{"title":"Accelerating precision oncology by converging pragmatic trials and real-world evidence","authors":"Kjetil Taskén, Piers Mahon","doi":"10.1038/d41573-025-00047-5","DOIUrl":"https://doi.org/10.1038/d41573-025-00047-5","url":null,"abstract":"Engaging sufficient numbers of patients with cancers that have particular molecular characteristics is a key challenge in building evidence to support precision medicine in oncology. These challenges could be addressed by converging pragmatic clinical trials and hospital cancer informatics infrastructures to integrate cancer care and research.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Tumour-agnostic kinase inhibitors","authors":"Jacob J. Adashek, Mina Nikanjam, Razelle Kurzrock","doi":"10.1038/s41573-025-01147-y","DOIUrl":"https://doi.org/10.1038/s41573-025-01147-y","url":null,"abstract":"<p>Protein kinases are crucial targets for cancer treatment as they orchestrate important signals for oncogenesis and are often aberrantly activated owing to genomic alterations. In the past two decades, multiple kinase inhibitors have been developed, including those that are clinically effective regardless of tumour location, provided that the tumour harbours the aberrantly activated kinase. Consequently, a biomarker-based therapy model, untethered from tumour histology and organ of origin, has been established, which has led to transformative regulatory approvals of tumour-agnostic kinase inhibitors such as larotrectinib, selpercatinib, dabrafenib–trametinib and pemigatinib. However, almost all such approvals are partial in nature, as they do not include both solid and haematological cancers, even if the kinase inhibitor has shown activity in both. Moreover, clinical trials to assess these compounds are challenging because genomic sequencing of hundreds or thousands of tumours may be required to find eligible patients whose malignancy bears the targeted genetic alterations. In this Review, we describe the precision medicine paradigm that has successfully launched tumour-agnostic drug development, concentrating on small-molecule inhibitors that target kinase pathway aberrations, and we discuss the challenges in developing tumour‐agnostic agents.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrew S. Robertson, Nahid Latif, Imein Bousnina, Donna Boyce, Kevin Carl, Sean P. Curtis, Jennifer Dudinak, Carlos O. Garner, Michael Garvin, Sabine Luik, Eddie Reilly, Michelle Rohrer, Katrin Rupalla, Jacintha Shenton, Jerry Stewart, Mark Taisey, Raymond C. Votzmeyer, Matthew P. Wagoner, Max Wegner, Kathy Williams
{"title":"Accelerating adoption of new approach methodologies in regulatory decision making: an industry perspective","authors":"Andrew S. Robertson, Nahid Latif, Imein Bousnina, Donna Boyce, Kevin Carl, Sean P. Curtis, Jennifer Dudinak, Carlos O. Garner, Michael Garvin, Sabine Luik, Eddie Reilly, Michelle Rohrer, Katrin Rupalla, Jacintha Shenton, Jerry Stewart, Mark Taisey, Raymond C. Votzmeyer, Matthew P. Wagoner, Max Wegner, Kathy Williams","doi":"10.1038/d41573-025-00038-6","DOIUrl":"https://doi.org/10.1038/d41573-025-00038-6","url":null,"abstract":"Clear and harmonized regulatory guidelines are needed to realize the potential of new approach methodologies for improving the predictivity of nonclinical drug candidate assessment.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Thirty years of NRF2: advances and therapeutic challenges","authors":"Donna D. Zhang","doi":"10.1038/s41573-025-01145-0","DOIUrl":"https://doi.org/10.1038/s41573-025-01145-0","url":null,"abstract":"<p>Over the last 30 years, NRF2 has evolved from being recognized as a transcription factor primarily involved in redox balance and detoxification to a well-appreciated master regulator of cellular proteostasis, metabolism and iron homeostasis. NRF2 plays a pivotal role in diverse pathologies, including cancer, and metabolic, inflammatory and neurodegenerative disorders. It exhibits a Janus-faced duality, safeguarding cellular integrity in normal cells against environmental insults to prevent disease onset, whereas in certain cancers, constitutively elevated NRF2 levels provide a tumour survival advantage, promoting progression, therapy resistance and metastasis. Advances in understanding the mechanistic regulation of NRF2 and its roles in human pathology have propelled the investigation of NRF2-targeted therapeutic strategies. This Review dissects the mechanistic intricacies of NRF2 signalling, its cross-talk with biological processes and its far-reaching implications for health and disease, highlighting key discoveries that have shaped innovative therapeutic approaches targeting NRF2.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Javier Sánchez Lorente, Aleksandr V. Sokolov, Gavin Ferguson, Helgi B. Schiöth, Alexander S. Hauser, David E. Gloriam
{"title":"GPCR drug discovery: new agents, targets and indications","authors":"Javier Sánchez Lorente, Aleksandr V. Sokolov, Gavin Ferguson, Helgi B. Schiöth, Alexander S. Hauser, David E. Gloriam","doi":"10.1038/s41573-025-01139-y","DOIUrl":"https://doi.org/10.1038/s41573-025-01139-y","url":null,"abstract":"<p>G protein-coupled receptors (GPCRs) form one of the largest drug target families, reflecting their involvement in numerous pathophysiological processes. In this Review, we analyse drug discovery trends for the GPCR superfamily, covering compounds, targets and indications that have reached regulatory approval or that are being investigated in clinical trials. We find that there are 516 approved drugs targeting GPCRs, making up 36% of all approved drugs. These drugs act on 121 GPCR targets, one-third of all non-sensory GPCRs. Furthermore, 337 agents targeting 133 GPCRs, including 30 novel targets, are being investigated in clinical trials. Notably, 165 of these agents are approved drugs being tested for additional indications and novel agents are increasingly allosteric modulators and biologics. Remarkably, diabetes and obesity drugs targeting GPCRs had sales of nearly US $30 billion in 2023 and the numbers of clinical trials for GPCR modulators in the metabolic diseases, oncology and immunology areas are increasing strongly. Finally, we highlight the potential of untapped target–disease associations and pathway-biased signalling. Overall, this Review provides an up-to-date reference for the drugged and potentially druggable GPCRome to inform future GPCR drug discovery and development.