靶向蛋白质泛素修饰及降解在前列腺癌治疗中的机遇与挑战

前列腺癌是中国发病率增长最快的男性肿瘤,抗雄激素治疗耐药是导致前列腺癌患者预后差的主要原因。因此,解决耐药性难题是前列腺癌转化研究的关键问题。哺乳动物细胞利用泛素-蛋白酶体系统实现蛋白质的靶向降解。因此,前列腺癌中关键的癌基因如雄激素受体（AR）的上游泛素化调控因子（如去泛素化酶）是潜在的治疗靶点。然而,这些酶具有较广的底物谱系,存在脱靶的可能性。近来,基于泛素-蛋白酶体系统开发的蛋白质降解靶向嵌合体（proteolysis-targeting chimeras,PROTAC）技术是最具前景和革命性的新型抗癌药物研发技术,能够利用特定E3泛素连接酶对靶蛋白进行降解而不影响其他底物。与传统小分子抑制剂相比,PROTAC分子在克服耐药性以及针对不可成药的靶点方面拥有巨大优势。目前,针对AR的PROTAC降解剂已在II期临床取得了成功,靶向蛋白质泛素化及降解途径的新技术将有望为前列腺癌的临床治疗带来新的突破。     

肿瘤基因治疗的靶向策略

对肿瘤组织的靶向性可以提高基因治疗的效果 ,避免对正常组织的损伤 ,并且能降低作为载体的微生物对机体的危害。对于瘤内注射的给药方法 ,靶向性似乎显得不是特别重要 ,但是如果要系统给药 ,靶向性是很关键的一个问题。靶向基因治疗肿瘤可以通过靶向基因导入和靶向基因表达来实现。近年来 ,在靶向基因导入方面的研究有很多进展 ,例如 ,用双亲性的桥连分子协助腺病毒和逆转录病毒靶向转导 ;在各种病毒载体的衣壳蛋白中插入靶向性的小肽或较大的多肽靶向结构域 ;增殖病毒作为一种很有前途的抗肿瘤制剂可有效地靶向杀伤肿瘤细胞。受体介导的DNA或DNA 脂质体复合物的靶向系统和其他一些靶向性的有疗效的载体 ,如细菌 ,也处于研究中。其中的一些载体已经进入临床实验。为了实现基因的靶向可调控表达 ,组织或肿瘤特异性的启动子和人工合成的可调控表达系统被用来调控治疗基因的表达。反义核酸、核酶以及脱氧核酶 (DNAzyme)被用来靶向抑制与肿瘤发生密切相关基因的表达。     

Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets

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The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer

Introduction

Abnormal cancer metabolism creates a glycolytic-dependency which can be exploited by lowering glucose availability to the tumor. The ketogenic diet (KD) is a low carbohydrate, high fat diet which decreases blood glucose and elevates blood ketones and has been shown to slow cancer progression in animals and humans. Abnormal tumor vasculature creates hypoxic pockets which promote cancer progression and further increase the glycolytic-dependency of cancers. Hyperbaric oxygen therapy (HBO₂T) saturates tumors with oxygen, reversing the cancer promoting effects of tumor hypoxia. Since these non-toxic therapies exploit overlapping metabolic deficiencies of cancer, we tested their combined effects on cancer progression in a natural model of metastatic disease.

Methods

We used the firefly luciferase-tagged VM-M3 mouse model of metastatic cancer to compare tumor progression and survival in mice fed standard or KD ad libitum with or without HBO₂T (2.5 ATM absolute, 90 min, 3x/week). Tumor growth was monitored by in vivo bioluminescent imaging.

Results

KD alone significantly decreased blood glucose, slowed tumor growth, and increased mean survival time by 56.7% in mice with systemic metastatic cancer. While HBO₂T alone did not influence cancer progression, combining the KD with HBO₂T elicited a significant decrease in blood glucose, tumor growth rate, and 77.9% increase in mean survival time compared to controls.

Conclusions

KD and HBO₂T produce significant anti-cancer effects when combined in a natural model of systemic metastatic cancer. Our evidence suggests that these therapies should be further investigated as potential non-toxic treatments or adjuvant therapies to standard care for patients with systemic metastatic disease.     

