Temozolomide

- Announced first patient dosed in Phase 1/2a clinical trial of GLIX1 for treatment of glioblastoma (GBM) - - Announced new GLIX1 data demonstrating potent anti-tumor effect in GBM across multiple in-vivo studies, including a temozolomide (TMZ)-resistant patient-derived xenograft model - - Management to host conference call today, May 27, at 8:30 am EDT - TEL AVIV, Israel, May 27, 2026 /PRNewswire/ -- BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a clinical-stage biopharmaceutical company pursuing life-changing therapies in oncology and rare diseases, today reported its unaudited financial results for the quarter ended March 31, 2026, and provided a corporate update. "Since our last quarterly update, we achieved a significant milestone for our company and for the GLIX1 development program with the dosing of the first patient in our Phase 1/2a clinical trial of GLIX1 in glioblastoma," stated Philip Serlin, Chief Executive Officer of BioLineRx. "We are also very encouraged by compelling new pre-clinical data showing that GLIX1 demonstrated robust dose-dependent tumor-growth inhibition and survival benefit in orthotopic cell-derived xenograft (CDX) GBM models. Furthermore, in a newly completed subcutaneous TMZ-resistant patient-derived xenograft (PDX) GBM model, GLIX1 demonstrated a robust anti-tumor effect while no effect was observed with TMZ, highlighting the potential to address the very high unmet need in GBM." "In the coming days, we look forward to engaging with the broader oncology community at this year's ASCO meeting with two abstracts featuring GLIX1. The abstracts highlight its novel mechanism of action and provide strong rationale for the development of GLIX1 in GBM as well as in other cancers. They also highlight that in safety studies in animals GLIX1 was safe up to the highest feasible doses tested, supporting the combination with other anti-cancer agents. Furthermore, the abstracts highlight the compelling mechanistic rationale for combining GLIX1 with PARP inhibitors supported by synergistic effect in cell lines across diverse cancers including from tumor types typically less responsive to PARP inhibition." Financial Updates With $17.4 million on its balance sheet as of March 31, 2026, BioLineRx is maintaining its cash runway guidance into the first half of 2027. Development Updates GLIX1 Phase 1/2a clinical trial of GLIX1 in glioblastoma and other cancers initiated in March 2026. The first patient was dosed at NYU Langone Health under the supervision of Dr. Alexandra Miller, Chief of