Pub Date : 2025-05-08DOI: 10.1016/j.coph.2025.102528
Amal El Daibani , Gwendolyn Burgess , Lauren Rysztak , Emily Jutkiewicz , Amynah A. Pradhan
The delta opioid receptor (DOR) is an often-overlooked member of the opioid receptor family, lacking the euphoric and addictive effects of mu receptors and the dysphoric properties of kappa. Instead, the DOR functions to restore balance, showing minimal impact in acute pain but alleviating allodynia and hyperalgesia associated with chronic pain and producing anxiolytic and antidepressant-like behaviors. Though past clinical trials for osteoarthritis and depression were unsuccessful, emerging evidence supports DOR’s therapeutic potential in migraine, substance use disorder, irritable bowel syndrome, and metabolic disorder. Advances in pharmacology, including structure-guided design and intracellular targeting, offer promising new directions for DOR-based drug development.
{"title":"Delta opioid receptors: Overlooked outlier or the next big thing","authors":"Amal El Daibani , Gwendolyn Burgess , Lauren Rysztak , Emily Jutkiewicz , Amynah A. Pradhan","doi":"10.1016/j.coph.2025.102528","DOIUrl":"10.1016/j.coph.2025.102528","url":null,"abstract":"<div><div>The delta opioid receptor (DOR) is an often-overlooked member of the opioid receptor family, lacking the euphoric and addictive effects of mu receptors and the dysphoric properties of kappa. Instead, the DOR functions to restore balance, showing minimal impact in acute pain but alleviating allodynia and hyperalgesia associated with chronic pain and producing anxiolytic and antidepressant-like behaviors. Though past clinical trials for osteoarthritis and depression were unsuccessful, emerging evidence supports DOR’s therapeutic potential in migraine, substance use disorder, irritable bowel syndrome, and metabolic disorder. Advances in pharmacology, including structure-guided design and intracellular targeting, offer promising new directions for DOR-based drug development.</div></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"83 ","pages":"Article 102528"},"PeriodicalIF":4.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144189767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-26DOI: 10.1016/j.coph.2025.102527
Raffaele Palmieri , Luca Maurillo , Maria Ilaria Del Principe , Adriano Venditti , Francesco Buccisano
Acute Myeloid Leukemia (AML) is a complex disease whose outcome can be variably influenced by several clinical and biological factors. Although there is still no consensus on how to integrate these elements to best guide treatment choice, multiparametric models, commonly called fitness scores, have been developed to evaluate each patient's ability to tolerate therapies. These models consider various risk factors, including disease biology, comorbidities, physical and cognitive function. To date, several scoring systems can be used to categorize patients on their fitness for intensive or non-intensive therapies. However, existing tools mainly focus on identifying patients suitable for conventional intensive chemotherapy and fail to address the complexities of less-fit patients who might benefit from innovative intensive, less-intensive, and even maintenance strategies. As treatment landscapes are in constant evolution, identifying intermediate level of fitness through recalibration of existing scores or development of new ones should be prioritized. Considering all the above, this review aims to report on the state of the art of fitness assessment in AML and discuss possible future directions on this topic.