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Clinical development success rates for durable cell and gene therapies","authors":"","doi":"10.1038/d41573-025-00036-8","DOIUrl":"https://doi.org/10.1038/d41573-025-00036-8","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"MYC in cancer: from undruggable target to clinical trials","authors":"Jonathan R. Whitfield, Laura Soucek","doi":"10.1038/s41573-025-01143-2","DOIUrl":"https://doi.org/10.1038/s41573-025-01143-2","url":null,"abstract":"<p><i>MYC</i> is among the most infamous oncogenes in cancer. A notable feature that distinguishes it from other common oncogenes is that its deregulation is not usually due to direct mutation, but instead to its relentless activation by other oncogenic lesions. These signalling pathways funnel through MYC to execute the transcriptional programmes that eventually lead to the uncontrolled proliferation of cancer cells. Indeed, deregulated MYC activity may be linked to most — if not all — human cancers. Despite this unquestionable role of MYC in tumour development and maintenance, no MYC inhibitor has yet been approved for clinical use. The main reason is that MYC has long fallen into the category of ‘undruggable’ or ‘difficult-to-drug’ targets, mainly because of its intrinsically disordered structure, which is not amenable to traditional drug development strategies. However, in recent years, attempts to develop MYC inhibitors have multiplied, and the first clinical trials have been testing their efficacy in patients. We are finally reaching the point at which its inhibition seems clinically viable. This Review provides an overview of the various strategies to inhibit MYC, focusing on the most recently described inhibitors and those that have reached clinical trials.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liese Barbier, Pierpaolo Moscariello, Hubert G Leufkens, Ralf Herold, Anna Maria Gerdina Pasmooij
{"title":"A new European platform for advancing regulatory science research","authors":"Liese Barbier, Pierpaolo Moscariello, Hubert G Leufkens, Ralf Herold, Anna Maria Gerdina Pasmooij","doi":"10.1038/d41573-025-00024-y","DOIUrl":"https://doi.org/10.1038/d41573-025-00024-y","url":null,"abstract":"Launching in 2025, the European Platform for Regulatory Science Research will bring together academia, regulators and other stakeholders to accelerate collaborative regulatory science research solutions.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthew Alsaloum, Sulayman D. Dib-Hajj, Dana A. Page, Peter C. Ruben, Adrian R. Krainer, Stephen G. Waxman
{"title":"Voltage-gated sodium channels in excitable cells as drug targets","authors":"Matthew Alsaloum, Sulayman D. Dib-Hajj, Dana A. Page, Peter C. Ruben, Adrian R. Krainer, Stephen G. Waxman","doi":"10.1038/s41573-024-01108-x","DOIUrl":"https://doi.org/10.1038/s41573-024-01108-x","url":null,"abstract":"<p>Excitable cells — including neurons, muscle cells and cardiac myocytes — are unique in expressing high densities of voltage-gated sodium (Na<sub>V</sub>) channels. This molecular adaptation enables these cells to produce action potentials, and is essential to their function. With the advent of the molecular revolution, the concept of ‘the’ sodium channel has been supplanted by understanding that excitable cells in mammals can express any of nine different forms of sodium channels (Na<sub>V</sub>1.1–Na<sub>V</sub>1.9). Selective expression in particular types of cells, together with a key role in controlling action potential firing, makes some of these Na<sub>V</sub> subtypes especially attractive molecular targets for drug development. Although these different channel subtypes display a common overall structure, differences in their amino acid sequences have provided a basis for the development of subtype-specific drugs. This approach has resulted in exciting progress in the development of drugs for epilepsy, cardiac disorders and pain. In this Review, we discuss recent progress in the development of drugs that selectively target each of the sodium channel subtypes.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Arthur Mulvey, Lionel Trueb, George Coukos, Caroline Arber
{"title":"Novel strategies to manage CAR-T cell toxicity","authors":"Arthur Mulvey, Lionel Trueb, George Coukos, Caroline Arber","doi":"10.1038/s41573-024-01100-5","DOIUrl":"https://doi.org/10.1038/s41573-024-01100-5","url":null,"abstract":"<p>The immune-related adverse events associated with chimeric antigen receptor (CAR)-T cell therapy result in substantial morbidity as well as considerable cost to the health-care system, and can limit the use of these treatments. Current therapeutic strategies to manage immune-related adverse events include interleukin-6 receptor (IL-6R) blockade and corticosteroids. However, because these interventions do not always address the side effects, nor prevent progression to higher grades of adverse events, new approaches are needed. A deeper understanding of the cell types involved, and their associated signalling pathways, cellular metabolism and differentiation states, should provide the basis for alternative strategies. To preserve treatment efficacy, cytokine-mediated toxicity needs to be uncoupled from CAR-T cell function, expansion, long-term persistence and memory formation. This may be achieved by targeting CAR or independent cytokine signalling axes transiently, and through novel T cell engineering strategies, such as low-affinity CAR-T cells, reversible on–off switches and versatile adaptor systems. We summarize the current management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and review T cell- and myeloid cell-intrinsic druggable targets and cellular engineering strategies to develop safer CAR-T cells.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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