来自杂志 Cancer cell 的文献。
当前共找到 14 篇文献分享。
1.
陆一幺
(2024-01-31 14:48):
#paper Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma, Cancer cell vol. 42,1 (2024): 135-156.e17. doi:10.1016/j.ccell.2023.11.010 本文利用基因组、转录组、单细胞转录组和空转,包括数字病理等多组学联合测序技术,对肝癌组织样本进行了转移机制的探索:1.肝癌瘤内异质性和进化轨迹:PT和MT病灶基因组层面比较类似(包括CNA层面),肝外转移主要是单中心谱系播种的,而非多中心模式,且来源比较多样化。多克隆播种方式预后会更差。2.低氧信号促进多克隆扩散:富含低氧信号的原发肿瘤被发现促进了多克隆扩散。3.新抗原异质性与T细胞反应性降低:转移肿瘤中观察到的显著肿瘤内新抗原异质性与T细胞反应性降低相关。可能是由于转移肿瘤细胞进化出了抗原递呈缺陷的能力。4.亚克隆选择机制:在亚克隆选择机制的研究中发现,没有Wnt突变的亚克隆显示出比有Wnt突变的亚克隆更强的转移选择性优势。此外,没有Wnt突变的转移肿瘤表现出更多的免疫抑制B细胞,这些B细胞通过HLA-E:CD94-NKG2A免疫检查点轴介导CD8+ T细胞的终末耗竭。 文章工作量非常大,但故事性非常好,值得精读。
Abstract:
Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in …
>>>
Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8 T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.
<<<
翻译
2.
张贝
(2023-09-30 13:45):
#paper Serial assessment of measurable residual disease in medulloblastoma liquid biopsies Cancer Cell. 2021 Nov 8;39(11):1519-1530.e4.髓母细胞瘤(Medulloblastoma,MB)是一种恶性的儿童胚胎中枢神经系统肿瘤,近三分之一的MB儿童死于这种疾病。通过影像学和脑脊液(CSF)细胞学进行常规反应监测仍然具有挑战性,并且缺乏可检测MRD的标志物。本文使用来自CSF的cfDNA作为MRD生物标志物,前瞻性验证从MB儿童(123名患者,476个样本)收集的CSF样本中的临床效用。使用低深度全基因组测序,研究了来自CSF的cfDNA中肿瘤相关拷贝数的变化。在基线时分别在85%和54%的转移性和局限性疾病患者中检测到MRD。MRD阳性患者的数量随着治疗的进行而下降,但那些持续性MRD阳性的患者有更高的进展风险。该研究阐释了cfDNA检测的疾病预测价值和诊断价值。
IF:48.800Q1
Cancer cell,
2021-11-08.
DOI: 10.1016/j.ccell.2021.09.012
PMID: 34678152
PMCID:PMC9620970
Abstract:
Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging, and …
>>>
Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging, and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients declines with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.
<<<
翻译
3.
小小小小小小萌
(2023-04-30 22:02):
#paper doi: 10.1016/j.ccell.2023.03.008 Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-b activation. 该研究对小鼠静脉注射乳腺癌细胞并待其转移7天,用化疗药物处理后,检测比较了肺部的细胞变化情况,结果发现对于肿瘤肺转移小鼠,化疗会导致肺部中性粒细胞增多。当用Ly6G抗体清除掉中性粒细胞之后,化疗效果又得到了显著增强。血液中的中性粒细胞通过形成NET以杀害微生物,该研究还表明了抑制NET可以增强化疗效果。最后解释了化疗促进NET 形成的生物学机制。
Abstract:
Metastasis is the major cause of cancer death, and the development of therapy resistance is common. The tumor microenvironment can confer chemotherapy resistance (chemoresistance), but little is known about how …
>>>
Metastasis is the major cause of cancer death, and the development of therapy resistance is common. The tumor microenvironment can confer chemotherapy resistance (chemoresistance), but little is known about how specific host cells influence therapy outcome. We show that chemotherapy induces neutrophil recruitment and neutrophil extracellular trap (NET) formation, which reduces therapy response in mouse models of breast cancer lung metastasis. We reveal that chemotherapy-treated cancer cells secrete IL-1β, which in turn triggers NET formation. Two NET-associated proteins are required to induce chemoresistance: integrin-αvβ1, which traps latent TGF-β, and matrix metalloproteinase 9, which cleaves and activates the trapped latent TGF-β. TGF-β activation causes cancer cells to undergo epithelial-to-mesenchymal transition and correlates with chemoresistance. Our work demonstrates that NETs regulate the activities of neighboring cells by trapping and activating cytokines and suggests that chemoresistance in the metastatic setting can be reduced or prevented by targeting the IL-1β-NET-TGF-β axis.
