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ROOT, Switzerland--(BUSINESS WIRE)-- Novocure (NASDAQ: NVCR) today announced 20 presentations on Tumor Treating Fields (TTFields) therapy will be delivered at the American Association for Cancer Research (AACR) Annual Meeting 2024, to be held April 5 to 10 in San Diego. The presentations, describing preclinical investigations, include new insights on how TTFields therapy can potentially enhance the immune system’s ability to combat cancer cells and on TTFields therapy’s effects and mechanisms in pancreatic cancer. “The research we and our collaborators are presenting at the AACR Annual Meeting underscores the potential of Tumor Treating Fields therapy in treating various solid tumor types,” said Moshe Giladi, Ph.D., Novocure’s Chief Science Officer. “We continually explore the science of TTFields therapy to improve our product and make a difference in the lives of patients with cancer, and we are eager to discuss some of our latest insights with leading cancer investigators.” Highlights include: A preclinical study in a murine model of pancreatic cancer showing that TTFields applied concurrently with standard chemotherapy led to significantly enhanced therapeutic effects. When used alongside gemcitabine and nab-paclitaxel (Gem/NabP), TTFields significantly reduced tumor growth compared to the control group, and a complete regression of tumors was observed in a number of animals. This is a treatment regimen similar to the PANOVA-3 clinical trial examining the efficacy of TTFields in patients with locally advanced pancreatic cancer. A preclinical study demonstrating a novel immunomodulatory role for TTFields by promoting in vitro pro-inflammatory polarization of macrophages. Macrophages exposed to TTFields showed an increase in markers and chemicals that indicate a shift towards a pro-inflammatory, tumor-fighting mode. The study suggests TTFields can potentially modulate macrophages to better attack cancer cells by pushing them toward a state more hostile to tumors. An in vitro study suggesting concomitant application of TTFields and PARP inhibitors in BRCA wild type pancreatic cancer cells leads to improvement over monotherapy. Applied individually, both PARP inhibitors and TTFields killed cancer cells, stopped them from multiplying, and triggered apoptosis. These effects were amplified when TTFields and PARP inhibitors were applied together. These findings contribute to existing data suggesting that TTFields induce a state of BRCAness in cancer cells. Presentations from Novocure-sponsored and partner programs include: Tumor Treating Fields (TTFields) targeted self assembling nanoparticles for pancreatic cancer treatment: In vitro and in vivo assessment. Presenter: P.P. Desai. 1:30 p.m. PDT on Sunday, April 7. Tumor Treating Fields induce the integrated stress response, alter the transcriptional signatures of cellular metabolism, and modulate immune-related cytokines dependent and independent of p53. Presenter: P.R. Srinivasan. 