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Ultra-High Dose Rate Helium Ion Beams: Minimizing Brain Tissue Damage while Preserving Tumor Control. 超高剂量率氦离子束:最大限度减少脑组织损伤,同时保持肿瘤控制。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-31 DOI: 10.1158/1535-7163.MCT-24-0536
Ivana Dokic, Mahmoud Moustafa, Thomas Tessonnier, Sarah Meister, Federica Ciamarone, Mahdi Akbarpour, Damir Krunic, Thomas Haberer, Jürgen Debus, Andrea Mairani, Amir Abdollahi

Ultra-high dose rate radiotherapy with electrons and protons has shown potential for cancer treatment by effectively targeting tumors while sparing healthy tissues (FLASH effect). This study aimed to investigate the potential FLASH sparing effect of ultra-high-dose rate helium ion irradiation, focusing on acute brain injury and subcutaneous tumor response in a preclinical in vivo setting. Raster-scanned helium ion beams were used to compare the effects of standard dose rate (SDR at 0.2 Gy/s) and FLASH (at 141 Gy/s) radiotherapy on healthy brain tissue. Irradiation-induced brain injury was studied in C57BL/6 mice via DNA damage response, using nuclear γH2AX as a marker for double-strand breaks (DSB). The integrity of neurovascular and immune compartments was assessed through CD31+ microvascular density and activation of microglia/macrophages. Iba1+ ramified and CD68+ phagocytic microglia/macrophages were quantified, along with the expression of inducible nitric oxide synthetase (iNOS). Tumor response to SDR (0.2 Gy/s) and FLASH (250 Gy/s) radiotherapy was evaluated in A549 carcinoma model, using tumor volume and Kaplan-Meier survival as endpoints. The results showed that helium FLASH radiotherapy significantly reduced acute brain tissue injury compared to SDR, evidenced by lower levels of DSB and preserved neurovascular endothelium. Additionally, FLASH radiotherapy reduced neuroinflammatory signals compared to SDR, as indicated by fewer CD68+ iNOS+ microglia/macrophages. FLASH radiotherapy achieved tumor control comparable to that of SDR radiotherapy. This study is the first to report the FLASH sparing effect of raster scanning helium ion radiotherapy in vivo, highlighting its potential for neuroprotection and effective tumor control.

利用电子和质子进行的超高剂量率放射治疗在有效靶向肿瘤的同时保留健康组织(FLASH效应),显示出癌症治疗的潜力。本研究旨在研究超高剂量率氦离子照射对急性脑损伤和皮下肿瘤反应的潜在FLASH保护作用,重点研究临床前体内环境。采用栅格扫描氦离子束比较标准剂量率(SDR为0.2 Gy/s)和FLASH (141 Gy/s)放疗对健康脑组织的影响。以核γ - h2ax作为双链断裂(DSB)标记物,通过DNA损伤反应研究辐照致C57BL/6小鼠脑损伤。通过CD31+微血管密度和小胶质细胞/巨噬细胞的激活来评估神经血管和免疫室的完整性。定量Iba1+分支化和CD68+吞噬小胶质细胞/巨噬细胞,以及诱导型一氧化氮合成酶(iNOS)的表达。在A549癌模型中,以肿瘤体积和Kaplan-Meier生存期为终点,评估肿瘤对SDR (0.2 Gy/s)和FLASH (250 Gy/s)放疗的反应。结果显示,与SDR相比,氦FLASH放疗可显著减轻急性脑组织损伤,表现为DSB水平降低,神经血管内皮得以保存。此外,与SDR相比,FLASH放疗减少了神经炎症信号,这表明CD68+ iNOS+小胶质细胞/巨噬细胞较少。FLASH放疗对肿瘤的控制与SDR放疗相当。本研究首次报道了光栅扫描氦离子放疗在体内的FLASH节约效应,突出了其在神经保护和有效肿瘤控制方面的潜力。
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引用次数: 0
OBI-992, a Novel TROP2-Targeted Antibody-Drug Conjugate, Demonstrates Antitumor Activity in Multiple Cancer Models. OBI-992,一种新的trop2靶向抗体-药物偶联物,在多种癌症模型中显示出抗肿瘤活性。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-30 DOI: 10.1158/1535-7163.MCT-24-0588
Wan-Fen Li, Ming-Feng Chiang, Hao-Cheng Weng, Jhih-Jie Yang, Hsin-Shan Wu, Szu-Yu Wu, Yu-Jung Chen, Chi-Huan Lu, Jyy-Shiuan Tu, Ren-Yu Hsu, Chi-Sheng Shia, Teng-Yi Huang, Ming-Tain Lai