<<<
翻译
4.
大勇
(2023-04-30 21:33):
#paper Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T cell immunity. Cancer Cell. 2021 Jul 12;39(7):973-988.e9. doi: 10.1016/j.ccell.2021.05.006. Epub 2021 Jun 10. PMID: 34115989; PMCID: PMC9115604.文章的概念比较新颖,探究了腹腔转移肿瘤对免疫检查点抑制剂耐药的相关机制,找到了体腔驻留的TIM4阳性的巨噬细胞在其中发挥的影响,利用TIM4阳性的巨噬细胞与CD8+CD39+T细胞的相互作用,阐释了体腔驻留巨噬细胞可以抑制CD8T细胞的功能,并且TIM4单抗可以与PD1单抗联合用药治疗肿瘤,提高疗效。
Abstract:
Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the …
>>>
Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8 T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer. We mechanistically demonstrate that viable and cytotoxic anti-tumor CD8 T cells upregulate PS and this renders them susceptible to sequestration away from tumor targets and proliferation suppression by Tim-4 macrophages. Tim-4 blockade abrogates this sequestration and proliferation suppression and enhances anti-tumor efficacy in models of anti-PD-1 therapy and adoptive T cell therapy in mice. Thus, Tim-4 cavity-resident macrophages limit the efficacy of immunotherapies in these microenvironments.
<<<
翻译
5.
大勇
(2023-02-28 23:35):
#paper CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell. 2022 Apr 11;40(4):365-378.e6. doi: 10.1016/j.ccell.2022.02.003. Epub 2022 Feb 24.
这篇文献主要讲述了CD8+T细胞通过分泌内源性的IFNγ,可以作用与肿瘤细胞,引起ACSL4的表达升高,与花生四烯酸协同促进肿瘤的脂质代谢并诱导肿瘤细胞铁死亡,在此过程中,可以促进肿瘤对免疫检查点抑制剂的疗效。
Abstract:
Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ferroptosis, serving as a mode of …
>>>
Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ferroptosis, serving as a mode of action for CD8 T cell (CTL)-mediated tumor killing. Mechanistically, IFNγ stimulates ACSL4 and alters tumor cell lipid pattern, thereby increasing incorporations of AA into C16 and C18 acyl chain-containing phospholipids. Palmitoleic acid and oleic acid, two common C16 and C18 fatty acids in blood, promote ACSL4-dependent tumor ferroptosis induced by IFNγ plus AA. Moreover, tumor ACSL4 deficiency accelerates tumor progression. Low-dose AA enhances tumor ferroptosis and elevates spontaneous and immune checkpoint blockade (ICB)-induced anti-tumor immunity. Clinically, tumor ACSL4 correlates with T cell signatures and improved survival in ICB-treated cancer patients. Thus, IFNγ signaling paired with selective fatty acids is a natural tumor ferroptosis-promoting mechanism and a mode of action of CTLs. Targeting the ACSL4 pathway is a potential anti-cancer approach.
<<<
翻译
6.
洪媛媛
(2022-11-29 16:40):
#paper https://doi.org/10.1016/j.ccell.2022.10.022 Cancer Cell 2022. Evaluation of cell-free DNA approaches for multi-cancer early detection. 这篇文章介绍了Grail CCGA研究的substudy 1结果。比较了WGBS平台的全基因组甲基化、基因靶向测序平台的SNV和白细胞配对SNV、WGS平台的拷贝数变异、白细胞配对拷贝数变异、片段末端、片段长度、等位基因不平衡和临床特征,这些不同方法的性能,结果显示不管在训练集还是验证集,全基因组甲基化在癌症检测性能和肿瘤溯源能力上最好,衍生出来的甲基化靶向测序使用于CCGA substudy 2和3。
Abstract:
In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection …
>>>
In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection (LOD) based on circulating tumor allele fraction (cTAF), enabling performance comparisons. Among 10 machine-learning classifiers trained on the same samples and independently validated, when evaluated at 98% specificity, those using whole-genome (WG) methylation, single nucleotide variants with paired white blood cell background removal, and combined scores from classifiers evaluated in this study show the highest cancer signal detection sensitivities. Compared with clinical stage and tumor type, cTAF is a more significant predictor of classifier performance and may more closely reflect tumor biology. Clinical LODs mirror relative sensitivities for all approaches. The WG methylation feature best predicts cancer signal origin. WG methylation is the most promising technology for MCED and informs development of a targeted methylation MCED test.
