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Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer. 胰腺癌患者对致癌 KRAS 抑制剂产生耐药性的机制。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0177
Julien Dilly, Megan T Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D Parent, Connor J Hennessey, Alexander C Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A Uribe, Annan Yang, Kevin S Kapner, Felix P Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M Lopez, Christopher A Bristow, Michael P Kim, Kimal I Rajapakshe, Vahid Bahrambeigi, Jennifer A Roth, Kavita Garg, Paola A Guerrero, Ben Z Stanger, Simona Cristea, Scott W Lowe, Timour Baslan, Eliezer M Van Allen, Joseph D Mancias, Emily Chan, Abraham Anderson, Yuliya V Katlinskaya, Alex K Shalek, David S Hong, Shubham Pant, Jill Hallin, Kenna Anderes, Peter Olson, Timothy P Heffernan, Seema Chugh, James G Christensen, Anirban Maitra, Brian M Wolpin, Srivatsan Raghavan, Jonathan A Nowak, Peter S Winter, Stephanie K Dougan, Andrew J Aguirre

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies. Significance: Acquired resistance may limit the impact of KRAS inhibition in patients with PDAC. Using clinical samples and multiple preclinical models, we define heterogeneous genetic and non-genetic mechanisms of resistance to KRAS inhibition that may guide combination therapy approaches to improve the efficacy and durability of these promising therapies for patients. See related commentary by Marasco and Misale, p. 2018.

KRAS抑制剂对胰腺导管腺癌(PDAC)具有临床疗效,但耐药性也很常见。在接受阿达拉西布或索托拉西布治疗的KRASG12C突变PDAC患者中,PIK3CA和KRAS突变以及KRASG12C、MYC、MET、表皮生长因子受体和CDK6扩增出现了获得性耐药。在用KRASG12D抑制剂MRTX1133治疗的PDAC细胞系和类器官模型中,上皮细胞向间质转化和PI3K-AKT-mTOR信号转导与耐药性有关。MRTX1133治疗KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre(KPC)小鼠模型可使肿瘤深度消退,但最终会出现耐药性,同时伴有Kras、Yap1、Myc和Cdk6/Abcb1a/b的扩增以及耐药性转录程序的共同进化。此外,在 KPC 和 PDX 模型中,间质细胞和基底样细胞状态对 KRAS 抑制的反应比经典状态更强。在 PDAC 小鼠模型中,KRASG12D 抑制与化疗的联合治疗能显著提高肿瘤控制率。总之,这些数据阐明了 KRAS 抑制的共同耐药机制,并支持多种联合治疗策略。
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引用次数: 0
Immunogenicity and Efficacy of Personalized Adjuvant mRNA Cancer Vaccines. 个性化 mRNA 癌症疫苗的免疫原性和疗效。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-1196
Pedro Berraondo, Raquel Cuesta, Miguel F Sanmamed, Ignacio Melero

In this issue, Gainor and colleagues report on the immunogenicity of personalized neoantigen-encoding mRNA vaccines that elicit measurable polyfunctional CD8+ and CD4+ T-cell responses in patients whose tumors have been resected. Reactivity is substantiated to 20% to 30% of the predicted MHC-I and MHC-II epitopes in four patients with NSCLC postsurgically treated with the vaccine alone and in 12 patients with melanoma treated with their individualized vaccines plus pembrolizumab in the context of a phase 1 clinical trial (NCT03313778). See related article by Gainor et al., p. 2209.

在本期杂志中,Gainor及其同事报告了个性化新抗原编码mRNA疫苗的免疫原性,这种疫苗能在肿瘤已切除的患者中引起可测量的多功能CD8+和CD4+T细胞反应。在一项 1 期临床试验(NCT03313778)中,4 名 NSCLC 患者术后单独接种了疫苗,12 名黑色素瘤患者接种了他们的个性化疫苗和 pembrolizumab,证实了他们与 20% 至 30% 的预测 MHC-I 和 MHC-II 表位的反应。参见 Gainor 等人的相关文章,第 2209 页。
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引用次数: 0
ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma. ROR2 调控胰腺肿瘤和腺癌的细胞可塑性
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0137
Simone Benitz, Alec Steep, Malak M Nasser, Jonathan Preall, Ujjwal Mukund Mahajan, Holly McQuithey, Ian Loveless, Erick T Davis, Hui-Ju Wen, Daniel W Long, Thomas Metzler, Samuel Zwernik, Michaela Louw, Donald Rempinski, Daniel J Salas-Escabillas, Sydney M Brender, Linghao Song, Ling Huang, Brian K Theisen, Zhenyu Zhang, Nina G Steele, Ivonne Regel, Filip Bednar, Howard C Crawford