1:30 p.m. PDT on Sunday, April 7. Tumor Treating Fields (TTFields) disrupt cancer cell invasion by impacting cell-ECM traction forces. Presenter: S.M. Short. 9 a.m. PDT on Monday, April 8. N-cadherin-mediated activation of PI3K/Akt pathway following application of Tumor Treating Fields (TTFields). Presenter: T. Voloshin. 9 a.m. PDT on Monday, April 8. Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure. Presenter: M. Mazzanti. 9 a.m. PDT on Monday, April 8. Co-treatment with KRAS G12D inhibitor MRTX1133 plus TTFields against human pancreatic and Colorectal cancer cell lines results in synergistic up-regulation of cleaved PARP in KRAS G12D & unexpectedly in KRAS G12V as well. Presenter: V. Tajiknia. 9 a.m. PDT on Monday, April 8. Tumor Treating Fields (TTFields) for spinal metastasis: Clinical trial concept for use of conductive implants as waveguides to enhance TTFields strength. Presenter: C.E. Tatsui. 9 a.m. PDT on Monday, April 8. Tumor Treating Fields (TTFields) increase cancer cell membrane permeability and improve sensitivity to doxorubicin in vitro and in vivo. Presenter: T. Voloshin. 9 a.m. PDT on Tuesday, April 9. Development of paclitaxel-loaded nanoparticles with high charge density. Presenter: K.Y. Bang. 1:30 p.m. PDT on Tuesday, April 9. Tumor Treating Fields alter PDGFR-β localization in immortalized human pericytes in an in vitro model of the blood-brain barrier. Presenter: C. Hagemann. 1:30 p.m. PDT on Tuesday, April 9. Designing arrays for delivering Tumor Treating Fields (TTFields) to the mouse head. Presenter: I Tzchori. 1:30 p.m. PDT on Tuesday, April 9. Tumor Treating Fields (TTFields) induce an anti-tumor immune response in a pancreatic cancer mouse model. Presenter: T. Voloshin. 9 a.m. PDT on Wednesday, April 10. Macrophage pro-inflammatory phenotype skewing by the application of Tumor Treating Fields (TTFields). Presenter: T. Voloshin. 9 a.m. PDT on Wednesday, April 10. Quantitative proteomics reveal the mechanism of TTFields therapy for glioblastoma. Presenter: Q. Mei. 9 a.m. PDT on Wednesday, April 10. Treatment of pancreatic cancer cells with Tumor Treating Fields (TTFields) and PARP inhibitors. Presenter: E. Dor-On. 9 a.m. PDT on Wednesday, April 10. Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer. Presenter: E. Dor-On. 9 a.m. PDT on Wednesday, April 10. Preclinical investigations of concomitant Tumor Treating Fields (TTFields) with cisplatin for treatment of cervical cancer. Presenter: I. Tzschori. 9 a.m. PDT on Wednesday, April 10. Tumor Treating Fields (TTFields) can induce immunogenic cell death in GBM resulting in enhanced immune modulation. Presenter: R.T. Nitta. 9 a.m. PDT on Wednesday, April 10. Tumor Treating Fields (TTFields) show efficacy in Triple-Negative breast cancer (TNBC) cells alone and in combination with PARP inhibitor Talazoparib. Presenter: M. Ghandali. 9 a.m. PDT on Wednesday, April 10. TTFields and imipridone ONC206 co-treatment inhibits p-AKT and spheroid growth and upregulates caspase-10 in human GBM cell lines. Presenter: V. Tajiknia. 