The Efficacy and Safety of Pyrotinib Plus Capecitabine in Human Epidermal Growth Factor Receptor 2-positive Breast Cancer Patients With Active Brain Metastases That Have Failed Antibody-drug Conjugate(ADC): a Prospective, Single Arm, Trial

To evaluate the efficacy and safety of pyrotinib plus capecitabine in HER2-positive breast cancer patients with active brain metastases that have failed ADCs

开始日期2024-06-15

申办/合作机构

河南省肿瘤医院

NCT05781633 / RecruitingN/AIIT

A Single-arm, Open-label， Phase Ⅱ Clinical Trial of Eutideron, Etoposide Combined With Bevacizumab for Breast Cancer Patients With Brain Metastases

This study was a single-arm, open-label, phase II study of breast cancer patients with brain metastases. Eligible patients received a regimen of eutidrone(30mg/m2/d,iv,d1-5,21d/cycle), etoposide(30mg/m2/d,iv,d1-3,21d/cycle), and bevacizumab (10mg/kg,d1,21d/cycle).At least 4 to 6 cycles were administered, and if patients had a response or stable disease, bevacizumab was used as maintenance therapy until disease progression or intolerable toxicity.

开始日期2022-07-20

申办/合作机构

天津市肿瘤研究所

NCT03796273 / Terminated早期临床1期IIT

tGLI1 as a Therapeutic Target in Brain Metastases: A Window of Opportunity Study in Breast Cancer Brain Metastases and Primary Gliomas

This trial studies the side effects and how well ketoconazole works before surgery in treating patients with glioma that has come back or breast cancer that has spread to the brain. Ketoconazole is an antifungal drug that may be able to block a protein, tGLI1 and may help to treat brain tumors.

开始日期2019-03-13

申办/合作机构

Wake Forest School of Medicine

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0 项与乳腺癌脑转移相关的专利（医药）

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项与乳腺癌脑转移相关的文献（医药）

2024-08-01·Journal of Controlled Release

Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy

Article

作者: Satterlee, Andrew Benson ; Baldwin, Albert ; Valdivia, Alain ; Taylor, Hannah ; Corcoran, David L ; Herring, Laura E ; Kanchi, Krishna ; Dasari, Rajaneekar ; Steindler, Dennis A ; Hingtgen, Shawn ; Zhang, Xiaopei ; Buckley, Andrew ; Nguyen, Juliane ; Bonacquisti, Emily

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate of their parental fibroblasts, and TRAIL produced by iNSCs was naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed that Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays demonstrated that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts by approximately 3000-fold compared to treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a novel, easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.

2023-10-24·ACS nano

Impact of Targeting Moiety Type and Protein Corona Formation on the Uptake of Fn14-Targeted Nanoparticles by Cancer Cells.

Article

作者: Pandey, Nikhil ; Woodworth, Graeme F ; Chen, Chixiang ; Winkles, Jeffrey A ; Carney, Christine P ; Kapur, Anshika ; Saadi, Hassan ; Ong, Hwei Ling ; Kim, Anthony J

The TWEAK receptor, Fn14, is a promising candidate for active targeting of cancer nanotherapeutics to many solid tumor types, including metastatic breast and primary brain cancers. Targeting of therapeutic nanoparticles (NPs) has been accomplished using a range of targeting moieties including monoclonal antibodies and related fragments, peptides, and small molecules. Here, we investigated a full-length Fn14-specific monoclonal antibody, ITEM4, or an ITEM4-Fab fragment as a targeting moiety to guide the development of a clinical formulation. We formulated NPs with varying densities of the targeting moieties while maintaining the decreased nonspecific adhesivity with receptor targeting (DART) characteristics. To model the conditions that NPs experience following intravenous infusion, we investigated the impact of serum exposure in relation to the targeting moiety type and surface density. To further evaluate performance at the cancer cell level, we performed experiments to assess differences in cellular uptake and trafficking in several cancer cell lines using confocal microscopy, imaging flow cytometry, and total internal reflection fluorescence microscopy. We observed that Fn14-targeted NPs exhibit enhanced cellular uptake in Fn14-high compared to Fn14-low cancer cells and that in both cell lines uptake levels were greater than observed with control, nontargeted NPs. We found that serum exposure increased Fn14-targeted NP specificity while simultaneously reducing the total NP uptake. Importantly, serum exposure caused a larger reduction in cancer cell uptake over time when the targeting moiety was an antibody fragment (Fab region of the monoclonal antibody) compared with the full-length monoclonal antibody targeting moiety. Lastly, we uncovered that full monoclonal antibody-targeted NPs enter cancer cells via clathrin-mediated endocytosis and traffic through the endolysosomal pathway. Taken together, these results support a pathway for developing a clinical formulation using a full-length Fn14 monoclonal antibody as the targeting moiety for a DART cancer nanotherapeutic agent.

