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Revisiting mechanisms of resistance to immunotherapies in metastatic clear-cell renal-cell carcinoma. 对转移性透明细胞肾细胞癌免疫治疗耐药机制的研究。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.09
Monica Sheila Chatwal, Jad Chahoud, Philippe E Spiess

Renal-cell carcinoma (RCC) remains a leading cause of cancer-related mortality worldwide. Though newer therapeutic combinations of immune checkpoint inhibitors and targeted therapies have greatly improved outcomes, resistance to these therapies is becoming a challenge for long-term control. Mechanisms of resistance have been explored in a variety of solid tumors, including RCC. Based upon our review of the current literature on the mechanisms of resistance to immunotherapies for the management of metastatic clear-cell renal cell carcinomas (mccRCC), the ensuing conclusions have been made: The management of mccRCC has progressed substantially with the advent of checkpoint inhibitors and targeted oral therapies, alone and/or in combination. Nevertheless, innate or developed resistance to these therapies remains an ongoing challenge, particularly to immune checkpoint inhibitors (ICIs). Several of the known mechanisms of resistance have been well defined, but recent progression in cellular therapies helps to expand the armamentarium of potential combination options that may overcome these modes of resistance and improve long-term disease control and survival for an otherwise dismal disease. In the ensuing review and update of the literature on the mechanisms of resistance to immunotherapies in mccRCC, we have revisited the known resistance mechanisms of immunotherapies in metastatic clear-cell RCC and explored ongoing and future strategies to overcome them.

肾细胞癌(RCC)仍然是世界范围内癌症相关死亡的主要原因。尽管免疫检查点抑制剂和靶向治疗的新治疗组合大大改善了结果,但对这些疗法的耐药性正在成为长期控制的挑战。耐药机制已在多种实体肿瘤中被探索,包括肾细胞癌。基于我们对目前转移性透明细胞肾细胞癌(mccRCC)免疫治疗耐药机制的文献回顾,得出以下结论:随着检查点抑制剂和靶向口服治疗(单独和/或联合)的出现,mccRCC的治疗取得了实质性进展。然而,对这些疗法的先天或发展耐药性仍然是一个持续的挑战,特别是对免疫检查点抑制剂(ICIs)。一些已知的耐药机制已经得到了很好的定义,但最近细胞疗法的进展有助于扩大潜在的联合选择的范围,这些选择可能克服这些耐药模式,并改善长期的疾病控制和其他令人沮丧的疾病的生存。在随后的回顾和更新mccRCC免疫治疗耐药机制的文献中,我们重新审视了转移性透明细胞RCC免疫治疗的已知耐药机制,并探讨了目前和未来克服这些机制的策略。
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引用次数: 0
Remodeling the tumor microenvironment to overcome treatment resistance in HPV-negative head and neck cancer. 重塑肿瘤微环境克服hpv阴性头颈癌的治疗耐药。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.141
Sergi Benavente

Despite intensive efforts and refined techniques, overall survival in HPV-negative head and neck cancer remains poor. Robust immune priming is required to elicit a strong and durable antitumor immune response in immunologically cold and excluded tumors like HPV-negative head and neck cancer. This review highlights how the tumor microenvironment could be affected by different immune and stromal cell types, weighs the need to integrate metabolic regulation of the tumor microenvironment into cancer treatment strategies and summarizes the emerging clinical applicability of personalized immunotherapeutic strategies in HPV-negative head and neck cancer.

尽管付出了巨大的努力和完善的技术,hpv阴性头颈癌的总体生存率仍然很低。在免疫冷淡和排除的肿瘤如hpv阴性头颈癌中,需要强大的免疫启动来引发强烈和持久的抗肿瘤免疫反应。本文重点介绍了不同类型的免疫细胞和基质细胞如何影响肿瘤微环境,权衡了将肿瘤微环境的代谢调节纳入癌症治疗策略的必要性,并总结了个性化免疫治疗策略在hpv阴性头颈癌中的临床适用性。
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引用次数: 1
Major hurdles of immune-checkpoint inhibitors in pancreatic ductal adenocarcinoma. 免疫检查点抑制剂治疗胰腺导管腺癌的主要障碍。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.142
Liia Akhuba, Zhanna Tigai, Dmitrii Shek

In 2030, pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related mortality in the world. Unfortunately, neither conventional chemotherapy nor novel immunotherapeutic strategies can provide durable responses and the survival prognosis remains very low. PDAC is notorious for its immune-resistant features and unique genomic landscape facilitating tumor escape from immunosurveillance. Novel immune-checkpoint inhibitors (ICI) failed to show promising efficacy and other multi-modal approaches are currently being validated in multiple clinical trials. In this paper, we provide our opinion on the major mechanisms responsible for PDAC resistance to ICI therapy and provide our view on future strategies which may overcome those barriers.