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor PDX1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in a mouse and human. We identified the receptor tyrosine kinase ROR2 as marker of a gastric metaplasia-like identity in pancreas neoplasms. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition. Significance: We discovered the receptor tyrosine kinase ROR2 as an important regulator of cellular identity in pancreatic precancerous lesions and pancreatic cancer. ROR2 drives an aggressive PDAC phenotype and confers resistance to KRAS inhibitors, suggesting that targeting ROR2 will enhance sensitivity to this new generation of targeted therapies. See related commentary by Marasco and Misale, p. 2018.

细胞可塑性是胰腺导管腺癌(PDAC)的一个特征,从正常细胞转化为癌前病变,到与侵袭性和治疗反应相关的癌亚型的发展。我们发现,由转录因子 Pdx1 维持的正常尖腺细胞分化抑制了广泛的胃细胞特性,这种特性在小鼠和人类的变性、瘤变和 PDAC 经典亚型中得以维持。我们发现,受体酪氨酸激酶 Ror2 是胰腺肿瘤中胃扁平化样特征的标志物。在小鼠胰腺肿瘤发生模型中,Ror2的消减促进了向胃凹陷细胞身份的转换,这种转换在进展为经典亚型PDAC时基本持续。在人类和小鼠胰腺癌中,ROR2的活性继续拮抗胃凹陷细胞特性,强烈促进上皮细胞向间充质细胞的转变,使其对KRAS抑制产生抵抗力,并易受AKT抑制的影响。
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引用次数: 0
Drugging p53: Barriers, Criteria, and Prospects. 给 p53 下药:障碍、标准和前景。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0837
Huaxin Song, Shujun Xiao, Jiaqi Wu, Min Lu

Pharmacologically targeting tumor suppressors necessitates an unprecedented strategy of restoring, rather than conventionally inhibiting, protein function, and p53, the most commonly mutated protein in cancer, has thus remained undruggable. In this study, we address long-standing misconceptions in the field and gaps in the scientific logic for a p53 function-restoration strategy, identify four barriers for drugging mutant p53, and accordingly propose effectiveness evaluation criteria, clinical-translating norms, and prospects for mutant p53 rescue compounds.

以肿瘤抑制因子为药理靶点需要采取前所未有的策略来恢复而非传统地抑制蛋白质的功能,而 p53 作为癌症中最常见的突变蛋白,却一直无法被药物治疗。在本研究中,我们针对该领域长期存在的误解和 p53 功能恢复策略科学逻辑上的空白,确定了突变 p53 药物治疗的四个障碍,并据此提出了有效性评估标准、临床转化规范和突变 p53 挽救化合物的前景。
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引用次数: 0
Rational Protein Engineering to Enhance MHC-Independent T-cell Receptors. 通过合理的蛋白质工程来增强不依赖于 MHC 的 T 细胞受体。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-23-1393
Ju-Fang Chang, Jack H Landmann, Tien-Ching Chang, Mehmet Emrah Selli, Yangdon Tenzin, John M Warrington, Julie Ritchey, Yu-Sung Hsu, Michael Slade, Deepesh Kumar Gupta, John F DiPersio, Alex S Holehouse, Nathan Singh