2022-02-01·Life Sciences3区 · 医学

Olvanil activates sensory nerve fibers, increases T cell response and decreases metastasis of breast carcinoma

3区 · 医学

Article

作者: Akman, Muhlis ; Tanrıöver, Gamze ; Aliyev, Elnur ; Korcum, Aylin F ; Erin, Nuray

BACKGROUNDInactivation of sensory neurons expressing transient receptor potential vanilloid 1 (TRPV1) enhances breast cancer metastasis. Sensory neurons have profound effects on immune response to a wide range of diseases including cancer. Hence, activation of sensory nerves using feasible approaches such as specific TRPV1 agonists may inhibit breast cancer metastasis through neuroimmune pathways. TRPV1 agonists are considered for the treatment of pain and inflammatory diseases.METHODSWe here first determined the effects of four different TRPV1 agonists on proliferation of three different metastatic breast carcinoma cells since TRPV1 is also expressed in cancer cells. Based on the results obtained under in-vitro conditions, brain metastatic breast carcinoma cells (4TBM) implanted orthotopically into the mammary-pad of Balb-c mice followed by olvanil treatment (i.p.). Changes in tumor growth, metastasis and immune response to cancer cells were determined.RESULTSOlvanil dose-dependently activated sensory nerve fibers and markedly suppressed lung and liver metastasis without altering the growth of primary tumors. Olvanil (5 mg/kg) systemically increased T cell count, enhanced intra-tumoral recruitment of CD8+ T cells and increased IFN-γ response to irradiated cancer cells and Con-A. Anti-inflammatory changes such as increased IL-10 and decrease IL-6 as well as S100A8+ cells were observed following olvanil treatment.CONCLUSIONSOur results show that anti-metastatic effects of olvanil is mainly due to activation of neuro-immune pathways since olvanil dose used here is not high enough to directly activate immune cells. Furthermore, olvanil effectively depletes sensory neuropeptides; hence, olvanil is a good non-pungent alternative to capsaicin.