9 a.m. PDT on Wednesday, April 10. ABOUT TUMOR TREATING FIELDS THERAPY Tumor Treating Fields (TTFields) are electric fields that exert physical forces to kill cancer cells via a variety of mechanisms. TTFields do not significantly affect healthy cells because they have different properties (including division rate, morphology, and electrical properties) than cancer cells. The multiple, distinct mechanisms of TTFields therapy work together to selectively target and kill cancer cells. Due to its multimechanistic actions, TTFields therapy can be added to cancer treatment modalities in approved indications and demonstrates enhanced effects across solid tumor types when used with chemotherapy, radiotherapy, immune checkpoint inhibition, or PARP inhibition in preclinical models. TTFields therapy provides clinical versatility that has the potential to help address treatment challenges across a range of solid tumors. To learn more about Tumor Treating Fields therapy and its multifaceted effect on cancer cells, visit tumortreatingfields.com. ABOUT NOVOCURE Novocure is a global oncology company working to extend survival in some of the most aggressive forms of cancer through the development and commercialization of its innovative therapy, Tumor Treating Fields. Novocure’s commercialized products are approved in certain countries for the treatment of adult patients with glioblastoma, malignant pleural mesothelioma and pleural mesothelioma. Novocure has ongoing or completed clinical studies investigating Tumor Treating Fields in brain metastases, gastric cancer, glioblastoma, liver cancer, non-small cell lung cancer, pancreatic cancer and ovarian cancer. Headquartered in Root, Switzerland and with a growing global footprint, Novocure has regional operating centers in Portsmouth, New Hampshire and Tokyo, as well as a research center in Haifa, Israel. For additional information about the company, please visit Novocure.com and follow @Novocure on LinkedIn and Twitter. FORWARD-LOOKING STATEMENTS In addition to historical facts or statements of current condition, this press release may contain forward-looking statements. Forward-looking statements provide Novocure’s current expectations or forecasts of future events. These may include statements regarding anticipated scientific progress on its research programs, clinical study progress, development of potential products, interpretation of clinical results, prospects for regulatory approval, manufacturing development and capabilities, market prospects for its products, coverage, collections from third-party payers and other statements regarding matters that are not historical facts. You may identify some of these forward-looking statements by the use of words in the statements such as “could” “anticipate,” “estimate,” “expect,” “project,” “intend,” “plan,” “believe” or other words and terms of similar meaning. Novocure’s performance and financial results could differ materially from those reflected in these forward-looking statements due to general financial, economic, environmental, regulatory and political conditions and other more specific risks and uncertainties facing Novocure such as those set forth in its Annual Report on Form 