Dietary composition specifies consumption, obesity, and lifespan in Drosophila melanogaster

The inability to properly balance energy intake and expenditure with nutrient supply forms the basis for some of today's most pressing health issues, including diabetes and obesity. Mechanisms of nutrient homeostasis may also lie at the root of dietary restriction, a manipulation whereby reduced nutrient availability extends lifespan and ameliorates age-related deteriorations in many species. The traditional belief that the most important aspect of the diet is its energetic (i.e. caloric) content is currently under scrutiny. Hypotheses that focus on diet composition and highlight more subtle characteristics are beginning to emerge. Using Drosophila melanogaster , we asked whether diet composition alone, independent of its caloric content, was sufficient to impact behavior, physiology, and lifespan. We found that providing flies with a yeast-rich diet produced lean, reproductively competent animals with reduced feeding rates. Excess dietary sugar, on the other hand, promoted obesity, which was magnified during aging. Addition of dietary yeast often limited or reversed the phenotypic changes associated with increased dietary sugar and vice versa, and dietary imbalance was associated with reduced lifespan. Our data reveal that diet composition, alone and in combination with overall caloric intake, modulates lifespan, consumption, and fat deposition in flies, and they provide a useful foundation for dissecting the underlying genetic mechanisms that link specific nutrients with important aspects of general health and longevity.     

前列腺癌的靶向治疗研究现状与展望

前列腺癌难以根治,研究雄激素非依赖型前列腺癌的靶向治疗具有实际的临床意义,涉及抗体靶向治疗、靶向抗前列腺癌药物研制、细胞生长信号转导通路抑制、微小RNA应用等多方面,而靶向清除肿瘤干细胞则是根治前列腺癌的有效策略。     

Steady state changes in mitochondrial electrical potential and proton gradient in perfused liver from rats fed a high fat diet

In this work the protonmotive force (p), as well as the subcellular distribution of malate, ATP, and ADP were determined in perfused liver from rats fed a low fat or high fat diet, using density gradient fractionation in non acqueous solvents.Rats fed a high fat diet, despite an enhanced hepatic oxygen consumption, exhibit similar p to that found in rats fed a low fat diet, but when we consider the two components of p, we find a significant decrease in mitochondrial/cytosolic pH difference (pH_m) and a significant increase in mitochondrial membrane potential (_m) in rats fed a high fat diet compared to rats fed a low fat diet, which tend to compensate each other. In rats fed a high fat diet the concentration ratio of malate and ATP/ADP does not reflect the changes in pH_m and _m, which represent the respective driving force for their transport.The findings are in line with an increase in substrate supply to the respiratory chain which is, however, accompanied by a higher energy turnover in livers from HFD rats. By this way the liver could contribute to the lack of weight gain from the high caloric intake in HFD rats.     

肿瘤干细胞靶向治疗研究进展

肿瘤干细胞是存在于肿瘤组织中的一小部分具有自我更新、多向分化和无限增殖能力的细胞,其控制着肿瘤的生长、分化,并且与 肿瘤的耐药性、转移以及复发密切相关。简述近年来国内外学者针对肿瘤干细胞的靶向治疗产品,包括抗体、多肽以及靶向药物的研究进展。 肿瘤干细胞的靶向治疗为临床肿瘤治疗提供了新的希望。     

Thematic Review Series: Calorie Restriction and Ketogenic Diets: The ketogenic diet for the treatment of malignant glioma

Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, thus reducing the efficacy of these treatments. In contrast, one trait shared by virtually all tumor cells is altered (dysregulated) metabolism. Tumor cells have an increased reliance on glucose, suggesting that treatments affecting cellular metabolism may be an effective method to improve current therapies. Indeed, metabolism has been a focus of cancer research in the last few years, as many pathways long associated with tumor growth have been found to intersect metabolic pathways in the cell. The ketogenic diet (high fat, low carbohydrate and protein), caloric restriction, and fasting all cause a metabolic change, specifically, a reduction in blood glucose and an increase in blood ketones. We, and others, have demonstrated that these metabolic changes improve survival in animal models of malignant gliomas and can potentiate the anti-tumor effect of chemotherapies and radiation treatment. In this review we discuss the use of metabolic alteration for the treatment of malignant brain tumors.     

分子靶向治疗在前列腺癌中的研究进展

前列腺癌是目前在全球男性中第二位最常见的肿瘤,其在恶性肿瘤死亡率中排名第六位[1]。在发病率方面,我国虽然不及西方国家,但是随着生活水平和诊疗技术的提高,也表现出了逐渐上升的态势。靶向治疗是以肿瘤细胞的特有位点作为治疗靶点,在纠正病变、稳定细胞、发挥更强的抗肿瘤活性的同时,能够对正常细胞减少毒副作用[2]。由于我们对于肿瘤发生发展的分子途径认知的逐渐提高,以及更好的利用这些途径作为有效的药物作用靶点,我们已经看到了越来越多的分子靶向药物的开发和生产随之增加。本文着重探讨了分子靶向药物对肿瘤的治疗起作用的不同的靶向机制,以及它们的研究现状及临床应用。     

Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet,Ketone Supplementation,and Hyperbaric Oxygen Therapy