到2030年,胰腺导管腺癌(PDAC)将成为全球癌症相关死亡的第二大原因。不幸的是,无论是传统的化疗还是新的免疫治疗策略都不能提供持久的反应,生存预后仍然很低。PDAC因其免疫抵抗特性和独特的基因组景观而臭名昭著,有助于肿瘤逃避免疫监视。新型免疫检查点抑制剂(ICI)未能显示出有希望的疗效,其他多模式方法目前正在多个临床试验中进行验证。在本文中,我们对PDAC对ICI治疗产生耐药性的主要机制提出了我们的观点,并对未来可能克服这些障碍的策略提出了我们的看法。
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引用次数: 0
Concomitant medications and circulating tumor cells: friends or foes? 伴随用药与循环肿瘤细胞:是友是敌?
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.68
Serena Di Cosimo, Vera Cappelletti

The use of concomitant medications by patients with cancer is observed almost globally; however, little attention has been paid to this topic in the medical literature. Most clinical studies do not describe the type and duration of drugs used at the time of inclusion and during treatment or how these drugs may affect the experimental and/or standard therapy. Even less information has been published on the potential interaction between concomitant medications and tumor biomarkers. However, we do know that concomitant drugs can complicate cancer clinical trials and biomarker development, thus contributing to their interaction, leading to side effects, and resulting in suboptimal adherence to anticancer treatment. On the basis of these premises and moving from the study by Jurisova et al., which reported the effect of commonly used drugs on the prognosis of women with breast cancer and the detection of circulating tumor cells (CTCs), we comment on the role of CTCs as an emerging diagnostic and prognostic tool for breast cancer. We also report the known and hypothesized mechanisms of CTC interplay with other tumor and blood components, possibly modulated by widespread drugs, including over-the-counter compounds, and discuss the possible implications of commonly used concomitant medications on CTC detection and clearance. After considering all these points, it is conceivable that concomitant drugs are not necessarily a problem, but on the contrary, their virtuous mechanisms can be exploited to reduce tumor spread and enhance the effect of anticancer therapies.

几乎在全球范围内都观察到癌症患者同时使用药物;然而,在医学文献中很少关注这一主题。大多数临床研究没有描述纳入时和治疗期间使用的药物的类型和持续时间,也没有描述这些药物如何影响实验和/或标准治疗。关于伴随药物与肿瘤生物标志物之间潜在相互作用的信息甚至更少。然而,我们确实知道,伴随药物会使癌症临床试验和生物标志物的开发复杂化,从而导致它们之间的相互作用,导致副作用,并导致抗癌治疗的依从性不理想。基于这些前提,并从Jurisova等人的研究出发,该研究报道了常用药物对乳腺癌女性预后的影响以及循环肿瘤细胞(CTCs)的检测,我们评论了CTCs作为一种新兴的乳腺癌诊断和预后工具的作用。我们还报道了CTC与其他肿瘤和血液成分相互作用的已知和假设机制,可能受到广泛的药物(包括非处方药)的调节,并讨论了常用的伴随药物对CTC检测和清除的可能影响。综上所述,可以想象,伴随药物不一定是一个问题,相反,它们的良性机制可以被利用来减少肿瘤的扩散,增强抗癌治疗的效果。
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引用次数: 0
Recent advances in access to overcome cancer drug resistance by nanocarrier drug delivery system. 纳米载体给药系统攻克癌症耐药途径的最新进展。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.16
Xiangyu Sun, Ping Zhao, Jierou Lin, Kun Chen, Jianliang Shen