<<<
翻译
7.
惊鸿
(2022-09-27 09:09):
#paper doi:Volume 40, Issue 9, 12 September 2022, Pages 999-1009.e6Detection and localization of early- and late-stage cancers using platelet 这篇论文解释了RNA癌症患者受益于早期肿瘤检测,因为治疗结果对不太晚期的癌症更有利。血小板参与癌症进展,被认为是癌症检测的有前途的生物来源,因为它们根据局部和全身线索改变其RNA含量。我们表明,基于肿瘤的血小板(TEP)RNA血液测试能够检测18种癌症类型。血栓形成Seq在无症状对照组的特异性为99%,在I-IV期癌症患者的1,096份血液样本中有三分之二和352名I-III期肿瘤中的一半中正确检测到癌症的存在。对症对照组,包括炎症和心血管疾病以及良性肿瘤,假阳性检测结果增加,平均特异性为78%。此外,血栓形成Seq在超过80%的癌症患者中正确确定了五种不同肿瘤类型的肿瘤起源部位。这些结果突出了TEP衍生的RNA组合的潜在特性,以补充当前基于血液的癌症筛查方法。
Abstract:
Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for …
>>>
Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.
<<<
翻译
8.
颜林林
(2022-08-12 07:42):
#paper doi:10.1016/j.ccell.2022.07.002 Cancer Cell, 2022, Integrative analysis of drug response and clinical outcome in acute myeloid leukemia. 这是一项关于AML(急性骨髓性白血病)的长达10年的真实世界临床研究,收集了来自多个中心的 805 名患者(942 个样本),对样本进行基因组和转录组的测序,同时使用离体细胞培养进行药物反应实验,此外还利用NLP技术整理和分析患者的病历数据。在数据分析方面,使用反卷积方法,通过转录组数据推断出样本的细胞类群组成,并结合临床信息和组学数据分析结果,识别出影响药物响应情况的因素(如年龄、基因表达、细胞分化状态等)。所建立的模型,揭示了单个基因 PEAR1 是患者生存的最强预测因子之一。所形成的数据集,也提供了一个在线交互式网站进行分析展示。分析方面基本都是很多生信数据挖掘类文章的常见套路,并没有特别新颖之处,但得益于长时间积累的队列及其完整的临床信息,作为一个重要的数据集资源,以及单病种的真实世界研究实例,也还是很有价值的。此外,关于药物响应的细胞实验部分相对独立,与患者预后进行关联解释并不容易,大概也是为了提升文章份量而加入的。
Abstract:
Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large …
>>>
Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.
<<<
翻译
9.
翁凯
(2022-07-31 08:58):
#paper doi:10.1016/j.ccell.2015.09.018 Cancer Cell, 2015, RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics. 发现血小板携带的mRNA可以预测(准确率96%)是否患癌,并且可以进一步预测(准确率74%)原发组织。
Abstract:
Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs …
>>>
Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based "liquid biopsies".
<<<
翻译
10.