项与乳腺癌脑转移相关的新闻（医药）

2024-09-13

·CPHI制药在线

罗氏斥巨资购入的HER2 BIC小分子新药拟纳入突破性治疗品种

近日，苏州赞荣医药自主研发的ZN-A-1041肠溶胶囊获得了国家药品监督管理局药品审评中心（CDE）的突破性疗法认定。ZN-A-1041的突破性在于其独特的联合治疗方案，即与卡培他滨和曲妥珠单抗联合使用，针对那些已经接受过含曲妥珠单抗治疗但仍出现病情进展的HER2阳性晚期脑转移乳腺癌患者。这一患者群体面临着极大的治疗挑战，传统疗法往往难以有效控制病情，而ZN-A-1041的加入为他们提供了新的治疗选择和希望。罗氏以总额6.8亿元购买了该药的全球权益授权。 ZN-A-1041是一款由赞荣医药自主研发的口服小分子HER2酪氨酸激酶抑制剂（TKI），它不仅具有高度的选择性，能够精准靶向HER2受体，还展现出卓越的血脑屏障通透性。这一特性在当前的抗癌药物中极为罕见，使得ZN-A-1041能够有效地穿越血脑屏障，针对脑转移病灶进行治疗，从而填补了当前市场的空白。此外，ZN-A-1041在临床试验中还表现出良好的安全性和耐受性，即使在联合治疗中也能保持稳定的疗效，这为其在临床上的广泛应用奠定了坚实的基础。在分子设计层面，ZN-A-1041通过精妙的化学结构调整，实现了对HER2的高选择性抑制，同时避免了对野生型EGFR等无关受体的影响，从而减少了不良反应的发生。这种"精准打击"的策略不仅提高了治疗效果，还改善了患者的生活质量。此外，ZN-A-1041还具备出色的药物代谢动力学特性，确保了药物在体内的稳定释放和有效浓度，为持续治疗提供了有力保障。 ZN-A-1041的I期临床试验还纳入了多种类型的肿瘤患者，包括伴或不伴脑转移的乳腺癌患者以及胃癌患者等。这一广泛的适应症研究不仅验证了ZN-A-1041的广谱治疗潜力，也为其在未来的药物开发和商业化道路上提供了更多的可能性。 ZN-A-1041在临床试验中展现出的疗效令人振奋。在2023年ASCO年会上公布的早期临床数据显示，ZN-A-1041在治疗HER2阳性乳腺癌脑转移患者方面取得了显著成果。在单药治疗组中，对于既往未接受TKI治疗的HER2阳性肿瘤患者，总客观缓解率（ORR）和颅内客观缓解率（iORR）均达到了50%，最长治疗时间更是达到了15个月。而在联合卡培他滨和曲妥珠单抗的联合治疗组中，对于完成至少两次肿瘤评估的脑转移乳腺癌（BCBM）患者，总ORR提升至78.9%，iORR达到73.7%，疾病控制率（DCR）更是实现了惊人的100%。这一数据不仅证明了ZN-A-1041在治疗HER2阳性乳腺癌脑转移方面的巨大潜力，也为其未来的广泛应用提供了有力支持。值得一提的是，ZN-A-1041的I期临床试验还纳入了多种类型的肿瘤患者，包括伴或不伴脑转移的乳腺癌患者以及胃癌患者等。这一广泛的适应症研究不仅验证了ZN-A-1041的广谱治疗潜力，也为其在未来的药物开发和商业化道路上提供了更多的可能性。罗氏斥资6.8亿美元购入ZN-A-1041的全球权益，是其在HER2阳性肿瘤治疗领域的重要布局。ZN-A-1041作为一款潜在的BIC小分子药物，凭借其高度的血脑屏障通透性和卓越的临床数据，展现了其在治疗HER2阳性乳腺癌脑转移方面的巨大潜力。此外，罗氏与赞荣医药的此次合作，不仅彰显了双方对创新药物研发的共同追求与坚定信念，也为全球肿瘤治疗领域注入了新的活力。罗氏作为全球制药巨头，其丰富的市场资源、强大的研发能力和广泛的销售网络，将为ZN-A-1041的后续研发、临床试验及市场推广提供强有力的支持。参考文献 1. 中国国家药监局药品评审中心官网 2. 罗氏制药宣布收购赞荣医药ZN-A-1041全球权益https://www.roche.com/media/releases/med-cor-2023-05-09 3. ZN-A-1041：一款潜在的BIC小分子HER2抑制剂在HER2阳性乳腺癌脑转移治疗中的早期临床研究内容来源于网络，如有侵权，请联系删除。