Neuro-Oncology & Co-Director of Brain and Spine Tumor Center, Perlmutter Cancer Center. Two additional leading cancer centers are participating in the study: Northwestern University, led by Dr. Roger Stupp and Dr. Ditte Primdahl; and Moffit Cancer Center, led by Dr. Patrick Grogan. Additional sites may be added to the study at a later date. The Phase 1 part of the trial is expected to recruit up to 30 patients with recurrent and progressive GBM and other high-grade gliomas. The objective is to establish a maximum tolerated dose (MTD) and/or a recommended dose based on safety, PK/PD and preliminary efficacy. The Phase 2a expansion part of the trial is planned to include additional indications, including newly diagnosed GBM, as well as select cancers, with GLIX1 as monotherapy or in combination with standard of care (including in combination with PARP inhibitors). These cohorts are expected to identify preliminary efficacy, PD assessments and dose optimization data, serving as the basis for a rapid and effective advanced clinical development plan. Announced new GLIX1 data demonstrating potent anti-tumor effect in GBM across multiple in-vivo studies, including a temozolomide (TMZ)-resistant patient-derived xenograft model Announced two abstracts on GLIX1 that were selected for publication during the American Society of Clinical Oncology (ASCO) Annual Meeting, which is scheduled for May 29-June 2, in Chicago, IL. Pre-clinical activities in support of clinical development for GLIX1 in additional cancer indications, including in combination with PARP inhibitors, are ongoing. Motixafortide Pancreatic Ductal Adenocarcinoma (mPDAC) Enrollment is continuing in the CheMo4METPANC Phase 2b clinical trial, which is being led by Columbia University, and supported by both Regeneron and BioLineRx. The trial is evaluating motixafortide in combination with the PD-1 inhibitor cemiplimab and standard chemotherapy (gemcitabine and nab-paclitaxel). A prespecified interim/futility analysis is planned when 40% of progression-free survival (PFS) events are observed, which the Company continues to anticipate will occur in 2026. APHEXDA Performance Update APHEXDA sales for the first quarter of 2026 were $2.7 million, which provided royalty revenues to the company of $0.5 million. Financial Results for the Quarter ended March 31, 2026 Revenues for the three months ended March 31, 2026 were $0.5 million, an increase of $0.2 million, compared to revenues of $0.3 million for the three months ended March 31, 2025. The increase in revenues from 2025 to 2026 