Trophoblast cell surface antigen 2 (TROP2) is highly expressed in multiple cancers relative to normal tissues, supporting its role as a target for cancer therapy. OBI-992 is an antibody-drug conjugate (ADC) derived from a novel TROP2-targeted antibody linked to the topoisomerase 1 (TOP1) inhibitor exatecan via an enzyme-cleavable hydrophilic linker, with a drug-antibody ratio of 4. This study evaluated and compared the antitumor activity of OBI-992 with that of benchmark TROP2-targeted ADCs datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan (SG) in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. OBI-992 treatment exhibited statistically significant antitumor activity versus controls at doses of 3 and 10 mg/kg in various CDX and PDX models, demonstrating comparable or better antitumor activity with benchmark ADCs. In a large-tumor model, longer survival times were observed in OBI-992-treated mice compared with Dato-DXd-treated mice. OBI-992 treatment induced marked bystander killing of TROP2-negative cells in the presence of nearby TROP2-positive cells in both in vitro and in vivo studies. In lung adenocarcinoma CDX models with overexpression of either P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) to mimic ATP-binding cassette transporter-mediated multidrug resistance, OBI-992 treatment maintained antitumor activity when Dato-DXd treatment became less effective. The combination of OBI-992 at suboptimal doses with either poly (ADP-ribose) polymerase (PARP) inhibitors or an immune check point inhibitor produced synergistic antitumor effects in mouse models. Taken together, these translational results support further development of OBI-992 as a cancer therapy.

与正常组织相比,滋养细胞表面抗原2 (Trophoblast cell surface antigen 2, TROP2)在多种癌症中高表达,支持其作为癌症治疗靶点的作用。OBI-992是一种抗体-药物偶联物(ADC),源于一种新型的trop2靶向抗体,通过酶可切割的亲水连接物与拓扑异构酶1 (TOP1)抑制剂exatecan连接,药物-抗体比为4。本研究在细胞系来源的异种移植(CDX)和患者来源的异种移植(PDX)模型中评估并比较了OBI-992与基准的trop2靶向adc datopotamab deruxtecan (Dato-DXd)和sacituzumab govitecan (SG)的抗肿瘤活性。在各种CDX和PDX模型中,剂量为3和10 mg/kg的OBI-992治疗与对照组相比,显示出统计学上显著的抗肿瘤活性,显示出与基准adc相当或更好的抗肿瘤活性。在大肿瘤模型中,obi -992治疗的小鼠比dato - dxd治疗的小鼠存活时间更长。在体外和体内研究中,OBI-992处理在附近有trop2阳性细胞存在的情况下诱导了明显的旁观者杀伤trop2阴性细胞。在p -糖蛋白(P-gp)或乳腺癌耐药蛋白(BCRP)过表达以模拟atp结合盒转运体介导的多药耐药的肺腺癌CDX模型中,OBI-992治疗在Dato-DXd治疗效果下降时保持抗肿瘤活性。在小鼠模型中,以次优剂量将OBI-992与聚(adp -核糖)聚合酶(PARP)抑制剂或免疫检查点抑制剂联合使用可产生协同抗肿瘤作用。综上所述,这些转化结果支持OBI-992作为癌症治疗的进一步发展。
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引用次数: 0
Pan-KRAS inhibitors BI-2493 and BI-2865 display potent anti-tumor activity in tumors with KRAS wild-type allele amplification. Pan-KRAS抑制剂BI-2493和BI-2865在KRAS野生型等位基因扩增的肿瘤中显示出有效的抗肿瘤活性。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-23 DOI: 10.1158/1535-7163.MCT-24-0386
Antonio Tedeschi, Fiorella Schischlik, Francesca Rocchetti, Johannes Popow, Florian Ebner, Daniel Gerlach, Antonia Geyer, Valeria Santoro, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Jesse Lipp, Matthias Samwer, Michael Gmachl, Norbert Kraut, Mark Pearson, Dorothea Rudolph