10-K filed on February 22, 2024, and subsequent filings with the U.S. Securities and Exchange Commission. Given these risks and uncertainties, any or all of these forward-looking statements may prove to be incorrect. Therefore, you should not rely on any such factors or forward-looking statements. Furthermore, Novocure does not intend to update publicly any forward-looking statement, except as required by law. Any forward-looking statements herein speak only as of the date hereof. The Private Securities Litigation Reform Act of 1995 permits this discussion. View source version on businesswire.com: Contacts INVESTORS & MEDIA: Ingrid Goldberg investorinfo@novocure.com media@novocure.com 610-723-7427 Source: Novocure View this news release online at:

导读骨肉瘤  (OS) 是骨骼系统最常见的恶性肿瘤之一，约占所有骨癌的 56%。OS 起源于恶性间充质细胞产生的类骨或未成熟骨，因此通常影响儿童和青少年。由于其恶性程度高、转移早、易复发、耐药等特点，其死亡率高，预后差。越来越多的证据表明，诱导非凋亡细胞死亡是一种新型抗肿瘤策略，能用来克服现有的肿瘤耐药问题。铁死亡是一种新发现的程序性细胞死亡形式，具有多种形态特征、诱导因子和调节机制。因此，靶向调控肿瘤细胞铁死亡可能是治疗肿瘤较有前景的方法。目前已证实在肝细胞癌、乳腺癌、黑色素瘤、卵巢癌和肾癌等不同类型的癌症中，铁死亡在限制癌细胞生长、增强细胞杀伤和克服耐药性方面发挥着关键作用。然而，不同肿瘤细胞对铁死亡的敏感性是高度异质性的，因此需要进一步深入了解调控整个过程的分子机制。最新研究发现，铁死亡抑制蛋白 1 ( Ferroptosis suppressor protein 1, FSP1)  能够减少脂质过氧化物，从而抑制铁死亡。值得关注的是，抑制 FSP1 可选择性地使癌细胞对铁死亡变得敏感，从而突出了其可作为潜在生物标志物和治疗靶点。2024 年 2 月 17 日，来自意大利东皮埃蒙特大学的研究团队在 Cell Death Discovery 杂志发表了题为 FSP1 is a predictive biomarker of osteosarcoma cells susceptibility to ferroptotic cell death and a potential therapeutic target 的文章，在这项研究中，他们发现 OS 细胞的异质性细胞反应和对铁死亡的敏感性与 FSP1 的基础表达直接相关，抑制 FSP1 的表达或活性可以有效地使耐药 OS 细胞对铁死亡重新敏感。此外，他们还揭示了调节 OS 细胞中 FSP1 基础表达的分子机制，从而表明 FSP1 是一种新的有价值的预测性生物标志物，可以预测 OS 对铁死亡的敏感性，并有可能成为一种新的治疗靶点。图片来源：Cell Death Discovery主要研究内容1. OS 对铁死亡的敏感性具有异质性根据肿瘤类型、微环境和获得性突变，癌细胞对铁死亡具有异质性的敏感性，使每个肿瘤成为一个独特的实体，增加了确定正确治疗方案的难度。因此，为了评估人骨肉瘤对铁死亡的敏感性，他们评估了 3 个人骨肉瘤细胞系 U2OS、MG63 和 HOS 中这种非凋亡细胞死亡过程的诱导和执行。将 3 株细胞系经 0.5µM RSL3 处理，8 小时后通过 qPCR 检测已知铁离子标记物 PTGS2 和 SLC7A11 的表达情况。结果表明，与未处理对照组相比，RSL3 处理细胞中 PTGS2 和 SLC7A11 均显著上调，脂质 ROS 在 HOS 中大量积累，在 MG63 中略少，在 U2OS 中明显降低。有趣的是，在三种细胞系中，铁细胞死亡的执行有显著差异，具体表现为：在 RSL3 的作用下，HOS 细胞的活力显著下降，为 17%，MG63 对处理也很敏感，细胞活力下降到 34%，而 U2OS 细胞对处理无反应  (细胞活力为 93%)。总的来说，这些结果清楚地表明，U2OS 对铁死亡最耐药，而 HOS 对铁死亡最敏感。图片来源：Cell Death Discovery2. 骨肉瘤的 EMT 和铁离子敏感性上皮-间充质转化  (Epithelial-to-mesenchymal transition, EMT) 是骨肉瘤从原发部位脱离并获得侵袭性和转移性表型的重要机制。此外，一些证据表明，化疗耐药或接受 EMT 的癌细胞可能对铁死亡表现出更大的脆弱性。他们在三种骨肉瘤细胞系  (U2OS、MG63 和 HOS) 中检测了 EMT 标记物的表达，包括转录因子 TWIST1 和 SNAIL、细胞粘附分子 N-Cadherin (N-Cad) 和 E-cadherin (E-Cad)、基质金属蛋白酶 9 (MMP9) 和中间丝蛋白 Vimentin (VIM) 的表达。除 E-Cad 外，EMT 标记物在铁死亡敏感的 HOS 细胞株中表达明显增强，上皮标记物 E-Cad 在最耐药的 U2OS 中表达最高，而在 MG63 和 HOS 中表达程度较低。他们还通过 Transwell 迁移实验评估了细胞的侵袭能力。结果表明，HOS 细胞的侵袭性高于 MG63 和 U2OS，而 U2OS 的侵袭性较小。总的来说，这些数据清楚地表明 EMT 与骨肉瘤细胞的铁死亡之间存在相关性。图片来源：Cell Death Discovery3. FSP1 在 OS 抵抗铁死亡诱导中起关键作用铁死亡抑制蛋白 1 (FSP1)，也被称为细胞凋亡诱导因子线粒体 2 (AIFM2)，是一种新近发现的铁死亡抑制因子，它与 GPX4 共同工作，但独立于 GPX4。因此，为了研究 FSP1 在 OS 细胞铁死亡中的潜在作用，他们首先评估了其基础表达水平。数据显示，U2OS 细胞的 FSP1 mRNA 表达量最高，HOS 细胞的 FSP1 mRNA 表达量最低，MG63 细胞的 FSP1 mRNA 表达量居中。这些结果提出了一种假设，即 FSP1 的基础表达可能被用作 OS 对铁死亡执行敏感性的潜在预测生物标志物。数据显示 RSL3 刺激的 FSP1 上调在最耐药的 U2OS 中尤为明显，而在 MG63 中不那么明显，在最敏感的 HOS 中更温和，这进一步证实了 FSP1 可能参与 OS 细胞对铁死亡的耐药性。为了验证我们的假设，他们使用特异性抑制剂 iFSP1(6µM) 抑制 FSP1 的活性，并将所有 OS 细胞株暴露在 0.5µM RSL3 环境下 24 小时。