颜林林
(2022-07-31 07:26):
#paper doi:10.1016/j.ccell.2022.07.003 Cancer Cell, 2022, Dark genome, bright ideas: Recent approaches to harness transposable elements in immunotherapies. 占比达到近一半人类基因组的转座元件(transposable element,TE)是个需要继续深入研究的存在。这篇评论文章,快速综述了有关TE与免疫之间的关系,如TE具备的免疫原性,它能激活 DNA 或 RNA 的传感器,也能引发免疫系统反应,从而可能形成新的免疫治疗方法。本文相继描述了 TE 表达对抗肿瘤免疫的影响,以及如何通过介导 TE 表达、介导 TE 免疫原性、辅助 CAR-T 细胞等方式,来实现对肿瘤开展免疫治疗。补充点个人想法:在 DNA 水平上研究各类重复片段,一直是相当困难的,这也是这些序列区间通常被称为“dark genome”(暗黑基因组)的原因;这种困难类似于想要通过地面的投影去反推空中漂浮的大量物件,许多物件的投影彼此重叠而无法区分;而所幸新技术让我们能从长读长、多组学等角度,开始一层层剥开迷雾。
Abstract:
Transposable elements (TEs), which make up almost half of the human genome, often display altered expression in cancers. Here, we review recent progress in elucidating the role of TEs as …
>>>
Transposable elements (TEs), which make up almost half of the human genome, often display altered expression in cancers. Here, we review recent progress in elucidating the role of TEs as mediators of immune responses in cancer and discuss how novel therapeutic strategies can harness TE immunogenicity for cancer immunotherapy.
<<<
翻译
11.
颜林林
(2022-05-29 23:45):
#paper doi:10.1016/j.ccell.2022.05.005 Cancer Cell, 2022, Redefining breast cancer subtypes to guide treatment prioritization and maximize response: Predictive biomarkers across 10 cancer therapies. 这篇论文是关于一项正在进行的、开放标签、适应性、随机II期、多中心的临床试验(NCT01042379)I-SPY2。该临床试验入组高危II期和III期乳腺癌患者,并用70基因MammaPrint测试来排除其中无法从化疗获益的患者,将她们随机分配到10个不同用药组,并在手术前的新辅助治疗期间的不同时间点,进行MRI检查、穿刺取样和/或外周血采集,新辅助治疗前的穿刺样本,同时开展了基因表达芯片、蛋白磷酸化和免疫组化/原位杂交的检测。通过这些检测数据和患者用药响应结果,本研究对入组的987例患者做了重新分类,定义出五种亚型:HER2-/Immune-/DRD-、HER2-/Immune+、HER2-/Immune-/DRD+、HER2+/BP-HER2_or_Basal及HER2+/BP-Luminal。这个重定义过程,除了纳入传统定义所采用的HR/HER2状态外,也包含了诸如增值、DRD、免疫等其他表型特征,在确保分型区分选取最佳治疗方案,即获得最高的pCR(病理完全缓解)的概率,同时也兼顾检测平台稳健性和临床实施简单。虽然目前每个单臂上的病例数还并不算特别多,但相信随着该临床试验的持续开展和更多病例数据的积累,这项研究将优化出相比当前指南建议更好的治疗决策路径。而相应的研究方法和数据分析套路,也预期可以套用到其他癌种上,并在各类高通量多组学检测方法快速发展的今天,持续产出更多精准医疗实践应用。
Abstract:
Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and …
>>>
Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from ∼990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization.
<<<
翻译
12.
颜林林
(2022-04-30 18:41):
#paper doi:10.1016/j.ccell.2022.04.002 Cancer Cell, 2022, The translational challenges of precision oncology. 这是一篇新近发表在Cancer Cell上的关于精准肿瘤学(precision oncology)的综述。所谓精准肿瘤学,是指基于肿瘤分子特征进行肿瘤诊治决策。这篇综述回顾了与肿瘤分子特征相关的研究历史和当前研究进展,从肿瘤发生、肿瘤预防、早期检测、新辅助治疗、微小病变残留监测、药物耐受、肿瘤演化过程、肿瘤转移等诊治不同阶段环节,讨论了相应重要分子特征的发现及应用。本文对于目前在肿瘤基因检测行业中涉及到的各类应用,包括涉及的临床队列研究和相关资源,都有提及,整体上内容全面、逻辑脉络清晰。比较适合初学者,快速了解这个方向的产业应用和临床应用,并强烈建议可追溯其参考文献,对各个具体应用场景,进行深入探索和学习。
Abstract:
The translational challenges in the field of precision oncology are in part related to the biological complexity and diversity of this disease. Technological advances in genomics have facilitated large sequencing …
>>>
The translational challenges in the field of precision oncology are in part related to the biological complexity and diversity of this disease. Technological advances in genomics have facilitated large sequencing efforts and discoveries that have further supported this notion. In this review, we reflect on the impact of these discoveries on our understanding of several concepts: cancer initiation, cancer prevention, early detection, adjuvant therapy and minimal residual disease monitoring, cancer drug resistance, and cancer evolution in metastasis. We discuss key areas of focus for improving cancer outcomes, from biological insights to clinical application, and suggest where the development of these technologies will lead us. Finally, we discuss practical challenges to the wider adoption of molecular profiling in the clinic and the need for robust translational infrastructure.