Chimeric antigen receptor (CAR)-based therapies have pioneered synthetic cellular immunity but remain limited in their long-term efficacy. Emerging data suggest that dysregulated CAR-driven T-cell activation causes T-cell dysfunction and therapeutic failure. To re-engage the precision of the endogenous T-cell response, we designed MHC-independent T-cell receptors (miTCR) by linking antibody variable domains to T-cell receptor constant chains. Using predictive modeling, we observed that this standard "cut and paste" approach to synthetic protein design resulted in myriad biochemical conflicts at the hybrid variable-constant domain interface. Through iterative modeling and sequence modifications, we developed structure-enhanced miTCRs which significantly improved receptor-driven T-cell function across multiple tumor models. We found that 41BB costimulation specifically prolonged miTCR T-cell persistence and enabled improved leukemic control in vivo compared with classic CAR T cells. Collectively, we have identified core features of hybrid receptor structure responsible for regulating function. Significance: Improving the durability of engineered T-cell immunotherapies is critical to enhancing efficacy. We used a structure-informed design to evolve improved miTCR function across several models. This work underscores the central role of synthetic receptor structure in T-cell function and provides a framework for improved receptor engineering.

基于嵌合抗原受体(CAR)的疗法开创了合成细胞免疫疗法,但其长期疗效仍然有限。新出现的数据表明,CAR 驱动的 T 细胞活化失调会导致 T 细胞功能障碍和治疗失败。为了重新精确激活内源性 T 细胞反应,我们将抗体可变域与 TCR 常链连接,设计出了不依赖 MHC 的 T 细胞受体(miTCRs)。通过预测建模,我们发现这种标准的 "剪切和粘贴 "合成蛋白质设计方法会在可变结构域与恒定结构域的混合界面上产生无数的生化冲突。通过迭代建模和序列修改,我们开发出了结构增强型 miTCR,在多个肿瘤模型中显著改善了受体驱动的 T 细胞功能。我们发现,与传统的 CAR T 细胞相比,41BB 成本刺激特异性地延长了 miTCR T 细胞的存活时间,并改善了体内的白血病控制。总之,我们确定了混合受体结构中负责调节功能的核心特征。
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引用次数: 0
T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study. 个体化新抗原疗法 mRNA-4157 (V940) 单独或与 Pembrolizumab 联用的 T 细胞反应在 KEYNOTE-603 1 期研究中。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0158
Justin F Gainor, Manish R Patel, Jeffrey S Weber, Martin Gutierrez, Julie E Bauman, Jeffrey M Clarke, Ricklie Julian, Aaron J Scott, Jessica L Geiger, Kedar Kirtane, Celine Robert-Tissot, Brandon Coder, Moomal Tasneem, Jing Sun, Wei Zheng, Lauren Gerbereux, Andressa Laino, Filippos Porichis, Jack Russella Pollard, Peijie Hou, Vasudha Sehgal, Xing Chen, Manju Morrissey, Hikmat N Daghestani, Igor Feldman, Lakshmi Srinivasan, Joshua P Frederick, Michelle Brown, Praveen Aanur, Robert Meehan, Howard A Burris

mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors. See related commentary by Berraondo et al., p. 2021.

