Pub Date : 2024-06-01Epub Date: 2024-05-22DOI: 10.1016/j.tips.2024.04.008
Philip E Thompson, Jake Shortt
Members of the MYC family of proteins are a major target for cancer drug discovery, but the development of drugs that block MYC-driven cancers has not yet been successful. Approaches to achieve success may include the development of combination therapies or dual-acting drugs that target MYC at multiple nodes. Such treatments hold the possibility of additive or synergistic activity, potentially reducing side effect profiles and the emergence of resistance. In this review, we examine the prominent MYC-related targets and highlight those that have been targeted in combination and/or dual-target approaches. Finally, we explore the challenges of combination and dual-target approaches from a drug development perspective.
{"title":"Defeating MYC with drug combinations or dual-targeting drugs.","authors":"Philip E Thompson, Jake Shortt","doi":"10.1016/j.tips.2024.04.008","DOIUrl":"10.1016/j.tips.2024.04.008","url":null,"abstract":"<p><p>Members of the MYC family of proteins are a major target for cancer drug discovery, but the development of drugs that block MYC-driven cancers has not yet been successful. Approaches to achieve success may include the development of combination therapies or dual-acting drugs that target MYC at multiple nodes. Such treatments hold the possibility of additive or synergistic activity, potentially reducing side effect profiles and the emergence of resistance. In this review, we examine the prominent MYC-related targets and highlight those that have been targeted in combination and/or dual-target approaches. Finally, we explore the challenges of combination and dual-target approaches from a drug development perspective.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088679","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}
Pub Date : 2024-06-01Epub Date: 2024-05-13DOI: 10.1016/j.tips.2024.04.006
Jessica M Konen, Haoyi Wu, Don L Gibbons
Immune checkpoint blockade (ICB) therapy works by inhibiting suppressive checkpoints that become upregulated after T cell activation, like PD-1/PD-L1 and CTLA-4. While the initial FDA approvals of ICB have revolutionized cancer therapies and fueled a burgeoning immuno-oncology field, more recent clinical development of new agents has been slow. Here, focusing on lung cancer, we review the latest research uncovering tumor cell intrinsic and extrinsic ICB resistance mechanisms as major hurdles to treatment efficacy and clinical progress. These include genomic and non-genomic tumor cell alterations, along with host and microenvironmental factors like the microbiome, metabolite accumulation, and hypoxia. Together, these factors can cooperate to promote immunosuppression and ICB resistance. Opportunities to prevent resistance are constantly evolving in this rapidly expanding field, with the goal of moving toward personalized immunotherapeutic regimens.
{"title":"Immune checkpoint blockade resistance in lung cancer: emerging mechanisms and therapeutic opportunities.","authors":"Jessica M Konen, Haoyi Wu, Don L Gibbons","doi":"10.1016/j.tips.2024.04.006","DOIUrl":"10.1016/j.tips.2024.04.006","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) therapy works by inhibiting suppressive checkpoints that become upregulated after T cell activation, like PD-1/PD-L1 and CTLA-4. While the initial FDA approvals of ICB have revolutionized cancer therapies and fueled a burgeoning immuno-oncology field, more recent clinical development of new agents has been slow. Here, focusing on lung cancer, we review the latest research uncovering tumor cell intrinsic and extrinsic ICB resistance mechanisms as major hurdles to treatment efficacy and clinical progress. These include genomic and non-genomic tumor cell alterations, along with host and microenvironmental factors like the microbiome, metabolite accumulation, and hypoxia. Together, these factors can cooperate to promote immunosuppression and ICB resistance. Opportunities to prevent resistance are constantly evolving in this rapidly expanding field, with the goal of moving toward personalized immunotherapeutic regimens.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11189143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-05-21DOI: 10.1016/j.tips.2024.04.010
Collin Y Ewald, Fadi E Pulous, Sarah Wing Yan Lok, Frank W Pun, Alex Aliper, Feng Ren, Alex Zhavoronkov
Traf2- and Nck-interacting kinase (TNIK) has emerged as a key regulator of pathological metabolic signaling in several diseases and is a promising drug target. Originally studied for its role in cell migration and proliferation, TNIK possesses several newly identified functions that drive the pathogenesis of multiple diseases. Specifically, we evaluate TNIK's newfound roles in cancer, metabolic disorders, and neuronal function. We emphasize the implications of TNIK signaling in metabolic signaling and evaluate the translational potential of these discoveries. We also highlight how TNIK's role in many biological processes converges upon several hallmarks of aging. We conclude by discussing the therapeutic landscape of TNIK-targeting drugs and the recent success of clinical trials targeting TNIK.