Cancer is currently one of the most intractable diseases causing human death. Although the prognosis of tumor patients has been improved to a certain extent through various modern treatment methods, multidrug resistance (MDR) of tumor cells is still a major problem leading to clinical treatment failure. Chemotherapy resistance refers to the resistance of tumor cells and/or tissues to a drug, usually inherent or developed during treatment. Therefore, an urgent need to research the ideal drug delivery system to overcome the shortcoming of traditional chemotherapy. The rapid development of nanotechnology has brought us new enlightenments to solve this problem. The novel nanocarrier provides a considerably effective treatment to overcome the limitations of chemotherapy or other drugs resulting from systemic side effects such as resistance, high toxicity, lack of targeting, and off-target. Herein, we introduce several tumor MDR mechanisms and discuss novel nanoparticle technology applied to surmount cancer drug resistance. Nanomaterials contain liposomes, polymer conjugates, micelles, dendrimers, carbon-based, metal nanoparticles, and nucleotides which can be used to deliver chemotherapeutic drugs, photosensitizers, and small interfering RNA (siRNA). This review aims to elucidate the advantages of nanomedicine in overcoming cancer drug resistance and discuss the latest developments.

癌症是目前导致人类死亡的最棘手的疾病之一。尽管各种现代治疗手段在一定程度上改善了肿瘤患者的预后,但肿瘤细胞的多药耐药(MDR)仍然是导致临床治疗失败的主要问题。化疗耐药性是指肿瘤细胞和/或组织对药物的耐药性,通常是固有的或在治疗期间形成的。因此,迫切需要研究理想的给药系统来克服传统化疗的缺点。纳米技术的迅速发展给我们解决这一问题带来了新的启示。这种新型纳米载体提供了一种相当有效的治疗方法,克服了化疗或其他药物由于耐药、高毒性、缺乏靶向性和脱靶等全身副作用而造成的局限性。在此,我们介绍了几种肿瘤耐多药机制,并讨论了新的纳米颗粒技术应用于克服癌症耐药。纳米材料包含脂质体、聚合物偶联物、胶束、树状大分子、碳基、金属纳米颗粒和核苷酸,可用于输送化疗药物、光敏剂和小干扰RNA (siRNA)。本文旨在阐述纳米医学在克服癌症耐药方面的优势,并讨论其最新进展。
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引用次数: 4
Mechanisms and clinical implications in renal carcinoma resistance: narrative review of immune checkpoint inhibitors. 肾癌耐药的机制和临床意义:免疫检查点抑制剂的叙述性回顾。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.02
Sunil Samnani, Faraz Sachedina, Mehul Gupta, Edward Guo, Vishal Navani

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma. The prognosis for patients with ccRCC has improved over recent years with the use of combination therapies with an anti-programmed death-1 (PD-1) backbone. This has enhanced the quality of life and life expectancy of patients with this disease. Unfortunately, not all patients benefit; eventually, most patients will develop resistance to therapy and progress. Recent molecular, biochemical, and immunological research has extensively researched anti-angiogenic and immune-based treatment resistance mechanisms. This analysis offers an overview of the principles underpinning the resistance pathways related to immune checkpoint inhibitors (ICIs). Additionally, novel approaches to overcome resistance that may be considered for the trial context are discussed.

透明细胞肾细胞癌(ccRCC)是肾细胞癌最常见的组织学亚型。近年来,随着抗程序性死亡-1 (PD-1)主干的联合治疗,ccRCC患者的预后有所改善。这提高了该病患者的生活质量和预期寿命。不幸的是,并非所有患者都能受益;最终,大多数患者会对治疗产生耐药性并取得进展。最近的分子、生化和免疫学研究广泛地研究了抗血管生成和免疫治疗的耐药机制。该分析概述了与免疫检查点抑制剂(ICIs)相关的耐药途径的基本原理。此外,本文还讨论了在试验环境中可能考虑的克服耐药性的新方法。
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引用次数: 0
Nano-TRAIL: a promising path to cancer therapy. 纳米trail:一种有前途的癌症治疗途径。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.82
Siri Chandana Gampa, Sireesha V Garimella, SanthiLatha Pandrangi

