advantage of our presented work lies in the multiplexing offered by combining two established labeling techniques, SILAC and IDAWG, both of which have been effectively used and widely cited in the scientific community. This combination enhances the applicability and accuracy of our method, as demonstrated by the extensive citations and successful use of these techniques independently. We believe that this multiplexing approach significantly advances the field, despite the method's current limitation to cell systems.

2025-01-01·Clinica Chimica Acta

High expression of CD3+T-lymphocytes in cerebrospinal fluid increases the risk of critical cerebral hemorrhage with systemic inflammatory response syndrome (SIRS) after surgery

Article

作者: Hao, Yongmei ; Li, Wei ; Shan, Xinjun ; Zhang, Yingfu ; Zhu, Chunying ; Yan, Liang

OBJECTIVETo assess the frequency of lymphocyte subsets and other laboratory indicators in paired cerebrospinal fluid (CSF) and peripheral blood (PB) samples from critically ill patients with intracerebral hemorrhage (ICH) who developed systemic inflammatory response syndrome (SIRS) following surgery.INTRODUCTIONNeuroinflammation and systemic inflammatory responses significantly contribute to secondary brain injury following ICH. Post-surgery SIRS is known to worsen clinical outcomes in ICH patients; however, the immune response in the CSF and PB has not been fully characterized. Understanding immunological changes in ICH patients with SIRS could lead to improved clinical management and prognostic outcomes.METHODSThis study involved a retrospective analysis of data from patients with ICH who underwent surgery in the Neurological Intensive Care Unit (NICU) of Baoding No. 1 Hospital, Hebei Province, China, between January and July 2022. Patients were divided into SIRS and non-SIRS groups based on the clinical criteria. Demographic, clinical, and laboratory data, including lymphocyte subsets in CSF and PB, were collected and analyzed. This study compared lymphocyte subsets and other inflammatory markers between the SIRS and non-SIRS groups.RESULTSPatients with SIRS demonstrated higher systolic blood pressure (SBP) at admission, worse 90-day prognoses, elevated inflammatory markers, increased levels of complement proteins C3 and C4, and lower levels of immunoglobulin G (IgG) compared to patients without SIRS. Between 3-6 days post-surgery, SIRS patients showed higher percentages of CD3+T cells, CD4+T cells, and CD4+/CD8+ ratios in the CSF than non-SIRS patients. CD3+T cell percentages in the CSF were consistently higher than those in the PB and were independent of PB levels. In contrast, CD3-CD16+CD56+ natural killer (NK) cell percentages were lower in patients with SIRS. No significant differences in PB lymphocyte subsets were found between the two groups. A high CSF CD3+T cell percentage (≥85.68 %) was identified as the strongest predictor of critical ICH with SIRS after surgery, with an appropriate use criterion (AUC) of 0.7742, sensitivity of 77.42 %, specificity of 76.19 %, and 95 % CI of 0.6655-0.8829 (P < 0.0001).CONCLUSIONElevated levels of CD3+T lymphocytes in CSF are strongly associated with an increased risk of severe cerebral hemorrhage and SIRS following surgery. These findings suggest that monitoring CSF immune markers, particularly CD3+T lymphocytes, could serve as valuable predictors for the development of SIRS in critically ill ICH patients and inform post-surgical treatment strategies.

490

项与脑转移瘤相关的新闻（医药）

2024-10-30

·PRNewswire

American Brain Tumor Association's Metastatic Brain Tumor Collaborative Announces $50,000 Research Grant Opportunity to Fund High-Risk, High-Impact CNS Metastasis Research