{"title":"TNIK's emerging role in cancer, metabolism, and age-related diseases.","authors":"Collin Y Ewald, Fadi E Pulous, Sarah Wing Yan Lok, Frank W Pun, Alex Aliper, Feng Ren, Alex Zhavoronkov","doi":"10.1016/j.tips.2024.04.010","DOIUrl":"10.1016/j.tips.2024.04.010","url":null,"abstract":"<p><p>Traf2- and Nck-interacting kinase (TNIK) has emerged as a key regulator of pathological metabolic signaling in several diseases and is a promising drug target. Originally studied for its role in cell migration and proliferation, TNIK possesses several newly identified functions that drive the pathogenesis of multiple diseases. Specifically, we evaluate TNIK's newfound roles in cancer, metabolic disorders, and neuronal function. We emphasize the implications of TNIK signaling in metabolic signaling and evaluate the translational potential of these discoveries. We also highlight how TNIK's role in many biological processes converges upon several hallmarks of aging. We conclude by discussing the therapeutic landscape of TNIK-targeting drugs and the recent success of clinical trials targeting TNIK.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081419","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}
Pub Date : 2024-06-01Epub Date: 2024-05-10DOI: 10.1016/j.tips.2024.04.011
Maxim Noeparast, Oleg Timofeev, Martin Pichler
Cancer-targeted therapies that inhibit oncogenic signaling often lead to resistance and recurrence. In a recent study, Dias et al. propose activating oncogenic pathways and inducing replication stress, resulting in cell death and tumor-suppressive mechanisms in colorectal cancer (CRC). This approach could spark a new wave of target discovery, and drug development and repurposing against cancer.
{"title":"Enhancing oncogenic signaling to kill cancer cells.","authors":"Maxim Noeparast, Oleg Timofeev, Martin Pichler","doi":"10.1016/j.tips.2024.04.011","DOIUrl":"10.1016/j.tips.2024.04.011","url":null,"abstract":"<p><p>Cancer-targeted therapies that inhibit oncogenic signaling often lead to resistance and recurrence. In a recent study, Dias et al. propose activating oncogenic pathways and inducing replication stress, resulting in cell death and tumor-suppressive mechanisms in colorectal cancer (CRC). This approach could spark a new wave of target discovery, and drug development and repurposing against cancer.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140909124","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}
Pub Date : 2024-05-18DOI: 10.1016/j.tips.2024.04.003
Michael D. Hadler, Henrik Alle, Jörg R.P. Geiger
Alzheimer’s disease (AD) and schizophrenia (SCZ) represent two major neuropathological conditions with a high disease burden. Despite their distinct etiologies, patients suffering from AD or SCZ share a common burden of disrupted memory functions unattended by current therapies. Recent preclinical analyses highlight cell-type-specific contributions of parvalbumin interneurons (PVIs), particularly the plasticity of their cellular excitability, towards intact neuronal network function (cell-to-network plasticity) and memory performance. Here we argue that deficits of PVI cell-to-network plasticity may underlie memory deficits in AD and SCZ, and we explore two therapeutic avenues: the targeting of PVI-specific neuromodulation, including by neuropeptides, and the recruitment of network synchrony in the gamma frequency range (40 Hz) by external stimulation. We finally propose that these approaches be merged under consideration of recent insights into human brain physiology.
