Pub Date : 2025-12-31DOI: 10.1158/2159-8290.cd-nw2025-0117
Twenty-five years ago, the FDA gave the first approval to an antibody-drug conjugate (ADC), the CD33-targeting gemtuzumab ozogamicin for acute myeloid leukemia. As the drug faced setbacks and redemption-it was withdrawn in 2010 following poor phase III trial results but reapproved in 2017 at a lower dose-a surge of pharmaceutical interest in ADCs has yielded newly approved agents and new strategies for developing them.
{"title":"Cancer Throughlines: 25 Years after First Approval, ADCs Continue to Pick up Steam.","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0117","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0117","url":null,"abstract":"Twenty-five years ago, the FDA gave the first approval to an antibody-drug conjugate (ADC), the CD33-targeting gemtuzumab ozogamicin for acute myeloid leukemia. As the drug faced setbacks and redemption-it was withdrawn in 2010 following poor phase III trial results but reapproved in 2017 at a lower dose-a surge of pharmaceutical interest in ADCs has yielded newly approved agents and new strategies for developing them.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"8 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897444","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 : 2025-12-22DOI: 10.1158/2159-8290.cd-nw2025-0115
Three trials report positive data for the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib and a potential successor, rocbrutinib, in chronic lymphocytic leukemia. One study of previously untreated patients found a 24-month progression-free survival of 93.4% for pirtobrutinib, versus 70.7% for bendamustine and rituximab. The second study suggests the drug is noninferior to the covalent inhibitor ibrutinib in previously untreated or relapsed or refractory patients. The third study found an overall response rate of 62.5% for rocbrutinib in previously treated patients.
{"title":"New BTK Inhibitors May Combat Resistance in CLL","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0115","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0115","url":null,"abstract":"Three trials report positive data for the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib and a potential successor, rocbrutinib, in chronic lymphocytic leukemia. One study of previously untreated patients found a 24-month progression-free survival of 93.4% for pirtobrutinib, versus 70.7% for bendamustine and rituximab. The second study suggests the drug is noninferior to the covalent inhibitor ibrutinib in previously untreated or relapsed or refractory patients. The third study found an overall response rate of 62.5% for rocbrutinib in previously treated patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801200","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 : 2025-12-22DOI: 10.1158/2159-8290.cd-nw2025-0114
By pairing a BCMA-targeted T-cell engager with an anti-CD38 antibody, researchers achieved strikingly deep remissions and sharply reduced relapse risk in patients with relapsed myeloma. The results suggest this dual immune-directed strategy could challenge current treatment sequencing, including when to deploy engineered T-cell therapies.
{"title":"Two Drugs, One Stunning Myeloma Result","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0114","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0114","url":null,"abstract":"By pairing a BCMA-targeted T-cell engager with an anti-CD38 antibody, researchers achieved strikingly deep remissions and sharply reduced relapse risk in patients with relapsed myeloma. The results suggest this dual immune-directed strategy could challenge current treatment sequencing, including when to deploy engineered T-cell therapies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"24 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801082","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 : 2025-12-19DOI: 10.1158/2159-8290.cd-25-0974
Yiyi Ji, Cheng-Wei Ju, Lei Chen, Kai Shen, Ruopeng Su, Ang Li, Xinyu Liu, Bo Liu, Xinran Zhang, Ruitu Lyu, Peng Xia, Han Li, Yiqian Pan, Yunzheng Liu, Man Hin Tse, Yizheng Xue, Hongyang Qian, Na Jing, Helen He. Zhu, Liangliang Wang, Li-Sheng Zhang, Shu-Heng Jiang, Weiwei Zhang, Liang Dong, Zejun Yan, Jiahua Pan, Yinjie Zhu, Jiangbo Wei, Qi Wang, Wei Xue
Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype of prostate cancer characterized by lineage plasticity. While metabolic and signaling molecules are increasingly recognized as modulators of tumor progression, their role in cell fate transition remains unclear. NE tumors produce and accumulate serotonin, a neurotransmitter that regulates diverse physiological processes. Here, we identify a tumor-intrinsic serotonin axis as key driver of NEPC lineage commitment and progression. NEPC endogenously synthesize serotonin via aromatic L-amino acid decarboxylase (DDC) and reuptake through the transporter SLC6A4. Mechanistically, high level of intracellular serotonin promotes histone serotonylation at H3K4me3Q5, reconfiguring the H3K4me3 chromatin landscape and downstream gene expression, which drives induced NE differentiation and is associated with suppressed androgen receptor signaling. Pharmacological inhibition of 5-HT synthesis using the FDA-approved DDC inhibitor carbidopa significantly impairs tumor growth and prolongs survival in both genetically engineered and patient-derived xenograft models, highlighting histone serotonylation as a druggable vulnerability in NEPC.