Letters of Intent Due by December 17, 2024 CHICAGO, Oct. 30, 2024 /PRNewswire/ -- The Metastatic Brain Tumor Collaborative (MBTC), created by the American Brain Tumor Association (ABTA), announced a request for applications for one-year, $50,000 research grants. Faculty – including early-career faculty – are encouraged to apply. Applicants should propose high-risk, high-impact research projects that will improve the understanding of brain metastasis and have the potential to change current diagnostic or treatment paradigms for metastatic brain tumor care. The letter of intent deadline for all interested applicants is December 17, 2024, and researchers can access the request for applications here. "When the ABTA discovered the lack of patient advocacy organizations dedicated to metastatic brain tumor education and support, we formed the Metastatic Brain Tumor Collaborative to bring together like-minded organizations who recognized more needs to be done to serve this patient population," said Nicole Willmarth, Chief Mission Officer of ABTA. "This new partnered research grant underscores our collective commitment to accelerate research and treatment discovery in metastatic brain tumors, understanding how providing vital seed money for promising new research can change lives." The MBTC partners working to support this research opportunity focused on CNS Metastasis, include the ABTA, Kidney Cancer Association, LUNGevity Foundation, the Melanoma Research Foundation, and Metastatic Breast Cancer Alliance. The larger MBTC (ten organizations in all) aims to support and empower patients diagnosed with a metastatic brain tumor and to collaboratively advance research that addresses the needs of this patient population. Metastatic brain tumors start somewhere else in the body and travel to the brain. Lung, breast, kidney, colon, and melanoma (skin) cancers are the most common primary cancers that spread to the brain. Metastatic brain tumors are the most common type of brain tumors in adults. Current estimates suggest approximately 200,000 adults are diagnosed annually in the United States, and the average prognosis following diagnosis is only a few months. MBTC is guided by national medical experts and offers a host of free educational resources for patients facing a metastatic brain tumor diagnosis. In addition, a first-of-its-kind survey of patients, caregivers and physicians on the diagnosis and treatment of brain metastases – conducted by the ABTA as part of the MBTC – revealed disparities in practice patterns and communication around metastatic brain tumors. The survey results, published in the journal Neuro-Oncology Practice, highlight the need to increase accessibility to clinical trials, establish clear standards of care and improve physician-patient communication reflective of the unique needs of patients with brain metastases. The survey also highlighted the need for more research on CNS metastases, which was the driving force behind developing a new grant mechanism to specifically fund research to improve care for this patient population. The MBTC appreciates the unwavering support of its partner organizations across the variety of programs for patients and now researchers, including Aim at Melanoma, Go2 for Lung Cancer, Fight Colorectal Cancer, Kidney Cancer Association, Living Beyond Breast Cancer, LUNGevity Foundation, the Melanoma Research Foundation, Metastatic Breast Cancer Alliance, Society for Neuro-Oncology, and Susan G. Komen. About the American Brain Tumor Association Founded in 1973, the American Brain Tumor Association provides comprehensive resources to support the complex needs of brain tumor patients and caregivers, across all ages and tumor types, as well as the critical funding of research in the pursuit of breakthroughs in brain tumor diagnoses, treatments, and care. To learn more, visit, abta.org or call 800-886-ABTA (2282). SOURCE American Brain Tumor Association WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