<<<
翻译
13.
吴增丁
(2022-03-07 16:08):
#paper doi: 10.1016/j.ccell.2022.01.007 这篇张力和沈琳于2022年1月份发表在Cancer Cell上的一篇letter,题目是《Time to raise the bar: Transition rate of phase 1 programs on anticancer drugs》。
这篇文章的核心主题正如文章标题:一期临床的研发药物太多了,需要提高进入一期临床的门槛。
1.文章通过分析在中国的于2012-2020年期间进入一期临床的413个抗肿瘤药物(剔除了生物仿制药和非专利药)各期临床的成功率、通过率、叫停率,发现最终NMPA通过批准比例是5.8%,相比FDA通过率5.3%差异不大。但是和上一个十年(13.2%)比降低了很多;
2.分析其中的原因:a. 近十年的肿瘤药物更多是分析靶向药(MTA)和免疫抑制剂药(IO),这些药物相比之前的化疗药物,其药效和安全性上面没有更多直接的关系,药效也更加复杂,增加了不少不可控因素;b. 另外在中国有很多ME-Too药物,这些药物最终不能很好证明优于其它药物导致不能获批;
3.对比分析ME-Too 和First-in-Class药物,first-in-class药物具有更高的通过率。而且First-in-class药物一遍具有更深的pre-clinical和研究,而且在first-in-human的临床研究中更多会采用全球多中心、大cohort、biomarker-enriched的patient筛选的方法,这些方法也更有利于药物最终获批。
所以文章最终观点是:呼吁加深pre-clinical的深入研究,同时在法规上提高进入临床实验的门槛。
Abstract:
No abstract available.
14.
Donny
(2022-01-22 21:24):
#paper doi:10.1016/j.ccell.2021.04.014 Conserved pan-cancer microenvironment subtypes predict response to immunotherapy
这是一篇MD Anderson和Boston Gene去年做的泛癌免疫分型的论文,作者先定义了20多个涉及肿瘤免疫相关特征的基因集,然后使用UCSC Xena的TCGA多种瘤种样本的TOIL RSEM标准化后的基因表达数据,使用ssGSEA算法计算特征基因集的富集打分,并针对瘤种内样本进行MAD标准化,并使用Louvain聚类进而将所有样本分为四大免疫亚型,分别是:免疫富集型、免疫富集纤维化型、纤维化型和免疫沙漠型。这四种分型依次表现为免疫浸润减少,免疫原性降低。这四个分型同时和之前所做的TCIA数据库的6种亚型分型基本一致,也从通路活性、关键肿瘤免疫指标、生存分析、HE免疫细胞数量、临床免疫治疗队列疗效等进行了多方面的佐证。
Abstract:
The clinical use of molecular targeted therapy is rapidly evolving but has primarily focused on genomic alterations. Transcriptomic analysis offers an opportunity to dissect the complexity of tumors, including the …
>>>
The clinical use of molecular targeted therapy is rapidly evolving but has primarily focused on genomic alterations. Transcriptomic analysis offers an opportunity to dissect the complexity of tumors, including the tumor microenvironment (TME), a crucial mediator of cancer progression and therapeutic outcome. TME classification by transcriptomic analysis of >10,000 cancer patients identifies four distinct TME subtypes conserved across 20 different cancers. The TME subtypes correlate with patient response to immunotherapy in multiple cancers, with patients possessing immune-favorable TME subtypes benefiting the most from immunotherapy. Thus, the TME subtypes act as a generalized immunotherapy biomarker across many cancer types due to the inclusion of malignant and microenvironment components. A visual tool integrating transcriptomic and genomic data provides a global tumor portrait, describing the tumor framework, mutational load, immune composition, anti-tumor immunity, and immunosuppressive escape mechanisms. Integrative analyses plus visualization may aid in biomarker discovery and the personalization of therapeutic regimens.
<<<
翻译