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, also called apo-2 ligand (TRAIL/Apo-2L), is a cytokine that triggers apoptosis by binding to TRAIL-R1 (DR4) and TRAIL-R2 (DR5) death receptors. Apoptosis occurs through either the extrinsic or intrinsic pathway. The administration of recombinant human TRAIL (rhTRAIL) or TRAIL-receptor (TRAIL-R) agonists promotes apoptosis preferentially in cancerous cells over normal cells in vitro; this phenomenon has also been observed in clinical studies. The limited efficacy of rhTRAIL in clinical trials could be attributed to drug resistance, short half-life, targeted delivery issues, and off-target toxicities. Nanoparticles are excellent drug and gene delivery systems characterized by improved permeability and retention, increased stability and biocompatibility, and precision targeting. In this review, we discuss resistance mechanisms to TRAIL and methods to overcome TRAIL resistance by using nanoparticle-based formulations developed for the delivery of TRAIL peptides, TRAIL-R agonists, and TRAIL genes to cancer cells. We also discuss combinatorial approaches of chemotherapeutic drugs with TRAIL. These studies demonstrate TRAIL's potential as an anticancer agent.

肿瘤坏死因子相关凋亡诱导配体,也称为载脂蛋白2配体(TRAIL/Apo-2L),是一种通过与TRAIL- r1 (DR4)和TRAIL- r2 (DR5)死亡受体结合而引发细胞凋亡的细胞因子。细胞凋亡可通过外在或内在途径发生。重组人TRAIL (rhTRAIL)或TRAIL-受体(TRAIL- r)激动剂在体外促进癌细胞比正常细胞优先凋亡;这一现象在临床研究中也有发现。rhTRAIL在临床试验中的有限疗效可归因于耐药、半衰期短、靶向给药问题和脱靶毒性。纳米颗粒是一种优良的药物和基因传递系统,其特点是渗透性和保留率提高,稳定性和生物相容性提高,靶向性精确。在这篇综述中,我们讨论了TRAIL的耐药机制,以及通过使用纳米颗粒为基础的配方来克服TRAIL耐药的方法,这些配方用于向癌细胞递送TRAIL肽、TRAIL- r激动剂和TRAIL基因。我们还讨论了化疗药物与TRAIL的联合治疗方法。这些研究证明了TRAIL作为抗癌剂的潜力。
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引用次数: 3
The role of antiangiogenic monoclonal antibodies combined to EGFR-TKIs in the treatment of advanced non-small cell lung cancer with activating EGFR mutations: acquired resistance mechanisms and strategies to overcome them. 抗血管生成单克隆抗体联合表皮生长因子受体-TKIs在治疗表皮生长因子受体活化突变的晚期非小细胞肺癌中的作用:获得性耐药机制及克服策略。
IF 4.6 Q1 ONCOLOGY Pub Date : 2022-11-02 eCollection Date: 2022-01-01 DOI: 10.20517/cdr.2022.77
Danilo Rocco, Luigi Della Gravara, Giovanni Palazzolo, Cesare Gridelli

As of today, only two antiangiogenic monoclonal antibodies plus epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) combinations are FDA and EMA-approved and are recommended by American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network for the first-line treatment of EGFR+ advanced non-small cell lung cancer patients: erlotinib plus bevacizumab and erlotinib plus ramucirumab. However, all treated patients eventually become unresponsive to such drugs, due to several different acquired resistance mechanisms, mainly represented by T790M substitutions and MET amplifications. While osimertinib treatment in T790M+ patients still represents the only approved treatment, MET-TKIs will likely change this status quo in the near future. In fact, existing clinical data strongly support a role for MET-TKI-based combinations in EGFR+ MET-amplified patients, possibly revolutionizing our current treatment algorithm. Chemotherapy plus immunotherapy plus antiangiogenic therapy combinations could also represent another useful addition.

截至目前,仅有两种抗血管生成单克隆抗体加表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)的组合获得了美国食品药品管理局(FDA)和欧洲药品管理局(EMA)的批准,并被美国临床肿瘤学会、欧洲肿瘤内科学会和美国国家综合癌症网络推荐用于EGFR+晚期非小细胞肺癌患者的一线治疗:厄洛替尼加贝伐单抗和厄洛替尼加雷莫芦单抗。然而,由于几种不同的获得性耐药机制,主要是以T790M置换和MET扩增为代表的耐药机制,所有接受治疗的患者最终都会对这类药物失去反应。尽管奥希替尼治疗 T790M+ 患者仍是唯一获批的治疗方法,但在不久的将来,MET-TKIs 很可能会改变这一现状。事实上,现有的临床数据有力地支持了以 MET-TKI 为基础的联合疗法在表皮生长因子受体(EGFR)+ MET 扩增患者中的作用,可能会彻底改变我们目前的治疗算法。化疗加免疫治疗加抗血管生成治疗的联合疗法也可能是另一种有益的补充。
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引用次数: 0
Mechanisms of neratinib resistance in HER2-mutant metastatic breast cancer. HER2突变转移性乳腺癌的奈瑞替尼耐药机制
IF 4.6 Q1 ONCOLOGY Pub Date : 2022-09-01 eCollection Date: 2022-01-01 DOI: 10.20517/cdr.2022.48
Lisa D Eli, Shyam M Kavuri