KRASG12C selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other KRAS mutant alleles in cancer patients. We report that KRAS wild-type amplified tumor models are sensitive to treatment with the small molecule KRAS inhibitors BI-2493 and BI-2865. These pan-KRAS inhibitors directly target the "OFF" state of KRAS and result in potent anti-tumor activity in pre-clinical models of cancers driven by KRAS mutant proteins. Here, we used the high-throughput cellular viability PRISM assay to assess the anti-proliferative activity of BI-2493 in a 900+ cancer cell line panel, expanding on our previous work. KRAS wild-type amplified cancer cell lines, with a copy number >7, were identified as the most sensitive, across cell lines with any KRAS alterations, to our pan-KRAS inhibitors. Importantly, our data suggest that a KRAS "OFF" inhibitor is better suited to treat KRAS wild-type amplified tumors than a KRAS "ON" inhibitor. KRAS wild-type amplification is common in patients with gastroesophageal cancers where it has been shown to act as a unique cancer driver with little overlap to other actionable mutations. The pan-KRAS inhibitors BI-2493 and BI-2865 show potent anti-tumor activity in vitro and in vivo in KRAS wild-type amplified cell lines from this and other tumor types. In conclusion, this is the first study to demonstrate that direct pharmacological inhibition of KRAS shows anti-tumor activity in preclinical models of cancer with KRAS wild-type amplification, suggesting a novel therapeutic concept for patients with cancers bearing this KRAS alteration.

KRASG12C选择性抑制剂,如sotorasib和adagrasib,已经为癌症患者靶向其他KRAS突变等位基因带来了希望。我们报道KRAS野生型扩增肿瘤模型对KRAS小分子抑制剂BI-2493和BI-2865治疗敏感。这些泛KRAS抑制剂直接靶向KRAS的“关闭”状态,并在由KRAS突变蛋白驱动的癌症临床前模型中产生有效的抗肿瘤活性。在这里,我们使用高通量细胞活力PRISM实验来评估BI-2493在900多个癌细胞系面板中的抗增殖活性,扩展了我们之前的工作。KRAS野生型扩增的癌细胞系,拷贝数为>7,被鉴定为对我们的泛KRAS抑制剂最敏感,跨越任何KRAS改变的细胞系。重要的是,我们的数据表明,KRAS“OFF”抑制剂比KRAS“ON”抑制剂更适合治疗KRAS野生型扩增肿瘤。KRAS野生型扩增在胃食管癌患者中很常见,它已被证明是一种独特的癌症驱动因素,与其他可操作的突变几乎没有重叠。泛KRAS抑制剂BI-2493和BI-2865在体外和体内对KRAS野生型扩增细胞系和其他肿瘤类型显示出有效的抗肿瘤活性。总之,这是第一个证明直接药理抑制KRAS在KRAS野生型扩增的癌症临床前模型中具有抗肿瘤活性的研究,为携带这种KRAS突变的癌症患者提供了一种新的治疗理念。
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引用次数: 0
Blocking feedback immunosuppression of antigen presentation in brain tumor during oncolytic virotherapy with oHSV-mshPKR. oHSV-mshPKR溶瘤病毒治疗中对脑肿瘤抗原呈递的阻断反馈免疫抑制
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-23 DOI: 10.1158/1535-7163.MCT-24-0629
Nobushige Tsuboi, Kimberly A Rivera-Caraballo, Upasana Sahu, Rafal Pacholczyk, Eugene Douglass, Theodore S Johnson, Qin Wang, Ravindra Kolhe, Catherine C Hedrick, David H Munn, Bangxing Hong

Glioblastoma (GBM) is the most frequent malignant brain tumor. We recently discovered that oncolytic herpes simplex virus engineered to disable tumor-intrinsic protein kinase R (PKR) signaling (oHSV-shPKR) could increase oHSV oncolysis and anti-tumor immune response. However, here we show that disabling tumor-intrinsic PKR signaling can also induce the activation of the indoleamine 2,3-dioxygenase (IDO) signaling pathway. Both GBM tumor progression and oHSV intratumoral therapy increased infiltration of IDO+CD11c+ dendritic cells into the tumor. The coculture of oHSV-infected human GBM neurospheres with monocytes-derived dendritic cells (MoDCs) dramatically increased IDO signaling activation in MoDCs through type-I interferon signaling. Addition of IDO inhibitor (indoximod) in the coculture significantly increased MoDCs activation and reduced the consumption of tryptophan. Combining indoximod and oHSV significantly inhibited tumor growth, and induced antigen specific CD8+ T cell activation. These results suggest that inhibition of the IDO pathway could significantly block feedback immunosuppression during oncolytic virotherapy of glioblastoma.