{"title":"Fitness in acute myeloid leukemia, state of the art and future directions","authors":"Raffaele Palmieri , Luca Maurillo , Maria Ilaria Del Principe , Adriano Venditti , Francesco Buccisano","doi":"10.1016/j.coph.2025.102527","DOIUrl":"10.1016/j.coph.2025.102527","url":null,"abstract":"<div><div>Acute Myeloid Leukemia (AML) is a complex disease whose outcome can be variably influenced by several clinical and biological factors. Although there is still no consensus on how to integrate these elements to best guide treatment choice, multiparametric models, commonly called fitness scores, have been developed to evaluate each patient's ability to tolerate therapies. These models consider various risk factors, including disease biology, comorbidities, physical and cognitive function. To date, several scoring systems can be used to categorize patients on their fitness for intensive or non-intensive therapies. However, existing tools mainly focus on identifying patients suitable for conventional intensive chemotherapy and fail to address the complexities of less-fit patients who might benefit from innovative intensive, less-intensive, and even maintenance strategies. As treatment landscapes are in constant evolution, identifying intermediate level of fitness through recalibration of existing scores or development of new ones should be prioritized. Considering all the above, this review aims to report on the state of the art of fitness assessment in AML and discuss possible future directions on this topic.</div></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"83 ","pages":"Article 102527"},"PeriodicalIF":4.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143947657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-08DOI: 10.1016/j.coph.2025.102526
Bofei Wang , Patrick K. Reville , Hussein A. Abbas
Acute myeloid leukemia (AML) is an aggressive and highly heterogeneous hematological malignancy characterized by clonal expansion and differentiation arrest in myeloid progenitor cells. Despite advancements in chemotherapy, allogeneic hematopoietic stem cell transplantation, and post-remission maintenance therapies, the long-term survival remains unsatisfactory with high rates of relapse and refractory. These therapeutic challenges are mediated by multiple factors, including the complexity of the cellular hierarchies in AML, the interaction of leukemic stem cells (LSCs) with the bone marrow niche, inflammation, and immune evasion mechanisms. Further, the absence of specific surface markers that distinguish LSCs from normal hematopoietic stem cells, together with LSCs’ functional heterogeneity, complicates targeted treatment approaches. Immune dysfunction, including T cell exhaustion and immune suppression within the bone marrow niche contributes to therapy resistance. In this brief review, we aim to explore current challenges in AML therapy, focusing on LSC-driven resistance, immune evasion, and the need for innovative therapeutic strategies.
{"title":"Therapeutic hurdles in acute myeloid leukemia: Leukemic stem cells, inflammation and immune dysfunction","authors":"Bofei Wang , Patrick K. Reville , Hussein A. Abbas","doi":"10.1016/j.coph.2025.102526","DOIUrl":"10.1016/j.coph.2025.102526","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is an aggressive and highly heterogeneous hematological malignancy characterized by clonal expansion and differentiation arrest in myeloid progenitor cells. Despite advancements in chemotherapy, allogeneic hematopoietic stem cell transplantation, and post-remission maintenance therapies, the long-term survival remains unsatisfactory with high rates of relapse and refractory. These therapeutic challenges are mediated by multiple factors, including the complexity of the cellular hierarchies in AML, the interaction of leukemic stem cells (LSCs) with the bone marrow niche, inflammation, and immune evasion mechanisms. Further, the absence of specific surface markers that distinguish LSCs from normal hematopoietic stem cells, together with LSCs’ functional heterogeneity, complicates targeted treatment approaches. Immune dysfunction, including T cell exhaustion and immune suppression within the bone marrow niche contributes to therapy resistance. In this brief review, we aim to explore current challenges in AML therapy, focusing on LSC-driven resistance, immune evasion, and the need for innovative therapeutic strategies.</div></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"82 ","pages":"Article 102526"},"PeriodicalIF":4.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-08DOI: 10.1016/j.coph.2025.102524
Gordon Victor Hoffmann , Adrian Gottschlich , Marion Subklewe , Sebastian Kobold
Identifying safe and effective CAR T cell targets in acute myeloid leukemia (AML) is challenging due to the disease’s complexity and overlap with normal hematopoiesis. This review highlights advances in target discovery for AML, emphasizing innovative approaches. Structural surfaceomics identifies tumor-specific protein conformations, while AI-driven single-cell RNA sequencing integrates multi-source data to pinpoint optimal targets. Refined cell surface capture technology maps the AML surfaceome without relying on predefined antibodies. These strategies enhance CAR T cell specificity and minimize off-tumor effects, offering promising pathways for safer and more effective AML treatments and broader cancer therapies.