{"title":"Serotonin modulates lineage plasticity in neuroendocrine prostate cancer via epigenetic reprogramming","authors":"Yiyi Ji, Cheng-Wei Ju, Lei Chen, Kai Shen, Ruopeng Su, Ang Li, Xinyu Liu, Bo Liu, Xinran Zhang, Ruitu Lyu, Peng Xia, Han Li, Yiqian Pan, Yunzheng Liu, Man Hin Tse, Yizheng Xue, Hongyang Qian, Na Jing, Helen He. Zhu, Liangliang Wang, Li-Sheng Zhang, Shu-Heng Jiang, Weiwei Zhang, Liang Dong, Zejun Yan, Jiahua Pan, Yinjie Zhu, Jiangbo Wei, Qi Wang, Wei Xue","doi":"10.1158/2159-8290.cd-25-0974","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0974","url":null,"abstract":"Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype of prostate cancer characterized by lineage plasticity. While metabolic and signaling molecules are increasingly recognized as modulators of tumor progression, their role in cell fate transition remains unclear. NE tumors produce and accumulate serotonin, a neurotransmitter that regulates diverse physiological processes. Here, we identify a tumor-intrinsic serotonin axis as key driver of NEPC lineage commitment and progression. NEPC endogenously synthesize serotonin via aromatic L-amino acid decarboxylase (DDC) and reuptake through the transporter SLC6A4. Mechanistically, high level of intracellular serotonin promotes histone serotonylation at H3K4me3Q5, reconfiguring the H3K4me3 chromatin landscape and downstream gene expression, which drives induced NE differentiation and is associated with suppressed androgen receptor signaling. Pharmacological inhibition of 5-HT synthesis using the FDA-approved DDC inhibitor carbidopa significantly impairs tumor growth and prolongs survival in both genetically engineered and patient-derived xenograft models, highlighting histone serotonylation as a druggable vulnerability in NEPC.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"93 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777585","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 : 2025-12-19DOI: 10.1158/2159-8290.cd-25-1187
Nilotpal Roy, Tine Wyseure, I-Chung Lo, Justine Lu, Christie L. Eissler, Steffen M. Bernard, Ilah Bok, Aaron N. Snead, Albert Parker, U-Ging Lo, Jason C. Green, Jordon Inloes, Sarah R. Jacinto, Brent Kuenzi, Marie Pariollaud, Kathleen Negri, Khoi Le, Benjamin D. Horning, Noah Ibrahim, Stephanie Grabow, Harit Panda, Dhaval P. Bhatt, Emily M. Wilkerson, Soma Saeidi, Paul Zolkind, Zoe Rush, Heather N. Williams, Eric Walton, Martha K. Pastuszka, John J. Sigler, Eileen Tran, Kenneth Hee, Joseph McLaughlin, Géza Ambrus-Aikelin, Jonathan Pollock, Robert T. Abraham, Todd M. Kinsella, Gabriel M. Simon, Michael B. Major, David S. Weinstein, Matthew P. Patricelli
The NRF2 transcription factor is constitutively active in cancer where it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2-dependency and resistance to chemo/radiotherapy. Here we characterize VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the KEAP1-CUL3 ubiquitin-ligase complex. VVD-065 specifically and covalently engages Cys151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported Cys151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1_Cys151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemo/radiotherapy, supporting an open Phase I clinical trial (NCT05954312).