Human epidermal growth factor receptor 2 (HER2) is a major drug target and clinical biomarker in breast cancer treatment. Targeting HER2 gene amplification is one of the greatest successes in oncology, resulting in the use of a wide array of HER2-directed agents in the clinic. The discovery of HER2-activating mutations as novel therapeutic targets in breast and other cancers marked a significant advance in the field, which led to the metastatic breast and other solid tumor trials MutHER (NCT01670877), SUMMIT (NCT01953926), and one arm of plasmaMATCH (NCT03182634). These trials reported initial clinical benefit followed by eventual relapse ascribed to either primary or acquired resistance. These resistance mechanisms are mediated by additional secondary genomic alterations within HER2 itself and via hyperactivation of oncogenic signaling within the downstream signaling axis.

人表皮生长因子受体 2(HER2)是乳腺癌治疗的主要药物靶点和临床生物标志物。以 HER2 基因扩增为靶点是肿瘤学取得的最大成功之一,因此临床上使用了大量 HER2 靶向药物。作为乳腺癌和其他癌症的新型治疗靶点,HER2 激活突变的发现标志着该领域取得了重大进展,并促成了转移性乳腺癌和其他实体瘤试验 MutHER(NCT01670877)、SUMMIT(NCT01953926)和 plasmaMATCH(NCT03182634)的一个臂。这些试验报告了最初的临床获益,但最终因原发性或获得性耐药性而复发。这些耐药机制是由 HER2 本身的其他继发性基因组改变以及下游信号轴的致癌信号超激活介导的。
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引用次数: 0
Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces. 癌症干细胞的抗药性和抗凋亡性:一块块拼图。
IF 4.6 Q1 ONCOLOGY Pub Date : 2022-08-02 eCollection Date: 2022-01-01 DOI: 10.20517/cdr.2022.20
Ahmad R Safa

Resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.

对抗癌药物和细胞凋亡的抵抗导致癌症复发,并与癌症死亡率相关。大量数据提供了令人信服的证据,证明人类癌症是由癌症干细胞(CSCs)产生的,CSCs 具有自我更新能力,对抗癌药物、辐射和细胞凋亡具有抵抗力,并表现出从上皮到间质的强化进展。CSCs 代表了一个异质性的肿瘤细胞群体,缺乏特异性细胞靶点,这使得靶向和根除 CSCs 成为一项巨大挑战。同样,它们与肿瘤微环境的密切关系也为开发针对 CSCs 的新型治疗策略带来了更大的复杂性。在各种癌症中,有多种机制参与了 CSCs 的耐药和耐凋亡表型。这些机制包括 ATP 结合盒膜转运体的表达增强、各种细胞保护和存活信号通路的激活、干性信号通路失调、DNA 修复机制异常、静止性增强、自噬、免疫逃避增强、缺乏嗜酸性粒细胞等、免疫逃避增加、线粒体介导的凋亡缺乏、抗凋亡蛋白(包括 c-FLIP [细胞 FLICE(FADD 样 IL-1β 转换酶)抑制蛋白])上调、Bcl-2 家族成员、凋亡抑制蛋白和 PI3K/AKT 信号转导。研究这些机制不仅能从机理上深入了解这些对药物无反应的细胞,还能开发出根除 CSCs 的靶向有效疗法。有几项研究发现了针对 CSCs 的有前途的策略。这些新出现的策略可能有助于在临床环境中针对与 CSC 相关的耐药性和转移。本文将综述CSCs的耐药和凋亡机制以及如何靶向治疗CSCs。
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引用次数: 0
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