reflects an increase in royalties paid by Ayrmid from the commercialization of APHEXDA. Cost of revenues for the three months ended March 31, 2026 was $0.1 million, compared to immaterial cost of revenues for the three months ended March 31, 2025. The cost of revenues reflects sub-license fees on royalties paid by Ayrmid from the commercialization of APHEXDA. Research and development expenses for the three months ended March 31, 2026 were $2.5 million, an increase of $0.9 million, or 55.8%, compared to $1.6 million for the three months ended March 31, 2025. The increase resulted primarily from expenses related to the new GLIX1 project. General and administrative expenses for the three months ended March 31, 2026 were $0.9 million, a decrease of $0.1 million, or 13.3%, compared to $1.0 million for the three months ended March 31, 2025. The decrease resulted primarily from a decrease in legal expenses, as well as a decrease in a number of other general and administrative expenses. Net non-operating income amounted to $0.5 million for the three months ended March 31, 2026, compared to net non-operating income of $7.6 million for the three months ended March 31, 2025. Non-operating income for the periods primarily relates to non-cash fair-value adjustments of warrant liabilities, as a result of changes in the Company's share price, offset by warrant offering expenses. Net financial expenses for the three months ended March 31, 2026 were immaterial compared to net financial expenses of $0.1 million for the three months ended March 31, 2025. Net financial expenses for the periods primarily relate to interest paid on loans, partially offset by investment income earned on bank deposits. Net loss for the quarter ended March 31, 2026 was $2.6 million, compared to net income of $5.1 million for the quarter ended March 31, 2025. As of March 31, 2026, the Company had cash, cash equivalents, and short-term bank deposits of $17.4 million. Conference Call and Webcast Information To access the conference call, please dial +1-888-407-2553 from the U.S. or +972-3-918-0685 internationally. A live webcast and a replay of the call can be accessed through the event page on the Company's website. Please allow extra time prior to the call to visit the site and download any necessary software to listen to the live broadcast. The call replay will be available approximately two hours after completion of the live conference call. A dial-in replay of the call will be available until May 28, 2026; please dial +1-888-295-2634 from the US or +972-3-925-5904 