The Warburg effect and tumor hypoxia underlie a unique cancer metabolic phenotype characterized by glucose dependency and aerobic fermentation. We previously showed that two non-toxic metabolic therapies – the ketogenic diet with concurrent hyperbaric oxygen (KD+HBOT) and dietary ketone supplementation – could increase survival time in the VM-M3 mouse model of metastatic cancer. We hypothesized that combining these therapies could provide an even greater therapeutic benefit in this model. Mice receiving the combination therapy demonstrated a marked reduction in tumor growth rate and metastatic spread, and lived twice as long as control animals. To further understand the effects of these metabolic therapies, we characterized the effects of high glucose (control), low glucose (LG), ketone supplementation (βHB), hyperbaric oxygen (HBOT), or combination therapy (LG+βHB+HBOT) on VM-M3 cells. Individually and combined, these metabolic therapies significantly decreased VM-M3 cell proliferation and viability. HBOT, alone or in combination with LG and βHB, increased ROS production in VM-M3 cells. This study strongly supports further investigation into this metabolic therapy as a potential non-toxic treatment for late-stage metastatic cancers.     

The Hormone FGF21 Stimulates Water Drinking in Response to Ketogenic Diet and Alcohol

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DNA Replication Licensing Factors: Novel Targets for Cancer Therapy via Inhibiting the Stemness of Cancer Cells

The replication licensing factors strictly regulate the DNA replication origin licensing process to guarantee the stability of the genome. Numerous experimental studies have recently demonstrated that the replication licensing factors as oncogenes are essential for the occurrence and development of cancers. Drug resistance, being one of the main characteristics of cancer stem cells, can cause a high recurrence rate and a low survival rate in patients with different cancers. However, the function of the replication licensing factors in cancer stemness remains unclear. The following article highlights the most recent research on DNA replication origin licensing factors in cancer and their function in anti-cancer drug resistance. Moreover, this article proposes a new perspective that replication licensing factors as chemotherapy shield affect anti-cancer drug resistance by promoting the stemness of cancer cells.     

Targeting HMGB1: An available Therapeutic Strategy for Breast Cancer Therapy

HMGB1 is a member of highly conserved high mobility group protein superfamily with intracellular and extracellular distribution. Abnormal HMGB1 levels are frequently manifested in various malignant diseases, including breast cancer. Numerous studies have revealed the clinical value of HMGB1 in the diagnosis and therapy of breast cancer. However, the dual function of pro- and anti-tumor makes HMGB1 in cancer progression requires more profound understanding. This review summarizes the functions and mechanisms of HMGB1 on regulating breast cancer, including autophagy, immunogenic cell death, and interaction with the tumor microenvironment. These functions determine the strategies for the development of chemotherapy, radiotherapy, immunotherapy and combination therapies by targeting HMGB1 in breast cancer. Defining the mechanisms of HMGB1 on regulating breast cancer development and progression will facilitate the application of HMGB1 as a therapeutic target for breast cancer.     

成纤维细胞生长因子受体-癌症治疗新靶点

成纤维细胞生长因子(FGFs)通过作用于其受体(成纤维细胞生长因子受体,FGFRs)在许多生理过程中发挥重要作用,如胚胎形成、创伤修复、血管生成等。近年来,越来越多的证据表明FGFRs是某些癌症的驱动基因,并且以"细胞自治"的方式维持肿瘤细胞的恶性特征,通过诱导促有丝分裂和生存信号、促进肿瘤细胞侵袭转移、促进上皮间质转化、促进血管生成及参与肿瘤复发耐药作用作为癌基因参与肿瘤发生发展进程的多重步骤,但也有研究证实FGFR信号在某些肿瘤类型中具有抑制肿瘤的功能。这些研究结果使得FGFRs成为越来越具有吸引力的癌症治疗新靶点。本文阐述了FGFRs信号通路在多种肿瘤中的作用,并且对处于研发或试验阶段的抗FGFRs药物(包括小分子酪氨酸激酶抑制剂和单克隆抗体)进行了概括。     

肿瘤发生的细胞离子动态及其作为抗癌药标的综合效应

大量肿瘤细胞的有关研究表明,H+、Na+、Ca2+等细胞离子的动态对肿瘤发生起着关键作用.然而,单个离子作为代谢基础的作用是多方面的,其涉癌效果很不一致,有时还是相反的.因此,以控制单个离子动态作为抗癌药物的靶标,其效果并不理想.迄今对细胞离子的致癌作用的研究虽然是大量的,但均散见各章,缺少综合考虑.为此,本文简要介绍了上述离子的致癌作用,并探讨了以控制离子动态为药标,设计抗癌药物时应考虑的综合效应,供癌药物学研究者参考.