mRNA-4157(V940)是一种个体化新抗原疗法(INT),它以多达34种患者特异性肿瘤新抗原为靶点,诱导T细胞反应并增强抗肿瘤活性。我们报告了在切除的非小细胞肺癌患者(A部分:1毫克mRNA-4157,n = 4)或切除的皮肤黑色素瘤患者(D部分:1毫克mRNA-4157 + 200毫克pembrolizumab,n = 12)中进行的首次人体1期KEYNOTE-603研究(NCT03313778)中T细胞对新抗原反应的表征,从机理上揭示了mRNA-4157的免疫原性。对安全性、耐受性和免疫原性进行了评估。所有患者都出现了≥1次治疗突发不良事件(AE);没有出现4/5级AE或剂量限制性毒性反应。联合治疗后,可观察到持续的mRNA-4157诱导的新抗原特异性T细胞反应以及细胞毒性CD8和CD4 T细胞的扩增。这些发现显示了新型 mRNA INT 方法在肿瘤学中的潜力。
{"title":"T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study.","authors":"Justin F Gainor, Manish R Patel, Jeffrey S Weber, Martin Gutierrez, Julie E Bauman, Jeffrey M Clarke, Ricklie Julian, Aaron J Scott, Jessica L Geiger, Kedar Kirtane, Celine Robert-Tissot, Brandon Coder, Moomal Tasneem, Jing Sun, Wei Zheng, Lauren Gerbereux, Andressa Laino, Filippos Porichis, Jack Russella Pollard, Peijie Hou, Vasudha Sehgal, Xing Chen, Manju Morrissey, Hikmat N Daghestani, Igor Feldman, Lakshmi Srinivasan, Joshua P Frederick, Michelle Brown, Praveen Aanur, Robert Meehan, Howard A Burris","doi":"10.1158/2159-8290.CD-24-0158","DOIUrl":"10.1158/2159-8290.CD-24-0158","url":null,"abstract":"<p><p>mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors. See related commentary by Berraondo et al., p. 2021.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2209-2223"},"PeriodicalIF":29.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma. 肺腺癌的 N6-甲基腺苷表转录组图谱
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-23-1212
Shiyan Wang, Yong Zeng, Lin Zhu, Min Zhang, Lei Zhou, Weixiong Yang, Weishan Luo, Lina Wang, Yanming Liu, Helen Zhu, Xin Xu, Peiran Su, Xinyue Zhang, Musaddeque Ahmed, Wei Chen, Moliang Chen, Sujun Chen, Mykhaylo Slobodyanyuk, Zhongpeng Xie, Jiansheng Guan, Wen Zhang, Aafaque Ahmad Khan, Shingo Sakashita, Ni Liu, Nhu-An Pham, Paul C Boutros, Zunfu Ke, Michael F Moran, Zongwei Cai, Chao Cheng, Jun Yu, Ming S Tsao, Housheng H He

Comprehensive N6-methyladenosine (m6A) epitranscriptomic profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 nonneoplastic lung tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptomic, proteomic, and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with nonneoplastic lung tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hypermethylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics by interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small-molecule inhibitor markedly diminished both EML4 m6A and protein abundance and efficiently suppressed lung metastases in vivo. Significance: Our study reveals a dynamic and functional epitranscriptomic landscape in LUAD, offering a valuable resource for further research in the field. We identified EML4 hypermethylation as a key driver of tumor metastasis, highlighting a novel therapeutic strategy of targeting EML4 to prevent LUAD metastasis.

对原发性肿瘤进行全面的 m6A 表转录组分析在很大程度上仍是未知的。在这里,我们分析了 10 个非肿瘤性肺(NL)组织和 51 个肺腺癌(LUAD)肿瘤的 m6A 表转录组,整合了相应的转录组、蛋白质组和大量临床注释。我们发现了通过 m6A 修饰与疾病进展密切相关的基因簇和基因。与 NL 组织相比,我们发现肿瘤中有 430 个转录本发生低甲基化,222 个发生高甲基化。m6A修饰促进了EML4的翻译,导致其在原发性肿瘤中广泛过表达。在功能上,EML4通过与ARPC1A相互作用来调节细胞骨架动力学,从而增强纤毛形成、细胞运动、局部侵袭和转移。在临床上,高EML4蛋白丰度与转移特征相关。METTL3小分子抑制剂可显著降低EML4 m6A和蛋白丰度,并有效抑制体内肺转移。
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引用次数: 0
Targeting Noncoding cis-Regulatory Elements for Cancer Therapy in the Context of the 3D Genome. 在三维基因组背景下瞄准非编码顺式调控元件治疗癌症
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0836
Kailong Li, Gong-Hong Wei, Yuxin Yin, Jiawen Feng

Significant efforts have been made to identify and validate oncoproteins and ncRNAs as therapeutic targets for cancer therapy; however, emerging observations suggest that noncoding cis-regulatory elements, which orchestrate the 3D organization of the genome and thus the transcriptional landscape, are potential therapeutic targets as well. In this commentary, we envisage that further efforts to decipher the noncoding cis-regulatory code and performing systematic surveys of functional noncoding cis-regulatory elements and recurrent 3D genome alterations in both cancerous and nonmalignant cells within tumor tissues will pave the way to the development of novel therapeutic strategies.