结果发现，所有 OS 细胞株对铁死亡的敏感性增强。重要的是，FSP1 抑制完全恢复了耐药 U2OS 细胞的表型，使这些细胞对铁死亡高度敏感。此外，他们也在 3D OS 球体中评估了 OS 细胞对 RSL3 诱导的铁死亡敏感性。与 2D 细胞培养的结果一致，3D 的实验结果也表明：HOS 细胞比 MG63 更敏感，并且 FSP1 抑制持续增加了两种细胞类型对 RSL3 处理的敏感性。图片来源：Cell Death Discovery4. NRF2 在 OS 细胞中不调控 FSP1 的表达为了检测 NRF2 是否参与了 FSP1 的基础表达调控，他们在骨肉瘤细胞系中评估了该转录因子的蛋白和 mRNA 水平。研究发现，在 U2OS 中 NRF2 的表达与 HOS 中非常相似，而在 MG63 中 NRF2 的表达在蛋白水平和 mRNA 水平上都略高。在评估 NRF2 负调控因子 KEAP1 的表达时也得到了类似的结果。这些结果表明了 NRF2 可能不参与 FSP1 基础表达的调节。不过，NRF2 在铁死亡过程中的作用已被描述，该因子参与铁死亡的氧化应激所引起的一般抗氧化靶基因的调控，以及铁诱导特异性因子的调控。因此，为了验证 NRF2 信号通路的完整性及其在铁离子刺激下的迅速激活，他们评估了氧化应激相关 HO-1 和 NQO1 以及铁离子相关 GPX4 和 SLC7A11 的表达。整体数据表明，NRF2 在铁死亡早期被激活，但不参与 FSP1 的基础表达。图片来源：Cell Death Discovery5. p53 在 OS 细胞中参与调节 FSP1 的基础表达接下来，他们在 p53 缺失的 MG63 细胞中短暂过表达野生型 p53，并评估 FSP1 的水平。结果发现，MG63 细胞中野生型 p53 的 FSP1 基因表达量呈剂量依赖性增加。后续的实验结果也表明，抑制 p53 的表达可以降低 FSP1 的基础表达，说明 p53 在骨肉瘤细胞中参与调控 FSP1 的基础表达。图片来源：Cell Death Discovery结语综上所述，他们基于最近描述的一种新的程序性细胞死亡形式，即铁死亡，探索了一种潜在的杀死骨肉瘤细胞的策略，它的特征是铁依赖的脂质过氧化物（非凋亡细胞死亡的执行者），为传统疗法抵抗的癌症提供了新的治疗机会。参考文献1. Panczyszyn, E., Saverio, V., Monzani, R. et al. FSP1 is a predictive biomarker of osteosarcoma cells』 susceptibility to ferroptotic cell death and a potential therapeutic target. Cell Death Discov. 10, 87 (2024).2. Gill J, Gorlick R. Advancing therapy for osteosarcoma. Nat Rev Clin Oncol. 2021;18:609–24.3. Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: molecular mechanisms and health implications. Cell Res. 2021;31:107–25.题图来源：图虫创意声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓

Abcuro on Thursday announced that it raised $155 million in Series B financing that will be used to complete a Phase II/III registrational trial of ABC008 for the treatment of inclusion body myositis (IBM). The investment was co-led by Redmile Group and Bain Capital Life Sciences, with other participants including RA Capital Management, Samsara BioCapital and Sanofi Ventures.The anti-KLRG1 antibody ABC008 has been designed to treat diseases mediated by highly cytotoxic T-cells, including IBM, T-cell large granular lymphocytic leukaemia (T-LGLL) and mature T-cell malignancies. The pivotal study in IBM, which began in April, aims to recruit around 230 patients and investigate the efficacy of ABC008 as measured by the IBM Functional Rating Scale (IBMFRS) at week 76."Targeting the depletion of cytotoxic T-cells that express KLRG1 with ABC008…has generated exciting early data in patients with IBM," remarked chief medical officer H. Jeffrey Wilkins. The company previously highlighted data from a Phase I trial showing that at the ABC008 dose levels being used in the Phase II/III study, 97% depletion of blood target cells was observed at 28 days post injection.Abcuro is also evaluating the antibody in a Phase I/II trial for T-LGLL, while plans are under way for a Phase I/II study in T- and NK-cell lymphomas. Meanwhile, the company, which closed a $42 million Series A-1 financing in 2021, has a monoclonal antibody dubbed ABC015 in preclinical development. The therapy is designed to interrupt the interaction of KLRG1 with E- and N-cadherin on the surface of cancer cells.