internationally. About BioLineRx BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX) is a clinical-stage biopharmaceutical company pursuing life-changing therapies in oncology and rare diseases. The Company's lead development asset is GLIX1, a first-in-class, oral, small molecule targeting DNA damage response in glioblastoma and other solid tumors, for which a Phase 1/2a clinical trial was initiated in the first quarter of 2026. GLIX1 is being developed under a collaboration with Hemispherian AS. The Company's first approved product, APHEXDA® (motixafortide), is indicated in the U.S. for stem cell mobilization for autologous transplantation in multiple myeloma, and is being commercialized by Ayrmid Ltd. (globally, except Asia) and developed by Gloria Biosciences (in Asia). BioLineRx has retained the rights to develop motixafortide in metastatic pancreatic cancer (PDAC) and has a Phase 2b PDAC trial currently ongoing under a collaboration with Columbia University. Learn more about who we are, what we do, and how we do it at , or on LinkedIn. Forward Looking Statement Various statements in this release concerning BioLineRx's future expectations constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include words such as "anticipates," "believes," "could," "estimates," "expects," "intends," "may," "plans," "potential," "predicts," "projects," "should," "will," and "would," and describe opinions about future events. These include statements regarding management's expectations, beliefs and intentions regarding, among other things, the expectations with regard to the planned Phase 1/2a GLIX1 clinical trial, expected timing of a clinical readout, and BioLineRx's business strategy. These forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the actual results, performance or achievements of BioLineRx to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Factors that could cause BioLineRx's actual results to differ materially from those expressed or implied in such forward-looking statements include, but are not limited to: the clinical development, commercialization and market acceptance of GLIX1 and motixafortide including the degree and pace of market uptake of APHEXDA for the mobilization of hematopoietic stem cells for autologous transplantation in multiple myeloma patients; the initiation, timing, progress and results of BioLineRx's preclinical studies, clinical trials and other therapeutic candidate development efforts; BioLineRx's ability to advance GLIX1 and motixafortide into clinical trials or to successfully complete