阿尔茨海默病(AD)和精神分裂症(SCZ)是疾病负担沉重的两大神经病理学疾病。尽管病因不同,但阿尔茨海默病和精神分裂症患者有一个共同的负担,即记忆功能紊乱,而目前的疗法却无法解决这一问题。最近的临床前分析凸显了蛛网膜旁中间神经元(PVIs)细胞类型的特异性,特别是其细胞兴奋性的可塑性,对完整的神经元网络功能(细胞到网络的可塑性)和记忆表现的贡献。在此,我们认为 PVI 细胞对网络可塑性的缺陷可能是 AD 和 SCZ 记忆缺陷的基础,并探讨了两条治疗途径:针对 PVI 特异性神经调节(包括神经肽),以及通过外部刺激在伽马频率范围(40 Hz)招募网络同步。最后,我们建议根据最近对人脑生理学的深入研究,将这些方法结合起来。
{"title":"Parvalbumin interneuron cell-to-network plasticity: mechanisms and therapeutic avenues","authors":"Michael D. Hadler, Henrik Alle, Jörg R.P. Geiger","doi":"10.1016/j.tips.2024.04.003","DOIUrl":"https://doi.org/10.1016/j.tips.2024.04.003","url":null,"abstract":"<p>Alzheimer’s disease (AD) and schizophrenia (SCZ) represent two major neuropathological conditions with a high disease burden. Despite their distinct etiologies, patients suffering from AD or SCZ share a common burden of disrupted memory functions unattended by current therapies. Recent preclinical analyses highlight cell-type-specific contributions of parvalbumin interneurons (PVIs), particularly the plasticity of their cellular excitability, towards intact neuronal network function (cell-to-network plasticity) and memory performance. Here we argue that deficits of PVI cell-to-network plasticity may underlie memory deficits in AD and SCZ, and we explore two therapeutic avenues: the targeting of PVI-specific neuromodulation, including by neuropeptides, and the recruitment of network synchrony in the gamma frequency range (40 Hz) by external stimulation. We finally propose that these approaches be merged under consideration of recent insights into human brain physiology.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141063672","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}
Pub Date : 2024-05-14DOI: 10.1016/j.tips.2024.04.005
Jianxiong Jiang, Ying Yu
No Abstract
无摘要
{"title":"Eflornithine for treatment of high-risk neuroblastoma","authors":"Jianxiong Jiang, Ying Yu","doi":"10.1016/j.tips.2024.04.005","DOIUrl":"https://doi.org/10.1016/j.tips.2024.04.005","url":null,"abstract":"No Abstract","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140925672","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}
Pub Date : 2024-05-03DOI: 10.1016/j.tips.2024.04.002
Binyou Wang, Matthew R. Pratt
Small heat shock proteins (sHSPs) play key roles in cellular stress and several human diseases. The direct effects of some post-translational modifications (PTMs) on certain sHSPs have been characterized, raising the possibility that small molecules could be used to modulate these modifications and indirectly up- or downregulate sHSP activity.
{"title":"Potential for targeting small heat shock protein modifications","authors":"Binyou Wang, Matthew R. Pratt","doi":"10.1016/j.tips.2024.04.002","DOIUrl":"https://doi.org/10.1016/j.tips.2024.04.002","url":null,"abstract":"<p>Small heat shock proteins (sHSPs) play key roles in cellular stress and several human diseases. The direct effects of some post-translational modifications (PTMs) on certain sHSPs have been characterized, raising the possibility that small molecules could be used to modulate these modifications and indirectly up- or downregulate sHSP activity.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841750","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}
Pub Date : 2024-05-02DOI: 10.1016/s0165-6147(24)00076-2
No Abstract
无摘要
{"title":"Subscription and Copyright Information","authors":"","doi":"10.1016/s0165-6147(24)00076-2","DOIUrl":"https://doi.org/10.1016/s0165-6147(24)00076-2","url":null,"abstract":"No Abstract","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841516","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}
Pub Date : 2024-05-02DOI: 10.1016/s0165-6147(24)00072-5
No Abstract
无摘要
{"title":"Advisory Board and Contents","authors":"","doi":"10.1016/s0165-6147(24)00072-5","DOIUrl":"https://doi.org/10.1016/s0165-6147(24)00072-5","url":null,"abstract":"No Abstract","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841544","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}
Pub Date : 2024-05-01DOI: 10.1016/j.tips.2024.04.007
Alexander R. Terry, Nissim Hay
{"title":"Emerging targets in lipid metabolism for cancer therapy","authors":"Alexander R. Terry, Nissim Hay","doi":"10.1016/j.tips.2024.04.007","DOIUrl":"https://doi.org/10.1016/j.tips.2024.04.007","url":null,"abstract":"","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141029448","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}