临床结果ASCO会议突破性疗法

2024-09-06

·Pharma CMC

今日，2款1类新药拟纳入突破性治疗品种！

今日（9月6日），CDE官网显示，赞荣医药的ZN-A-1041肠溶胶囊与武田的TAK-861片拟纳入突破性治疗品种。 ZN-A-1041肠溶胶囊适应症为：联合卡培他滨和曲妥珠单抗用于既往接受过含曲妥珠单抗治疗进展的人表皮生长因子受体2 阳性（HER2 阳性）晚期脑转移乳腺癌患者。 TAK-861片适应症为：治疗发作性睡病1型 ZN-A-1041是一款靶向人表皮生长因子受体2（HER2）的口服选择性酪氨酸激酶抑制剂，同时具备高度血脑屏障通透性，因此可潜在用于治疗HER2阳性乳腺癌脑转移的患者以及预防脑转移的发生。高达50%的HER2阳性转移性乳腺癌患者在病程中会发生脑转移。 2023年5月9日，赞荣医药宣布与罗氏就收购口服小分子HER2抑制剂ZN-A-1041的全球权益达成协议。根据协议，罗氏将获得ZN-A-1041在全球的进一步开发、生产和商业化权利。为此，罗氏将向赞荣医药支付7000万美金首付款和近期里程碑付款，另外高达6.1亿美元的开发和商业化里程碑付款，以及未来基于全球年度销售净额的梯度分成。 TAK-861片是一种口服食欲素受体2（OX2R）激动剂。今年6月，武田宣布TAK-861在治疗1型发作性睡病的2b期临床试验中获得的积极结果。这项随机双盲、含安慰剂对照的临床试验（n=112）达到主要和次要终点。2b期试验的主要终点显示，在维持清醒测试（MWT）中，所有剂量组与安慰剂组相比在推迟睡眠发生指标上均表现出统计学显著和具有临床意义的改善（p≤0.001）。改善在8周内持续保持。内容来源于网络，如有侵权，请联系删除。

并购突破性疗法

2024-09-06

·药渡Daily

罗氏6.8亿收购HER2小分子抑制剂拟纳入突破性疗法

今日（9月6日），从国家药品监督管理局药品审评中心（CDE）官网公示，赞荣医药申报的靶向HER2小分子抑制剂ZN-A-1041（已被罗氏收购）肠溶胶囊拟纳入突破性治疗品种，适应症为ZN-A-1041联合卡培他滨和曲妥珠单抗用于既往接受过含曲妥珠单抗治疗进展的HER2阳性晚期脑转移乳腺癌患者。 BD交易 ZN-A-1041是一款靶向人表皮生长因子受体2（HER2）的口服选择性酪氨酸激酶抑制剂，同时具备高度血脑屏障通透性。 2023年5月罗氏与赞荣医药就收购口服小分子HER2抑制剂ZN-A-1041的全球权益达成协议，根据协议，罗氏将获得ZN-A-1041在全球的进一步开发、生产和商业化权利。为此，罗氏将向赞荣医药支付7000万美金首付款和近期里程碑付款，另外高达6.1亿美元的开发和商业化里程碑付款，以及未来基于全球年度销售净额的梯度分成。临床疗效 2023年ASCO年会上，ZN-1041治疗HER2阳性乳腺癌脑转移（BCBM）的临床前和早期临床数据公布，该研究包括ZN-1041单药在HER2+实体瘤患者（包括有或没有脑转移的患者）中的首次人体剂量递增研究（Ia期），以及ZN-1041联合卡培他滨和曲妥珠单抗在HER2+ BCBM患者（包括有活动性脑转移的患者）中的剂量递增（Ib期）和扩展（Ic期）研究。在既往未接受TKI治疗的HER2阳性实体瘤患者，接受ZN-1041单药治疗，客观缓解率（ORR）和颅内客观缓解率（iORR）为50%。截至数据截止（2022年12月2日），共入组了35名TKI初治、HER2+ BCBM患者，治疗中位数为二线，在至少进行两次肿瘤评估的19名BCBM患者中，整体ORR为78.9%，iORR为73.7%，疾病控制率（DCR）为100%。此外，6名患者完成了首次肿瘤评估，5名达到部分缓解（PR），1名达到稳定病情（SD）。参考文献 CDE官网赞荣医药官网 Preclinical and early clinical data of ZN-1041, a best-in-class BBB penetrable HER2 inhibitor to treat breast cancer with CNS metastases.

ASCO会议并购突破性疗法临床结果临床1期