its preclinical studies or clinical trials; whether the clinical trial results for GLIX1 and motixafortide will be predictive of real-world results; BioLineRx's receipt of regulatory approvals for GLIX1 and motixafortide and the timing of other regulatory filings and approvals; whether access to GLIX1 and motixafortide is achieved in a commercially viable manner and whether GLIX1 and motixafortide receives adequate reimbursement from third.-party payors; BioLineRx's ability to establish, manage, and maintain corporate collaborations, as well as the ability of BioLineRx's collaborators to execute on their development and commercialization plans; BioLineRx's ability to integrate new therapeutic candidates and new personnel, as well as new collaborations; the interpretation of the properties and characteristics of BioLineRx's therapeutic candidates and of the results obtained with its therapeutic candidates in preclinical studies or clinical trials; the implementation of BioLineRx's business model and strategic plans for its business and therapeutic candidates; the scope of protection that BioLineRx's is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; estimates of BioLineRx's expenses, future revenues, capital requirements and its need for and ability to access sufficient additional financing; risks related to changes in healthcare laws, rules and regulations in the United States or elsewhere; competitive companies, technologies and BioLineRx's industry; BioLineRx's ability to maintain the listing of its ADSs on Nasdaq; statements as to the impact of the political and security situation in Israel on BioLineRx's business which may exacerbate the magnitude of the factors discussed above. These and other factors are more fully discussed in the "Risk Factors" section of BioLineRx's most recent annual report on Form 20-F filed with the Securities and Exchange Commission on March 23, 2026. In addition, any forward-looking statements represent BioLineRx's views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. BioLineRx does not assume any obligation to update any forward-looking statements unless required by law. Contacts: United States Chuck Padala LifeSci Advisors, LLC [email protected] Israel Moran Meir LifeSci Advisors, LLC [email protected] Logo - SOURCE BioLineRx Ltd. 21% more press release views with Request a Demo