{"title":"Novel approaches to CAR T cell target identification in acute myeloid leukemia","authors":"Gordon Victor Hoffmann , Adrian Gottschlich , Marion Subklewe , Sebastian Kobold","doi":"10.1016/j.coph.2025.102524","DOIUrl":"10.1016/j.coph.2025.102524","url":null,"abstract":"<div><div>Identifying safe and effective CAR T cell targets in acute myeloid leukemia (AML) is challenging due to the disease’s complexity and overlap with normal hematopoiesis. This review highlights advances in target discovery for AML, emphasizing innovative approaches. Structural surfaceomics identifies tumor-specific protein conformations, while AI-driven single-cell RNA sequencing integrates multi-source data to pinpoint optimal targets. Refined cell surface capture technology maps the AML surfaceome without relying on predefined antibodies. These strategies enhance CAR T cell specificity and minimize off-tumor effects, offering promising pathways for safer and more effective AML treatments and broader cancer therapies.</div></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"82 ","pages":"Article 102524"},"PeriodicalIF":4.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-04DOI: 10.1016/j.coph.2025.102525
Memnon Lysandrou, Robert Zeiser
Acute myeloid leukaemia (AML) was an incurable disease prior to allogeneic haematopoietic cell transplantation (allo-HCT), which was proven to be a potent cellular immunotherapy-approach. However, allo-HCT has major side effects, with disease relapse presenting as a frequent complication. Novel immunotherapies aim to reduce toxicity and increase the anti-leukaemia activity of allo-HCT. Technological advancements in genetic engineering approaches enable potent immunotherapeutic activity while limiting toxicities. A biology-driven application of small molecules that target AML vulnerabilities holds promise to enhance anti-leukaemia immunotherapy. Extensive preclinical testing of these approaches is essential to reduce toxicity and to find the ideal combination partners for future clinical testing.
{"title":"Strategies to enhance anti-leukaemia immunotherapy","authors":"Memnon Lysandrou, Robert Zeiser","doi":"10.1016/j.coph.2025.102525","DOIUrl":"10.1016/j.coph.2025.102525","url":null,"abstract":"<div><div>Acute myeloid leukaemia (AML) was an incurable disease prior to allogeneic haematopoietic cell transplantation (allo-HCT), which was proven to be a potent cellular immunotherapy-approach. However, allo-HCT has major side effects, with disease relapse presenting as a frequent complication. Novel immunotherapies aim to reduce toxicity and increase the anti-leukaemia activity of allo-HCT. Technological advancements in genetic engineering approaches enable potent immunotherapeutic activity while limiting toxicities. A biology-driven application of small molecules that target AML vulnerabilities holds promise to enhance anti-leukaemia immunotherapy. Extensive preclinical testing of these approaches is essential to reduce toxicity and to find the ideal combination partners for future clinical testing.</div></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"82 ","pages":"Article 102525"},"PeriodicalIF":4.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-21DOI: 10.1016/j.coph.2025.102523
Gregory T. Rognon , Anna Yu-an Liao , Rodahina Philihina Pasteurin , Avinash Soundararajan , Padmanabhan Paranji Pattabiraman
Increased intraocular pressure is the strongest correlated modifiable risk factor for developing primary open-angle glaucoma (POAG). Lipids have long been known to be a major constituent of aqueous humor. Lipid mediators, prostaglandins for example, are the first-line treatment for glaucoma. Innovative technologies have made the investigation of lipids in small quantities possible, and interest in identifying lipids as new pharmacological targets has grown in ophthalmology. There is expanding evidence to suggest that lipids and their active metabolites play a role in POAG pathophysiology, as differences between control and diseased eyes have now been demonstrated. The role of these differences is yet to be determined and is the subject of this review.