我们已经做出了巨大努力来识别和验证肿瘤蛋白和 ncRNA,并将其作为癌症治疗的靶点;然而,新出现的观察结果表明,非编码顺式调控元件也是潜在的治疗靶点,它们协调了基因组的三维组织,从而协调了转录格局。在这篇评论中,我们设想进一步努力破译非编码顺式调控密码,并对肿瘤组织内癌细胞和非癌细胞中的功能性非编码顺式调控元件和反复出现的三维基因组改变进行系统调查,这将为开发新型治疗策略铺平道路。
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引用次数: 0
Combination Diagnostics: Adding Blood-Based ctDNA Screening to Low-Dose CT Imaging for Early Detection of Lung Cancer. 联合诊断:在低剂量 CT 成像中加入基于血液的 ctDNA 筛查以早期检测肺癌。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-1195
Daniel A Haber, Steven J Skates

Annual low-dose CT screening of individuals with a smoking history identifies early curable lung tumors and reduces cancer mortality by 20%, yet only a minority of eligible patients undergo such monitoring. Mazzone and colleagues apply a blood-based cfDNA fragmentomic assay as a high-sensitivity/low-specificity pre-screen to help stratify individuals who may benefit most from more definitive low-dose CT imaging. See related article by Mazzone et al., p. 2224.

每年对有吸烟史的人进行低剂量 CT 筛查可以发现早期可治愈的肺部肿瘤,并将癌症死亡率降低 20%,但只有少数符合条件的患者接受了这种监测。Mazzone 及其同事将基于血液的 cfDNA 片段组测定作为一种高灵敏度/低特异性的预筛查方法,帮助对可能从更明确的低剂量 CT 成像中获益最多的人进行分层。请参阅 Mazzone 等人的相关文章,第 2224 页。
{"title":"Combination Diagnostics: Adding Blood-Based ctDNA Screening to Low-Dose CT Imaging for Early Detection of Lung Cancer.","authors":"Daniel A Haber, Steven J Skates","doi":"10.1158/2159-8290.CD-24-1195","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1195","url":null,"abstract":"<p><p>Annual low-dose CT screening of individuals with a smoking history identifies early curable lung tumors and reduces cancer mortality by 20%, yet only a minority of eligible patients undergo such monitoring. Mazzone and colleagues apply a blood-based cfDNA fragmentomic assay as a high-sensitivity/low-specificity pre-screen to help stratify individuals who may benefit most from more definitive low-dose CT imaging. See related article by Mazzone et al., p. 2224.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 11","pages":"2025-2027"},"PeriodicalIF":29.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Early Cancer Detection Through Comprehensive Mapping of Dynamic Tumorigenesis. 通过全面绘制动态肿瘤发生图早期发现癌症
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1158/2159-8290.CD-24-0831
Jiang Chang, Tongsen Zheng, Chen Wu

Current strategies for early cancer detection and diagnosis need updating to achieve greater precision, necessitating the creation of a comprehensive evolutionary map of tumorigenesis. This requires establishing high-quality prospective cohorts, systematically collecting samples for integrated spatiotemporal multiomics analyses, and efficiently translating laboratory findings into clinical applications.

目前的早期癌症检测和诊断策略需要更新,以实现更高的精确度,这就需要绘制一张全面的肿瘤发生进化图。这就需要建立高质量的前瞻性队列,系统地收集样本进行综合时空多组学分析,并有效地将实验室研究结果转化为临床应用。
{"title":"Early Cancer Detection Through Comprehensive Mapping of Dynamic Tumorigenesis.","authors":"Jiang Chang, Tongsen Zheng, Chen Wu","doi":"10.1158/2159-8290.CD-24-0831","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0831","url":null,"abstract":"<p><p>Current strategies for early cancer detection and diagnosis need updating to achieve greater precision, necessitating the creation of a comprehensive evolutionary map of tumorigenesis. This requires establishing high-quality prospective cohorts, systematically collecting samples for integrated spatiotemporal multiomics analyses, and efficiently translating laboratory findings into clinical applications.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 11","pages":"2037-2040"},"PeriodicalIF":29.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Cancer discovery
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