Delta样配体3（DLL3，Delta-like ligand 3）是一种 Notch 抑制性配体，目前正被探索作为复发性弥漫性胶质瘤的治疗靶点。由于临床试验可能根据原发肿瘤的 DLL3 表达筛选复发胶质瘤患者，本研究旨在明确胶质瘤初始 DLL3 表达在复发时是否得以保留。研究者从荷兰鹿特丹伊拉斯姆斯医学中心生物库获取 198 例配对的原发与复发胶质瘤福尔马林固定石蜡包埋（FFPE）样本。队列包括 IDH 突变型（IDHmt）伴 1p/19q 共缺失少突胶质细胞瘤（n=36）、IDH 突变型星形细胞瘤（n=38）与 IDH 野生型（IDHwt）胶质母细胞瘤（n=124）。采用免疫组化检测 DLL3 蛋白表达，并根据存活肿瘤组织中 DLL3 阳性细胞比例分为 DLL3 阴性（0%）、DLL3 低表达（>0–10%）、DLL3 中表达（10%–50%）与 DLL3 高表达（>50%）。 绝大多数胶质瘤样本（86%，164/190）可检测到 DLL3 表达。少突胶质细胞瘤（94% 为中 / 高表达）与星形细胞瘤（78.4% 为中 / 高表达）表达水平最高，胶质母细胞瘤最低（42% 为中 / 高表达）。26/190 例样本为 DLL3 阴性。多数患者复发时 DLL3 表达保持同一等级或升高（少突胶质细胞瘤 87.6%，星形细胞瘤 66.6%，胶质母细胞瘤 77.2%）。仅 7/91 例患者（7.7%）在复发时丢失初始 DLL3 阳性表达。 多数复发胶质瘤中 DLL3 表达水平保持稳定或升高。基于原发肿瘤组织样本筛选复发胶质瘤患者入组 DLL3 靶向药物临床试验具有合理性，具体取决于入组所需的 DLL3 阳性阈值。 Notch 抑制性配体 DLL3 在多数胶质瘤中表达； 多数患者肿瘤复发时 DLL3 表达得以保留； 本研究为在临床试验中评估 DLL3 靶向（免疫）治疗提供转化依据。 研究背景 成人弥漫性胶质瘤占成人原发性恶性脑肿瘤的大多数，且始终致命。2021 版 WHO 中枢神经系统肿瘤分类结合组织学与分子参数对胶质瘤进行亚型与分级。主要亚型包括 IDHmt 伴 1p/19q 共缺失少突胶质细胞瘤、IDHmt 星形细胞瘤与 IDHwt 胶质母细胞瘤；其他类型原发性胶质脑肿瘤在成人中罕见。初诊胶质瘤的标准治疗通常包括最大安全范围切除，联合放疗和 / 或化疗（替莫唑胺或 PCV 方案：丙卡巴肼、洛莫司汀与长春新碱）。但此类治疗无法根治，所有患者最终均会在一线治疗后进展。进展期治疗策略差异大且疗效有限。进展期治疗选择通常取决于肿瘤大小、部位、推测的化疗敏感性、初始治疗至复发的间隔时间、患者临床功能状态与治疗目标。多数情况下，进展期应考虑参与临床试验。 DLL3 是 Notch 信号通路中的抑制性配体，该通路是高度保守的信号通路，在胚胎发育过程中的细胞命运决定中发挥关键作用。生理状态下，DLL3 仅在胚胎发育过程中短暂表达。DLL3 主要表达于前体节中胚层（成人椎骨前体），DLL3 突变可导致轴向骨骼缺陷。此外，DLL3 表达在神经发生中发挥重要作用，已有研究在胎儿脑与脊髓中检测到其表达。DLL3 与 Notch 通路参与多种恶性肿瘤相关生物学过程，包括细胞增殖、恶性转化与上皮–间质转化。 DLL3 在多种恶性肿瘤（包括小细胞肺癌（SCLC）与其他神经内分泌肿瘤）的细胞表面高且均一表达，而健康成人组织中无 DLL3 表达。这使 DLL3 成为肿瘤相关抗原与潜在治疗靶点，并推动了多种靶向 DLL3 的（免疫）治疗药物研发，如抗体药物偶联物（ADCs）、双特异性 T 细胞衔接器（TCEs）、嵌合抗原受体（CAR）-T 细胞以及放射免疫治疗（将抗 DLL3 抗体与放射性同位素偶联用于成像或治疗）。其中，双特异性 TCE塔拉妥单抗（tarlatamab）近期获 FDA 批准，用于治疗化疗耐药的晚期 SCLC，此前一项 2 期临床试验报告其客观缓解率达 40%，远超历史对照基准 15%。目前，将 DLL3 靶向治疗扩展至其他恶性肿瘤的应用备受关注。 在研究肺神经内分泌肿瘤中的 DLL3 时，Saunders 及其同事分析癌症基因组图谱（TCGA）的 RNA 测序数据，发现弥漫性胶质瘤中 DLL3 表达水平同样升高。Spino 及其同事报道，TCGA 数据集中 IDHmt 胶质瘤的 DLL3 表达显著高于 IDHwt 胶质瘤，且在以原发肿瘤样本为主（58/63）的 63 例胶质瘤患者队列中采用 DLL3 免疫组化（IHC）检测，发现多数 IDHmt 胶质瘤（尤其是 1p/19q 共缺失少突胶质细胞瘤）呈高且均一的 DLL3 表达，而 IDHwt 肿瘤中呈斑片状、弱表达。2021 年 Noor 及其同事证实低级别胶质瘤中 DLL3 蛋白高表达，报告显示 72.9%（35/48）的低级别胶质瘤 DLL3 IHC 染色阳性（星形细胞瘤 67.7%，21/31；少突胶质细胞瘤 82.3%，14/17）。因此，DLL3 靶向治疗也引起胶质瘤治疗领域的关注，一项针对一线治疗后复发胶质瘤患者的双特异性 T 细胞衔接器（TCE）obrixtamig（BI 764532）临床试验正在开展（NCT05916313）。该试验基于原发肿瘤存档组织的 DLL3 蛋白表达（IHC）筛选患者，鉴于复发时活检的侵袭性与风险，这是神经肿瘤学领域的常规方法；但这要求肿瘤进展时靶点仍有合理可能性存在。因此，本研究目的为：（1）在大样本、注释完善的配对原发与复发胶质瘤队列中明确 DLL3 表达与 IDH 突变状态的关系；（2）明确原发肿瘤的 DLL3 表达状态在复发时是否保留。 图1 研究结果 患者人口统计学特征： 收集 99 例患者的 198 份配对原发与复发胶质瘤样本，包括 IDHmt 伴 1p/19q 共缺失少突胶质细胞瘤（18 例患者，36 例样本）、IDHmt 星形细胞瘤（19 例患者，38 例样本）与 IDHwt 胶质母细胞瘤（62 例患者，124 例样本）。198 例样本中 190 例质量达标可用于分析，91 例患者的 182 例样本可完成配对分析。患者特征总结见表 1。少突胶质细胞瘤与星形细胞瘤患者确诊中位年龄低于胶质母细胞瘤患者（分别为 42.5 岁、29 岁与 52 岁）。多数 IDHmt 胶质瘤患者确诊时为 WHO 2 级肿瘤（27/37 例患者，73%）。少突胶质细胞瘤与星形细胞瘤首次至二次手术间隔长于胶质母细胞瘤（分别为 62.5 个月、54 个月与 11 个月），与其生长缓慢一致。首次与二次切除间的治疗策略存在异质性，尤其是少突胶质细胞瘤与星形细胞瘤患者，分别有 50% 与 53% 的患者在手术间未接受任何抗肿瘤治疗。