胶质母细胞瘤是最常见的恶性脑肿瘤。我们最近发现,溶瘤性单纯疱疹病毒(oHSV- shpkr)被设计成使肿瘤内在蛋白激酶R (PKR)信号失活,可以增加oHSV的溶瘤和抗肿瘤免疫反应。然而,我们在这里表明,禁用肿瘤内在的PKR信号也可以诱导吲哚胺2,3-双加氧酶(IDO)信号通路的激活。GBM肿瘤进展和oHSV肿瘤内治疗均增加IDO+CD11c+树突状细胞向肿瘤的浸润。ohsv感染的人GBM神经球与单核细胞来源的树突状细胞(MoDCs)共培养,通过i型干扰素信号传导显著增加MoDCs中IDO信号的激活。在共培养中添加IDO抑制剂(indoximod)显著增加了modc的激活并减少了色氨酸的消耗。indoximod与oHSV联合使用可显著抑制肿瘤生长,诱导抗原特异性CD8+ T细胞活化。这些结果表明,在胶质母细胞瘤溶瘤病毒治疗过程中,IDO通路的抑制可以显著阻断反馈免疫抑制。
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引用次数: 0
Combination of Bremachlorin PDT and immune checkpoint inhibitor anti-PD-1 shows response in murine immunological T-cell high and T-cell low PDAC models. Bremachlorin PDT联合免疫检查点抑制剂anti-PD-1在小鼠免疫t细胞高和t细胞低PDAC模型中显示出应答。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-20 DOI: 10.1158/1535-7163.MCT-23-0733
Roisin McMorrow, Henriette S de Bruijn, Stefania Farina, Ruben J L van Ardenne, Ivo Que, Pier G Mastroberardino, Dominic J Robinson, Laura Mezzanotte, Clemens W G M Löwik

Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging types of cancer with little or no response to immune checkpoint inhibitors (ICIs). Photodynamic therapy (PDT) has been shown to ablate tumors and induce an immune response. In our study, we investigated the effect of photodynamic therapy (PDT), using the photosensitizer Bremachlorin, in its ability to reduce tumor burden and to sensitize immunologically T-cell high and T-cell low murine PDAC tumors to the ICI that blocks programmed cell death-1 (PD-1) immune checkpoint. In addition, we monitored the effect on survival and investigated if there was a response in PDT-treated and non PDT-treated distant tumors. Our results showed that Bremachlorin PDT induces direct tumor killing which increased survival in both 'hot' T-cell high and 'cold' T-cell low PDAC tumors and that it can make the T-cell high tumors more sensitive to ICI blocking PD-1. We found that T-cell high tumor bearing mice had an overall greater response to therapy than T-cell low tumor bearing mice. One mouse with T-cell high tumors exhibited complete tumor regression in both the treated and non-treated distant tumor 90 days after treatment. These results indicate that combining immune checkpoint inhibitors (ICIs) with Bremachlorin PDT could be a promising therapeutic intervention for enhancing PDAC's response to therapy.

胰腺导管腺癌(PDAC)是最具挑战性的癌症类型之一,对免疫检查点抑制剂(ICIs)很少或没有反应。光动力疗法(PDT)已被证明可以消融肿瘤并诱导免疫反应。在我们的研究中,我们研究了光动力疗法(PDT),使用光敏剂Bremachlorin,在其减少肿瘤负担和使免疫t细胞高和t细胞低的小鼠PDAC肿瘤对阻断程序性细胞死亡-1 (PD-1)免疫检查点的ICI的能力方面的作用。此外,我们监测了对生存的影响,并调查了pdt治疗和非pdt治疗的远处肿瘤是否有反应。我们的研究结果表明,短甲氯胺PDT诱导直接杀伤肿瘤,增加了“热”t细胞高和“冷”t细胞低PDAC肿瘤的生存率,并且可以使t细胞高肿瘤对ICI阻断PD-1更敏感。我们发现t细胞高荷瘤小鼠比t细胞低荷瘤小鼠对治疗的总体反应更大。一只高t细胞肿瘤小鼠在治疗后90天,治疗和未治疗的远端肿瘤均表现出完全的肿瘤消退。这些结果表明,联合免疫检查点抑制剂(ICIs)和Bremachlorin PDT可能是一种有希望的治疗干预措施,可以增强PDAC对治疗的反应。
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引用次数: 0
First-in-human Study of ABY-029, a Novel Fluorescent Peptide that Targets Epidermal Growth Factor Receptor, Applied to Soft-Tissue Sarcomas. 针对表皮生长因子受体的新型荧光肽ABY-029用于软组织肉瘤的首次人体研究。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-17 DOI: 10.1158/1535-7163.MCT-24-0378
Kimberley S Samkoe, Hira Shahzad Sardar, Jason R Gunn, Jonathan Thomas Elliott, Sally Mansur, Joachim Feldwisch, Brian W Pogue, Konstantinos Linos, Keith D Paulsen, Eric R Henderson