2024-10-30

·CPHI制药在线

晶锐医药可入脑的BET抑制剂获批临床，拥挤赛道是否还有突围机会

关注并星标CPHI制药在线近日，中国国家药监局药品审评中心（CDE）官网公示，晶锐医药1类新药JRD-018片获批临床，拟开发治疗晚期恶性肿瘤。 JRD-018是一款可入脑的BET抑制剂，今年4月已经获美国FDA批准开展1期临床研究。晶锐医药拟开启1期临床试验并将针对晚期实体瘤患者进行招募，继而扩展到血液瘤、脑转移或原发性脑瘤，旨在探索JRD-018在患者中的安全性、耐受性、药代动力学以及初步抗肿瘤活性。体内药效研究结果表明，JRD-018单独使用在脑胶质瘤模型、小细胞肺癌模型、非小细胞肺癌模型、髓性单核细胞白血病模型以及乳腺癌模型中均表现出良好的抗肿瘤活性。在临床前动物模型研究中，JRD-018已显示出良好的对脑转移或原发性脑瘤、恶性脑肿瘤的抑制效果。表观遗传学靶点之BET 溴结构域和超末端结构域（bromodomain and extra terminal domain，BET）属于溴结构域蛋白家族，BET蛋白家族包含四个异构体BRD2、BRD3、BRD4、BRDT，它们的结构相似，在N端有2个串联的溴结构域（BD1和BD2）以及一个超末端结构域（ET）。BD1和BD2识别并结合乙酰化赖氨酸残基，与染色质重塑和基因转录的调控过程相关；ET结构域与多种转录因子相互作用。BET蛋白家族通过溴结构域与乙酰化的染色质结合，从而实现在表观遗传学水平上对基因表达进行调控。 BET蛋白家族在人体内表达广泛，与多种实体瘤和恶性血液性肿瘤、炎症、肥胖、肺纤维化等多种疾病的发生和发展密切相关。如原癌基因Myc在超过一半的肿瘤中过表达，BET抑制剂通过竞争性结合阻止BRD4与染色质结合，进而抑制Myc的转录，从而实现抑制肿瘤的目的。 BET抑制剂是一类新型抗癌药，这类药物在治疗血液癌症如白血病和淋巴瘤方面具有良好的前景。BET抑制剂能够通过阻断BET蛋白的功能从而抑制肿瘤生长。研发BET蛋白选择性抑制剂是目前的新方向。目前，一系列BET抑制剂正在临床试验中检验它们治疗包括白血病、淋巴瘤、脑瘤和骨髓瘤在内的多种癌症的疗效。 BET抑制剂：诺华高调购入，加思科、正大天晴加速推进 BET被认为是抗肿瘤药物研发潜力靶点。目前，全球药企针对该靶点已开发出多款药物，详见下表。在研BET抑制剂大多为小分子化学药，此外还包括蛋白水解靶向嵌合体（PROTACs）。适应症上，BET抑制剂主要被开发用于实体瘤和血液性肿瘤，其中部分还被开发用于治疗炎症性疾病如白癜风等。全球至今还尚无BET抑制剂获批，进度最快的就是MorphoSys的Pelabresib，是首个三期临床试验取得成功的BET抑制剂。MorphoSys围绕该药物布局了骨髓纤维化、恶性外周神经鞘瘤、多发性骨髓瘤等多项适应症。 Pelabrisib是由MorphoSys AG公司研制的first-in-class BET抑制剂，近期Pelabrisib治疗骨髓纤维化III期达到了主要研究终点SVR35（脾脏缩小超过35%），从214例患者的临床数据来看， Pelabrisib与JAK抑制剂芦可替尼联用24周，有65.9%的患者脾脏缩小超过35%，而对照组（芦可替尼与安慰剂）仅有35.2%的患者达到SVR35，实验组的疗效比对照组高30.4%。今年年初，诺华以29亿美元收购MorphoSys AG从而拥有了pelabresib这款BET抑制剂。诺华将基于III期MANIFEST-2研究的积极数据在今年下半年向FDA和EMA提交pelabresib联合芦可替尼治疗骨髓纤维化的上市申请。 ZEN-3694是一种领先的差异化BET抑制剂，被开发联合免疫检查点抑制剂、PARP抑制剂、MEK抑制剂、CDK4/6抑制剂、HDAC抑制剂治疗多种肿瘤。ZEN-3694可以降低BRCA1/2和RAD51等蛋白的DNA修复活性，以提高肿瘤细胞对PARP抑制的敏感性，当前用以治疗转移性去势抵抗性前列腺癌II期临床正在开展中。2019年8月，Zenith Epigenetics 与恒翼生物就该药签订超7800万美元的许可协议，授权恒翼生物获得ZEN-3694在中国（包括中国香港、中国台湾和中国澳门地区）的权益。 JAB-8263是加科思自主研发、具有全球知识产权的小分子BET抑制剂，临床前研究显示其对多种实体瘤和血液瘤均能发挥抗肿瘤作用。从公开数据来看，JAB-8263是同类临床项目中活性最强的BET抑制剂，有望在极低剂量下有效抑制多种肿瘤生长，和Pelabrisib相比具有巨大的差异化优势。目前，加科思正在中美两地开展JAB-8263的多中心、开放性I/IIa期临床研究，适应症涉及白血病及实体瘤。 TQB3617是正大天晴自主研发的一款具有全新化学结构的BET抑制剂，能够通过抑制BET蛋白功能减少c-Myc、NF-κB、Aurora B和BCL-2等致癌基因的异常表达，进而发挥抗肿瘤作用。临床前研究结果显示，TQB3617对BET家族的BRD2、BRD3、BRD4、BRDT蛋白均具有较强的抑制活性。TQB3617用于晚期恶性肿瘤的I期临床试验显示，2例骨髓纤维化患者在治疗第12周结束时，脾脏体积较基线分别缩小13%和30%，展现出潜在的抗骨髓纤维化疗效。在28例接受疗效评估的淋巴瘤中，总缓解率（ORR）为39.3%（11/28），其中4例CR，7例PR。 Trotabresib（CC-90010）是一种新型、口服、可逆性、小分子BET抑制剂，可穿透高级别胶质瘤患者的脑肿瘤组织，临床前研究显示其可增强替莫唑胺（TMZ）的抗肿瘤作用。已公布的1b/2期开放标签、剂量探索研究结果显示：在长期随访中，新诊断胶质母细胞瘤（GBM）患者接受Trotabresib+TMZ辅助治疗或Trotabresib+TMZ+RT（放疗）同步治疗耐受性良好，未出现新的不良反应。结语整体来看，BET是进展相对较慢的一个表观遗传学药物靶点。BET蛋白家族在人体内表达广泛，与多种实体瘤和恶性血液性肿瘤、炎症、肥胖、肺纤维化等多种疾病的发生和发展密切相关，是非常有潜力的药物靶点，全球首个BET抑制剂pelabresib III期临床试验的成功宣告了该靶点的成效性，目前全球围绕BET靶点研发火热，值得一提的是，随着科学技术的发展，BET抑制剂的研发不再局限于小分子化药，已有多家企业、机构研发出BET靶向PROTACs。目前国内药企也积极布局BET靶点，而布局方式除了自主研发，还从外部企业引进，如恒翼生物。期待在药企的不懈努力下，BET靶点可以早日迎来重大突破。参考来源 1.Raajit Rampal, Sebastian Grosicki, Dominik Chraniuk et al.Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-na?ve patients with myelofibrosis.?JCO?42,?6502-6502(2024).DOI:10.1200/JCO.2024.42.16_suppl.6502 2.2024 ASCO. Abstract?#6502: Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-na?ve patients with myelofibrosis. END 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~