多数胶质母细胞瘤患者按照 Stupp 方案接受放疗联合同步与辅助替莫唑胺治疗（53/62，85%）。 表1 DLL3 在多数胶质瘤中表达，且在 IDHmt 肿瘤中最高： 在本胶质瘤患者队列中，观察到绝大多数样本（86%）存在 DLL3 表达。在 IDHmt 肿瘤中，IDH-R132H 与 DLL3 染色模式大体一致，进一步支持 DLL3 主要表达于恶性细胞（图 2A 与 B）。但在 IDHmt 胶质瘤中，并非所有 IDH 阳性细胞均为 DLL3 阳性（如图 2A 与 B 方框所示）。IDHmt 胶质瘤中 DLL3 染色更强且更均一，而 IDHwt 胶质母细胞瘤中染色更不均一 / 斑片状且更弱（代表性图像见图 2C 与 D）。本队列中，所有 IDHmt 肿瘤均为非阴性评分等级，总人群中 86%（164/190 例样本）为非阴性等级（图 3A 与 B）。26/190 例完全 DLL3 阴性的样本均为 IDHwt 胶质母细胞瘤（图 3B）。少突胶质细胞瘤 DLL3 表达最高（94% 为中 / 高表达），星形细胞瘤次之（78.4% 为中 / 高表达），胶质母细胞瘤最低（42% 为中 / 高表达）（图 3B）。38% 的少突胶质细胞瘤、24% 的星形细胞瘤与 5% 的胶质母细胞瘤观察到高 DLL3 表达（定义为存活肿瘤组织中 > 50% DLL3 阳性细胞）（分别见图 4A、D、G）。 图2 图3 为明确 IDHmt 与 IDHwt 肿瘤间观察到的差异是否具有统计学意义，首先采用非参数 Kruskal–Wallis 检验，该检验适用于反应变量为有序分类且可能违背正态分布假设时的多组独立样本比较。结果显示不同肿瘤类型间 DLL3 表达水平存在统计学显著差异（P=2.97×10⁻¹¹）。后续采用 Dunn 检验联合 Benjamini-Hochberg 校正进行两两比较，证实胶质母细胞瘤与少突胶质细胞瘤（P=1.7×10⁻⁹）、胶质母细胞瘤与星形细胞瘤（P=9.6×10⁻⁶）间存在显著差异，而少突胶质细胞瘤与星形细胞瘤间无显著差异（P=0.135）。这些结果表明，与 IDHwt 胶质母细胞瘤相比，IDHmt 伴 1p/19q 共缺失少突胶质细胞瘤与 IDHmt 星形细胞瘤的 DLL3 表达显著更高（图 3B）。 复发肿瘤中 DLL3 表达大体保留： 如预期，原发肿瘤组织切片含比例更高的存活肿瘤组织，而治疗后复发肿瘤中观察到更多治疗效应（如放射性坏死）。研究发现，在所有肿瘤类型中，存活肿瘤组织内的 DLL3 表达在原发与复发肿瘤间大体保留。配对样本中，77% 的患者（70/91 例患者）复发时 DLL3 表达保持同一等级或升高（图 3C 与 D）。按胶质瘤亚型分层时，IDHmt 伴 1p/19q 共缺失少突胶质细胞瘤的 DLL3 表达稳定性最高；14/16 例患者（87.6%）复发时保持同一等级或升高（图 4B 与 C）。IDHmt 星形细胞瘤的 DLL3 表达变化略高（12/18 例患者，66.6% 复发时保持同一等级或升高；图 4E 与 F），IDHwt 胶质母细胞瘤为 44/57 例患者（77.2% 复发时保持同一等级或升高；图 4H 与 I）。此外，即使在复发时 DLL3 表达降低的患者组中，多数患者仅降低一个等级；因此，多数复发肿瘤在复发时仍保留至少一定程度的 DLL3 表达。仅 7/91 例既往表达 DLL3 的肿瘤在复发时转为 DLL3 阴性（7.7%；图 4H）；所有此类病例均为 IDHwt 胶质母细胞瘤。相反，9/91 例首次切除时归类为 DLL3 阴性的患者在复发时转为阳性；所有此类病例也均为 IDHwt 胶质母细胞瘤（9.9%；图 4H）。 图4 讨 论 尽管对胶质瘤生物学（包括肿瘤微环境（TME））的认知取得显著进展，但近期探索的多数新型治疗仍未能改善胶质瘤患者的临床结局。关键挑战之一在于胶质瘤的高度时间异质性、瘤内与瘤间异质性；在胶质瘤中广泛且均一表达、而正常脑组织中不存在的治疗靶点相对罕见。由于复发胶质瘤靶向治疗临床试验通常依赖初诊时靶点表达的证实，极少要求进展时再次确认，因此在未证实复发时靶点表达的情况下将靶点应用于复发患者前，应在系列样本中记录进展期样本靶点表达的持续性与稳定性。 本研究在迄今最大样本量的患者队列中评估配对原发与复发胶质瘤中的肿瘤相关抗原 DLL3 表达。结果显示，DLL3 在各胶质瘤亚型中均高且稳定表达，尤其是 IDHmt 胶质瘤，且多数患者复发后 DLL3 表达得以保留。这些数据支持 DLL3 作为潜在合适且有吸引力的治疗靶点，并鼓励该领域推进复发胶质瘤 DLL3 靶向（免疫）治疗临床试验。 与既往研究一致，本研究发现 IDHmt 胶质瘤的 DLL3 表达显著高于 IDHwt 胶质母细胞瘤。但本研究中 IDHmt 星形细胞瘤与少突胶质细胞瘤均为 DLL3 阳性，与 Noor 等既往发表的 IHC 结果不同，后者采用与本研究相似的视觉评分法报告 67.7%（21/31）的星形细胞瘤与 82.3%（14/17）的少突胶质细胞瘤 DLL3 阳性。这一差异部分反映 WHO 中枢神经系统肿瘤分类的更新：值得注意的是，Noor 等研究中归类为星形细胞瘤的 31 例病例中有 6 例为 IDHwt，按照现行标准将重新归类为胶质母细胞瘤。但即使在其数据集中经证实 IDH 突变的病例中，仍有 7/39 例报告为 DLL3 阴性。DLL3 免疫组化染色在技术上具有挑战性，抗体灵敏度与染色方案的差异可能导致这种变异。本研究采用验证合格且认可的 IHC 检测方法（Ventana，美国亚利桑那州），该方法广泛用于临床试验并证实对 DLL3 检测具有高灵敏度与特异性；Brcic 等的对比研究显示 Ventana 检测方法显著优于多数其他市售抗体。因此，采用不同抗体可能导致既往研究报告的阴性病例。此外，肿瘤异质性可能引入抽样偏倚，并导致本研究与既往研究间的差异，尤其是在 IDHwt 胶质母细胞瘤样本中。 与既往研究一致，本研究发现 DLL3 在 IDHmt 伴 1p/19q 共缺失少突胶质细胞瘤中表达最广泛且最均一。