ABY-029, an anti-epidermal growth factor receptor (EGFR) Affibody® molecule conjugated to IRDye 800CW, recently underwent first-in-human testing in soft-tissue sarcoma (STS). FDA Exploratory Investigational New Drug status was obtained for the Phase 0 clinical trial in which study objectives were to determine whether biological variance ratio (BVR) of 10 was achievable, fluorescence intensity correlated with EGFR expression, and doses were well tolerated. Patients (N=12) with STS were recruited based on positive EGFR immunohistochemical staining of diagnostic biopsies. ABY-029 was administered at micro- (30 nanomole, n=3), medium (90 nanomole, n=3), or high dose (171 nanomole, n=6), 1-3 hours prior to surgery. Following tumor resection, ex vivo tissue was imaged to determine mean fluorescence intensity (MFI), BVR, and other contrast measures. EGFR expression was correlated with immunohistochemistry. For micro-, medium, and high doses, mean BVR (SD) in cross-sectional slices were 4 (4), 10 (6), and 7 (8), respectively, for the whole tumor region and 6 (5), 13 (11), and 8 (6), respectively, for pathology-confirmed regions-of-interest. Strong linear correlations were found between all ABY-029 contrast metrics and total EGFR (r≥0.86, p<0.029) in cross-sectional tissue slices, and MFI and EGFR percent area (r=0.63, p<0.0001) in excised region-of-interest tissue sections. No ABY-029 related adverse events were observed. When administered above the microdose, ABY-029 demonstrated high correlation to EGFR expression and contrast values that were encouraging for translation to clinical practice. Contrast was similar to those observed with antibody agents, but with substantially reduced imaging-to-resection time, and no drug-related adverse events.

ABY-029是一种与IRDye 800CW共轭的抗表皮生长因子受体(EGFR)Affibody®分子,最近在软组织肉瘤(STS)中首次进行了人体试验。该研究的目标是确定生物变异比(BVR)是否能达到10,荧光强度与表皮生长因子受体表达是否相关,以及剂量是否能被很好地耐受。根据诊断性活检的表皮生长因子受体(EGFR)免疫组化染色阳性结果,招募了12名STS患者。ABY-029在手术前1-3小时以微量(30纳摩尔,n=3)、中量(90纳摩尔,n=3)或高剂量(171纳摩尔,n=6)给药。肿瘤切除后,对体内外组织进行成像,以确定平均荧光强度(MFI)、BVR和其他对比度指标。表皮生长因子受体的表达与免疫组化相关。对于微剂量、中剂量和高剂量,整个肿瘤区域横截面切片的平均 BVR(标度)分别为 4(4)、10(6)和 7(8),病理证实的相关区域分别为 6(5)、13(11)和 8(6)。所有ABY-029对比度指标与总表皮生长因子受体之间均存在很强的线性相关(r≥0.86,p
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引用次数: 0
Olaparib and Radiotherapy Induce Type I Interferon- and CD8+ T Cell-Dependent Sensitization to Immunotherapy in Pancreatic Cancer. 奥拉帕尼和放疗诱导I型干扰素和CD8+ T细胞依赖的胰腺癌免疫治疗致敏。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-17 DOI: 10.1158/1535-7163.MCT-24-0210
Victoria M Valvo, Qiang Zhang, Long Jiang, Erin A Holcomb, Ashley N Pearson, Anna G Edmunds, Hailey G Faulkner, Jadyn G James, Akshay Tate, Amanda K Huber, Zhuwen Wang, Yupei Guo, David Karnak, Leslie A Parsels, Joshua D Parsels, Yu L Lei, Alnawaz Rehemtulla, Heng Lin, Eileen S Carpenter, Daniel R Wahl, Vaibhav Sahai, Theodore S Lawrence, Michael D Green, Meredith A Morgan

PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN)-mediated antitumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote antitumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and sensitivity to αPD-L1 immunotherapy, as well as on the tumor microenvironment by single-cell RNA sequencing. We found that olaparib enhanced T1IFN production after radiation and had superior therapeutic efficacy in immunocompetent models. Olaparib and radiation treatment sensitized PDAC tumors to αPD-L1, resulting in decreased tumor burden and a 33% complete response rate. Combination treatment provided durable immune responses as shown by tumor rejection upon tumor rechallenge of previously cured mice. Furthermore, single-cell RNA sequencing analysis revealed that combination treatment induced an immunogenic tumor microenvironment characterized by interferon (IFN) responses in both PDAC and myeloid cell populations, macrophage polarization, and increased CD8+ terminal effector T-cell frequency and activity, findings which were confirmed by IHC and flow cytometry. Furthermore, CD8+ T cells and T1IFN signaling were required for therapeutic efficacy as host depletion of CD8+ T cells or the T1IFN receptor diminished treatment responses. Overall, our results indicate that olaparib enhances radiation-induced T1IFN-mediated immune signaling and subsequently an adaptive immune response, thus sensitizing pancreatic cancer to αPD-L1 therapy, supporting an ongoing clinical trial of this therapy in patients with PDAC.

PARP 抑制剂通过诱导 DNA 损伤和复制应激,使胰腺导管腺癌(PDAC)对辐射敏感。这些机制还有可能增强辐射诱导的 I 型干扰素(T1IFN)介导的抗肿瘤免疫反应。我们假设,PARP 抑制剂奥拉帕利也会增强辐射诱导的 T1IFN,从而促进抗肿瘤免疫反应,并使原本耐药的 PDAC 对免疫疗法敏感。为了验证这一假设,我们通过单细胞RNA测序评估了奥拉帕利和辐射对T1IFN产生和对αPD-L1免疫疗法敏感性的影响,以及对肿瘤微环境的影响。我们发现,奥拉帕利能增强放疗后T1IFN的产生,并在免疫功能正常的模型中具有更优越的疗效。奥拉帕利和放射治疗使PDAC肿瘤对αPD-L1敏感,从而减少了肿瘤负荷,完全应答率达到33%。联合治疗提供了持久的免疫反应,这体现在对先前治愈的小鼠进行肿瘤再挑战时出现的肿瘤排斥反应。此外,单细胞 RNA 测序分析表明,联合治疗诱导了一种免疫原性肿瘤微环境,其特征是 PDAC 和髓样细胞群中的干扰素(IFN)反应、巨噬细胞极化以及 CD8+ 末端效应 T 细胞频率和活性的增加,这些结果都得到了 IHC 和流式细胞术的证实。此外,CD8+ T细胞和T1IFN信号转导是疗效的必要条件,因为宿主CD8+ T细胞或T1IFN受体耗竭会降低治疗反应。总之,我们的研究结果表明,奥拉帕利能增强辐射诱导的 T1IFN 介导的免疫信号转导,进而增强适应性免疫反应,从而使胰腺癌对 αPD-L1 治疗敏感,支持正在进行的针对 PDAC 患者的临床试验。
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引用次数: 0
TEAD-independent cell growth of Hippo-inactive mesothelioma cells: Unveiling resistance to TEAD inhibitor K-975 through MYC signaling activation. 不依赖TEAD的海马失活间皮瘤细胞生长:通过MYC信号激活揭示对TEAD抑制剂K-975的抗性
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-17 DOI: 10.1158/1535-7163.MCT-24-0308
Ken Akao, Tatsuhiro Sato, Emi Mishiro-Sato, Satomi Mukai, Farhana Ishrat Ghani, Lisa Kondo-Ida, Kazuyoshi Imaizumi, Yoshitaka Sekido