临床1期临床3期蛋白降解靶向嵌合体临床2期临床结果

2024-10-25

·生物探索

Cdk5调控乳腺癌脑转移

脑转移（BrM）是一种癌细胞从身体其他部位转移到大脑的现象，原发性癌症转移至大脑的最常见类型是肺癌、乳腺癌等，BrM可能发生在原发性癌症治疗后数月甚至数年，BrM患者的生存期较短。到目前为止，BrM的免疫逃避机制仍不清楚。近日，来自美国德克萨斯大学MD安德森癌症中心的Dihua Yu研究团队在Nature Cell Biology上发表题为Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition的文章，发现大脑中的星形胶质细胞可以诱导来源于乳腺癌的BrM细胞中Cdk5高表达，Cdk5通过Irf2bp1-Stat1-importin α-Nlrc5通路抑制MHC-I表达和抗原呈递通路，从而促进免疫逃逸和BrM生长，用Cdk5抑制剂RSV单独处理或与免疫检查点抑制剂联合处理可以显著抑制BrM。研究人员首先比较了21个人类BrM和对应的原发性乳腺癌中Cdk基因的表达，发现在BrM中Cdk5是上调最明显的，并且通过分析数据库发现更高的Cdk5表达与乳腺癌BrM患者更差的生存率相关。为了研究BrM的发展是否需要Cdk5，他们将敲降了Cdk5的乳腺癌细胞注射到小鼠的颈内动脉中诱导BrM，发现与对照相比，注射了Cdk5敲降的乳腺癌细胞的小鼠生存期明显更长。因此，Cdk5促进BrM进展。为了研究其中的机制，他们检测了Cdk5敲降对于BrM微环境的影响，通过单细胞RNA-seq发现与MHC功能和抗原呈递相关的基因表达上调，CD8+肿瘤浸润T细胞也显著增加。为了验证T细胞在BrM中的作用，他们将上述乳腺癌细胞注射到T细胞反应缺陷的裸鼠体内，发现Cdk5敲降组和对照组之间的差别消失。进一步，CD8+T细胞抑制抗体处理也可以抑制Cdk5敲降导致的生存期延长。因此，Cdk5敲降导致的BrM抑制依赖于CD8+ T细胞。为了检测Cdk5是否促进癌细胞逃逸T细胞，他们将Cdk5敲降的乳腺癌细胞与激活的T细胞共培养，发现Cdk5敲降的乳腺癌细胞更易被杀死，Cdk5促进癌细胞抵抗抗原特异性T细胞杀伤。癌细胞通常通过下调MHC-I表达来进行免疫逃逸，乳腺癌患者中具有更高MHC-I表达水平的通常也具有更长的无复发生存期。他们发现Cdk5敲降或敲除会显著上调MHC-I表达水平，过表达Cdk5会导致MHC-I下调，因此，Cdk5抑制MHC-I表达。Stat1和Nlrc5是调控MHC-I的转录因子，他们发现Cdk5敲降会导致这两个转录因子表达上调，Cdk5通过Stat1-importin α-Nlrc5信号通路抑制MHC-I表达。接下来他们用磷酸蛋白质组筛选了Cdk5的底物中可能调控Stat1的蛋白，鉴定到了Irf2bp1，Cdk5可以直接结合并磷酸化Irf2bp1的第66位丝氨酸，从而抑制Stat1的表达和其第727位丝氨酸的磷酸化，因此，Cdk5通过磷酸化Irf2bp1调控Stat1-importin α-NNlrc5信号通路。接下来他们将新鲜分离的原位肿瘤细胞与对应的BrM细胞进行体外培养，发现体外培养6天后BrM细胞中Cdk5的高表达消失了，说明脑部的肿瘤微环境调控Cdk5的表达，进一步分析发现是星形胶质细胞通过分泌emilin-1诱导了BrM细胞中Cdk5的高表达。最后他们发现用Cdk5抑制剂RSV处理小鼠可以通过恢复MHC-I表达和增强T细胞反应延缓BrM生长，并且还进行了临床前实验，发现用RSV和PD-1抑制剂联合用药可以抑制乳腺癌BrM。总的来说，这项研究揭示了星形胶质细胞诱导乳腺癌来源的BrM细胞中Cdk5高表达，抑制MHC-I表达，促进免疫逃逸和脑转移，为将来临床上通过靶向Cdk5提高肿瘤免疫疗法的效果和治疗脑转移肿瘤提供了相关理论基础。参考文献 https://doi-org.libproxy1.nus.edu.sg/10.1038/s41556-024-01509-5 内容来源于网络，如有侵权，请联系删除。