{"title":"Lipids and lipid regulators in intraocular pressure homeostasis","authors":"Gregory T. Rognon , Anna Yu-an Liao , Rodahina Philihina Pasteurin , Avinash Soundararajan , Padmanabhan Paranji Pattabiraman","doi":"10.1016/j.coph.2025.102523","DOIUrl":"10.1016/j.coph.2025.102523","url":null,"abstract":"<div><div>Increased intraocular pressure is the strongest correlated modifiable risk factor for developing primary open-angle glaucoma (POAG). Lipids have long been known to be a major constituent of aqueous humor. Lipid mediators, prostaglandins for example, are the first-line treatment for glaucoma. Innovative technologies have made the investigation of lipids in small quantities possible, and interest in identifying lipids as new pharmacological targets has grown in ophthalmology. There is expanding evidence to suggest that lipids and their active metabolites play a role in POAG pathophysiology, as differences between control and diseased eyes have now been demonstrated. The role of these differences is yet to be determined and is the subject of this review.</div></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"82 ","pages":"Article 102523"},"PeriodicalIF":4.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-19DOI: 10.1016/j.coph.2025.102522
Sudha Sharma, Srijita Dhar, Sagar Sengupta
{"title":"Balancing genome integrity and carcinogenesis: Insights into DNA damage response, repair pathways, and cancer therapies","authors":"Sudha Sharma, Srijita Dhar, Sagar Sengupta","doi":"10.1016/j.coph.2025.102522","DOIUrl":"10.1016/j.coph.2025.102522","url":null,"abstract":"","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"82 ","pages":"Article 102522"},"PeriodicalIF":4.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.coph.2024.102504
Sheng-Tao Hou
{"title":"Message from the New Editor-in-Chief, Prof. Sheng-Tao Hou","authors":"Sheng-Tao Hou","doi":"10.1016/j.coph.2024.102504","DOIUrl":"10.1016/j.coph.2024.102504","url":null,"abstract":"","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"80 ","pages":"Article 102504"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
DNA damage signaling is a highly coordinated cellular process which is required for the removal of DNA lesions. Amongst the different types of DNA damage, double-strand breaks (DSBs) are the most harmful type of lesion that attenuates cellular proliferation. DSBs are repaired by two major pathways—homologous recombination (HR), and non-homologous end-joining (NHEJ) and in some cases by microhomology-mediated end-joining (MMEJ). Preference of the pathway depends on multiple parameters including site of the DNA damage, the cell cycle phase and topology of the DNA lesion. Deregulated repair response contributes to genomic instability resulting in a plethora of diseases including cancer. This review discusses the different molecular players of HR, NHEJ, and MMEJ pathways that control the switch among the different DSB repair pathways. We also highlight the various functions of chromatin modifications in modulating repair response and how deregulated DNA damage repair response may promote oncogenic transformation.
{"title":"Regulation of pathway choice in DNA repair after double-strand breaks","authors":"Nitu Kumari , Ekjot Kaur , Sathees C. Raghavan , Sagar Sengupta","doi":"10.1016/j.coph.2024.102496","DOIUrl":"10.1016/j.coph.2024.102496","url":null,"abstract":"<div><div>DNA damage signaling is a highly coordinated cellular process which is required for the removal of DNA lesions. Amongst the different types of DNA damage, double-strand breaks (DSBs) are the most harmful type of lesion that attenuates cellular proliferation. DSBs are repaired by two major pathways—homologous recombination (HR), and non-homologous end-joining (NHEJ) and in some cases by microhomology-mediated end-joining (MMEJ). Preference of the pathway depends on multiple parameters including site of the DNA damage, the cell cycle phase and topology of the DNA lesion. Deregulated repair response contributes to genomic instability resulting in a plethora of diseases including cancer. This review discusses the different molecular players of HR, NHEJ, and MMEJ pathways that control the switch among the different DSB repair pathways. We also highlight the various functions of chromatin modifications in modulating repair response and how deregulated DNA damage repair response may promote oncogenic transformation.</div></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"80 ","pages":"Article 102496"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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