有趣的是，DLL3 基因位于染色体 19q13.13，该区域属于此类胶质瘤特征性杂合性缺失（LOH）区域。一种可能的解释是 1p/19q-LOH 与 DLL3 表达在功能上相关，例如 1p/19q LOH 导致 DLL3 蛋白表达的（代偿性）转录或表观遗传上调，但这仍为推测。或者，鉴于 DLL3 在神经发育过程中细胞命运决定的重要作用以及胚胎发育过程中 DLL3 表达的短暂性，无论是否存在 1p/19q LOH，少突胶质细胞瘤细胞可能更接近 DLL3 “生理性” 高表达的发育状态。Tirosh 等此前提出少突胶质细胞瘤的细胞发育层级结构，其中星形胶质细胞样（AC）、少突胶质细胞样（OC）与神经祖细胞样（NPC）细胞分别具有不同的发育程序与转录特征，且 Notch 信号通路已被证实参与此类谱系分化决定。Notch 通路失活与少突胶质细胞瘤更具侵袭性的病程相关。有趣的是，在胶质母细胞瘤中，DLL3 表达历来被认为是前神经元亚型的标志，该亚型富集与少突胶质细胞发育相关的基因。 此外，既往研究提示 SCLC 中 DLL3 表达与肿瘤微环境（TME）改变相关。Shirasawa 等发现，高 DLL3 表达 SCLC 肿瘤（定义为基于转录组数据的 DLL3 表达高于中位数）中多种免疫相关通路受抑制，而低 DLL3 表达肿瘤（DLL3 表达低于中位数）则无此现象，包括抗原呈递与 T 细胞迁移相关通路。其研究中，高 DLL3 表达样本含显著更小比例的 T 细胞、巨噬细胞与树突状细胞。Noor 等也提示胶质瘤中 DLL3 蛋白表达与 DLL3 甲基化和免疫微环境改变相关，尽管其发现的效应因免疫细胞亚群而异，且在 IDHmt 与 IDHwt 胶质瘤中存在差异。这一方向可在未来研究中进一步探索。 本研究存在若干局限性，包括可能引入抽样偏倚的肿瘤异质性，以及采用人工评估方法。尽管人工评估方法可能引发观察者内与观察者间变异性的担忧，但本研究目的为尽可能贴近临床实践，且由单一神经病理学家进行 IHC 评估与样本分类仍是临床常规中 DLL3 表达评估的金标准，尤其是在临床试验背景下。此外，本研究的分类方法可避免对可能无生物学意义的微小表达差异过度解读。另一个需考虑的重要方面是，本研究选择的 DLL3 表达等级的临床相关性目前未知。鉴于胶质瘤中尚无确定的 DLL3 表达阈值，本研究根据多学科专家共识将样本分为四个表达组（阴性、低、中、高）。但 DLL3 靶向治疗获益所需的明确 DLL3 表达水平尚未确定，且可能因肿瘤类型与治疗结构而异。例如，乳腺癌中符合抗 HER2 单克隆抗体曲妥珠单抗治疗资格的 HER2 阳性截断值在临床指南中定义为 10%，尽管缓解与生物标志物表达并非线性相关，而非小细胞肺癌中靶向 PD-1 的检查点抑制剂仅需 > 1% 表达即可诱导临床有意义的缓解。鉴于 SCLC 中 DLL3 高且均一的表达，迄今为止 SCLC 中多数 DLL3 靶向治疗临床试验无论 DLL3 表达水平均开展，且 FDA 批准 tarlatamab 用于 SCLC 不依赖 DLL3 表达水平。DeLLphi 试验的回顾性分析显示，在难治性 SCLC 中，塔拉妥单抗治疗后的客观缓解与 DLL3 表达水平无关。因此，SCLC 中治疗缓解在多大程度上依赖 DLL3 表达水平目前未知，且可能因治疗结构而异。因此，未来研究必须明确 DLL3 表达水平对胶质瘤治疗缓解与生存的临床相关性。由于目前尚无胶质瘤中 DLL3 靶向治疗试验的数据，这一问题目前仍未解决。每个细胞的表达强度也可能影响治疗缓解，应在未来研究中考虑。但鉴于某些 T 细胞衔接器即使在低抗原密度下仍具有高效能，即使低或斑片状 DLL3 表达也可能足以诱导对某些治疗的有意义缓解，但这仍需未来研究证实。 综上，本研究显示 DLL3 在本队列的弥漫性胶质瘤各亚型中广泛表达，尤其是 IDHmt 胶质瘤，且多数患者复发时表达得以保留。但尽管总体 DLL3 表达稳定性高，本研究确实观察到胶质瘤亚组间存在一定变异性。特别是 IDHmt 星形细胞瘤 66.6% 的一致率意味着此类肿瘤的一个亚组（6/18 例患者）复发时 DLL3 表达降低。这是否具有临床相关性仍待确定。重要的是，本队列中仅 7 例患者缺失 DLL3 表达，均诊断为 IDHwt 胶质母细胞瘤；因此，IDHmt 胶质瘤患者复发时 DLL3 表达从未完全缺失。 生物标志物动态变化对临床试验设计具有重要意义，因为神经肿瘤学研究中复发患者的入组资格通常基于首次切除存档组织的生物标志物表达。尽管本研究结果提示原发肿瘤组织可作为多数患者复发时 DLL3 状态的合理替代指标，但对存档组织的依赖程度应与所研究的特定治疗方案所要求的 DLL3 阳性阈值相一致。总体而言，DLL3 表达的高发生率与相对稳定性支持在初诊与复发胶质瘤中继续研发 DLL3 靶向治疗。 “DLL3蛋白表达检测”项目，基于IHC平台，送检样本要求4-5张厚度4-5微米防脱切片（烤片、挂胶），报告周期为5个自然日。 参考文献： Luning R, Maas SLN, French PJ, Hoogstrate Y, van Hijfte L, Head R, de Heer I, van den Bosch TPP, Woehrer A, van den Bent MJ, Geurts M. Delta-like ligand 3 expression in isocitrate dehydrogenase-mutant and isocitrate dehydrogenase-wildtype glioma is largely retained at recurrence, supporting its potential as a therapeutic target. Neurooncol Adv. 2026 Mar 17;8(1):vdag027. doi: 10.1093/noajnl/vdag027. 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