Inactivation of the Hippo tumor suppressive pathway is frequently observed in mesothelioma, which leads to the activation of YAP and TAZ (YAP/TAZ) transcriptional coactivators. YAP/TAZ form complexes with TEAD family members, DNA-binding proteins, to activate transcription, which promotes cancer cell growth and proliferation. Recently developed TEAD inhibitors exhibit antitumor activity by inhibiting the formation of the transcription complex through binding to TEAD; however, the antitumor activity of TEAD inhibitors against mesothelioma remains to be fully elucidated. Here, we show that the TEAD inhibitor K-975 acts as a pan-TEAD inhibitor and selectively inhibits the binding of TEAD-binding proteins, especially YAP/TAZ, in mesothelioma cells. In studies using a panel of mesothelioma cell lines, K-975 showed a significant growth inhibitory effect on Hippo-inactivated mesothelioma cells, but some of these cell lines exhibited primary resistance to K-975. Differential gene expression analysis revealed that cells resistant to K-975 exhibited activation of MYC signaling in the presence of K-975, and cells overexpressed with MYC showed strong drug resistance, both in vitro and in vivo. Our study revealed the features of a subset of mesothelioma cells that proliferate in a TEAD-independent manner and provides important insights for the successful development of therapeutic strategies for mesothelioma with Hippo pathway inactivation.

在间皮瘤中经常可以观察到 Hippo 抑瘤通路失活的现象,这会导致 YAP 和 TAZ(YAP/TAZ)转录辅激活因子的激活。YAP/TAZ与DNA结合蛋白TEAD家族成员形成复合物,激活转录,从而促进癌细胞生长和增殖。最近开发的 TEAD 抑制剂通过与 TEAD 结合抑制转录复合物的形成,从而显示出抗肿瘤活性;然而,TEAD 抑制剂对间皮瘤的抗肿瘤活性仍有待全面阐明。在这里,我们发现 TEAD 抑制剂 K-975 是一种泛 TEAD 抑制剂,能选择性地抑制间皮瘤细胞中 TEAD 结合蛋白(尤其是 YAP/TAZ)的结合。在使用一组间皮瘤细胞系进行的研究中,K-975 对 Hippo 失活的间皮瘤细胞有显著的生长抑制作用,但其中一些细胞系对 K-975 表现出了原发性耐药性。差异基因表达分析表明,对K-975耐药的细胞在K-975存在的情况下表现出MYC信号的激活,MYC过表达的细胞在体外和体内都表现出很强的耐药性。我们的研究揭示了间皮瘤细胞亚群以不依赖TEAD的方式增殖的特征,为成功开发Hippo通路失活的间皮瘤治疗策略提供了重要启示。
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引用次数: 0
All-trans retinoic acid sensitizes epithelial ovarian cancer to PARP inhibition after exposure to cisplatin. 全反式维甲酸使上皮性卵巢癌在暴露于顺铂后对 PARP 抑制敏感。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-16 DOI: 10.1158/1535-7163.MCT-24-0140
Bingjie Mei, Junyang Li, Dengfeng Wang, Lu Feng, Jianming Huang, Guonan Zhang

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Notably, Platinum-based chemotherapy induces resistance of EOC to poly (ADP-ribose) polymerase (PARP) inhibition. However, therapeutic approaches targeting PARP inhibitors (PARPi) resistance remain to be explored. Here, we show that all-trans retinoic acid (ATRA) reduces PARPi resistance-associated EOC cells induced by cisplatin (CDDP) treatment. Clinically applicable ATRA suppressed the outgrowth of CDDP-treated EOC cells both in vitro and in vivo. Moreover, a CDDP treatment followed by niraparib maintenance therapy in combination with ATRA improved the survival of EOC-bearing mice. These phenotypes correlated with PARPi resistant EOC signature, which consists of elevated expression of ALDH1A1, NAMPT, PARP1 and Chk1, as well as elevated NAD+ level-mediated high activity of ALDH1A1 and PARP1. Mechanistically, ATRA down-regulates the expression of these genes and level of intracellular NAD+. Our results suggest that ATRA in conjunction with PARPi represents a promising maintenance therapeutic strategy for EOC.

上皮性卵巢癌(EOC)是最致命的妇科恶性肿瘤。治疗 EOC 的标准疗法是顺铂等铂类化疗。值得注意的是,铂类化疗会诱导 EOC 对多(ADP-核糖)聚合酶(PARP)抑制产生耐药性。然而,针对 PARP 抑制剂(PARPi)耐药性的治疗方法仍有待探索。在这里,我们发现全反式维甲酸(ATRA)可减少顺铂(CDDP)治疗诱导的 PARPi 抗性相关的 EOC 细胞。临床应用的ATRA可抑制CDDP处理的EOC细胞在体外和体内的生长。此外,CDDP治疗后,尼拉帕利与ATRA联合进行维持治疗,可提高EOC小鼠的存活率。这些表型与 PARPi 耐药的 EOC 特征相关,其中包括 ALDH1A1、NAMPT、PARP1 和 Chk1 表达的升高,以及 NAD+ 水平升高介导的 ALDH1A1 和 PARP1 的高活性。从机理上讲,ATRA 下调了这些基因的表达和细胞内 NAD+ 的水平。我们的研究结果表明,ATRA与PARPi联用是一种很有前景的EOC维持治疗策略。
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引用次数: 0
Preclinical Evaluation of Bavdegalutamide (ARV-110), a Novel PROteolysis TArgeting Chimera Androgen Receptor Degrader. 靶向嵌合体雄激素受体降解物Bavdegalutamide (ARV-110)的临床前评价。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-12-13 DOI: 10.1158/1535-7163.MCT-23-0655
Lawrence B Snyder, Taavi K Neklesa, Ryan R Willard, Deborah A Gordon, Jennifer Pizzano, Nicholas Vitale, Kaitlynn Robling, Madeline A Dorso, Walid Moghrabi, Sean Landrette, Richard Gedrich, Sang Hyun Lee, Ian C A Taylor, John G Houston

Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone and enzalutamide) are standard treatments for metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer (mCRPC). However, continual evolution during prostate cancer progression can result in AR alterations (e.g., mutation, amplification, splicing) that can cause tumors to become resistant to these therapies. Bavdegalutamide (ARV-110) is a PROteolysis TArgeting Chimera (PROTAC®) protein degrader that recruits the cereblon-containing E3 ubiquitin ligase to direct the polyubiquitination and subsequent proteasomal degradation of AR. Bavdegalutamide selectively degrades wild-type AR and most clinically relevant mutants with low nanomolar potency. The superiority of the degradation mechanism of action is demonstrated by bavdegalutamide's higher activity relative to the AR antagonist enzalutamide in cell-based systems that assess effects on prostate-specific antigen (PSA) synthesis, prostate cancer cell proliferation, and induction of apoptosis. In an AR-expressing patient-derived xenograft mouse model, bavdegalutamide showed substantial AR degradation and greater tumor growth inhibition compared with enzalutamide. Bavdegalutamide also showed robust tumor growth inhibition in enzalutamide- and abiraterone-resistant prostate cancer animal models and enhanced activity in combination with abiraterone. These promising preclinical data supported clinical development of bavdegalutamide as a potential treatment for patients with prostate cancer. Bavdegalutamide was the first PROTAC protein degrader to enter human clinical trials, specifically in patients with mCRPC in a phase 1/2 study (NCT03888612).

雄激素受体(AR)信号转导是前列腺癌的主要驱动因素,靶向这一通路的药物(如阿比特龙和恩杂鲁胺)是治疗转移性激素敏感性前列腺癌和转移性阉割耐药前列腺癌(mCRPC)的标准疗法。然而,前列腺癌发展过程中的持续演变会导致AR发生改变(如突变、扩增、剪接),从而导致肿瘤对这些疗法产生耐药性。Bavdegalutamide(ARV-110)是一种PROteolysis TArgeting Chimera (PROTAC®)蛋白降解剂,它能招募含有脑隆的E3泛素连接酶,引导AR的多泛素化和随后的蛋白酶体降解。巴夫地加鲁胺能选择性地降解野生型AR和大多数临床相关突变体,药效低至纳摩尔。在评估对前列腺特异性抗原(PSA)合成、前列腺癌细胞增殖和诱导细胞凋亡的影响的细胞系统中,巴夫地加鲁胺的活性高于AR拮抗剂恩杂鲁胺,这证明了降解作用机制的优越性。在表达 AR 的患者异种移植小鼠模型中,与恩扎鲁胺相比,巴夫地加鲁胺显示出大量的 AR 降解和更强的肿瘤生长抑制作用。在恩扎鲁胺和阿比特龙耐药的前列腺癌动物模型中,巴夫地加鲁胺也显示出强大的肿瘤生长抑制作用,与阿比特龙联用时活性更强。这些前景看好的临床前数据支持了巴夫地加鲁胺作为前列腺癌患者潜在治疗药物的临床开发。巴夫地加鲁胺是第一个进入人体临床试验的PROTAC蛋白降解剂,特别是在一项1/2期研究(NCT03888612)中用于mCRPC患者。
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Molecular Cancer Therapeutics
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