{"title":"A covalent allosteric molecular glue suppresses NRF2-dependent cancer growth","authors":"Nilotpal Roy, Tine Wyseure, I-Chung Lo, Justine Lu, Christie L. Eissler, Steffen M. Bernard, Ilah Bok, Aaron N. Snead, Albert Parker, U-Ging Lo, Jason C. Green, Jordon Inloes, Sarah R. Jacinto, Brent Kuenzi, Marie Pariollaud, Kathleen Negri, Khoi Le, Benjamin D. Horning, Noah Ibrahim, Stephanie Grabow, Harit Panda, Dhaval P. Bhatt, Emily M. Wilkerson, Soma Saeidi, Paul Zolkind, Zoe Rush, Heather N. Williams, Eric Walton, Martha K. Pastuszka, John J. Sigler, Eileen Tran, Kenneth Hee, Joseph McLaughlin, Géza Ambrus-Aikelin, Jonathan Pollock, Robert T. Abraham, Todd M. Kinsella, Gabriel M. Simon, Michael B. Major, David S. Weinstein, Matthew P. Patricelli","doi":"10.1158/2159-8290.cd-25-1187","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1187","url":null,"abstract":"The NRF2 transcription factor is constitutively active in cancer where it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2-dependency and resistance to chemo/radiotherapy. Here we characterize VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the KEAP1-CUL3 ubiquitin-ligase complex. VVD-065 specifically and covalently engages Cys151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported Cys151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1_Cys151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemo/radiotherapy, supporting an open Phase I clinical trial (NCT05954312).","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"16 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777586","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 : 2025-12-18DOI: 10.1158/2159-8290.cd-nw2025-0113
The oral selective estrogen receptor degrader giredestrant prolonged invasive disease-free survival more than standard endocrine therapies, such as tamoxifen, letrozole, anastrozole, and exemestane, in the phase III lidERA study. Despite the lack of comparisons between the drug and CDK4/6 inhibitors and concerns over its potential cost, researchers were excited by the data, noting that it’s the first improvement in adjuvant endocrine therapy in two decades.
{"title":"Giredestrant Delivers Long-Sought Adjuvant Benefit","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0113","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0113","url":null,"abstract":"The oral selective estrogen receptor degrader giredestrant prolonged invasive disease-free survival more than standard endocrine therapies, such as tamoxifen, letrozole, anastrozole, and exemestane, in the phase III lidERA study. Despite the lack of comparisons between the drug and CDK4/6 inhibitors and concerns over its potential cost, researchers were excited by the data, noting that it’s the first improvement in adjuvant endocrine therapy in two decades.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"9 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770721","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 : 2025-12-17DOI: 10.1158/2159-8290.cd-nw2025-0106
The African Oncogenetics Network issued its Hammamet Declaration on Oncogenetics in Africa, which outlines priorities for improving cancer care by implementing genetic and genomic testing across the continent. Because Africa has the world’s most genetically diverse population, this effort could provide a better understanding of how cancer mutates as populations move and change.
{"title":"Cancer Leaders Aim to Improve Oncogenetics in Africa","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0106","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0106","url":null,"abstract":"The African Oncogenetics Network issued its Hammamet Declaration on Oncogenetics in Africa, which outlines priorities for improving cancer care by implementing genetic and genomic testing across the continent. Because Africa has the world’s most genetically diverse population, this effort could provide a better understanding of how cancer mutates as populations move and change.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"12 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765230","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 : 2025-12-17DOI: 10.1158/2159-8290.cd-nw2025-0107
ZL-1310, an antibody–drug conjugate that targets DLL3-expressing small cell lung cancer cells, led to responses in nearly half of patients in a phase I study. These results provide further evidence that targeting DLL3 may be a promising approach for treating this cancer.
{"title":"ADC for SCLC Clears Phase I","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0107","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0107","url":null,"abstract":"ZL-1310, an antibody–drug conjugate that targets DLL3-expressing small cell lung cancer cells, led to responses in nearly half of patients in a phase I study. These results provide further evidence that targeting DLL3 may be a promising approach for treating this cancer.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"17 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765228","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 : 2025-12-17DOI: 10.1158/2159-8290.cd-nw2025-0109
Measurable residual disease (MRD) is associated with survival in acute myeloid leukemia (AML) but is not an accepted trial endpoint. A new study that combined data from seven clinical trials found that MRD predicted individual survival within trials and correlated with overall survival across trials. The results support use of MRD as a surrogate endpoint for AML trials.
{"title":"Study Backs MRD as AML Trial Endpoint","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0109","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0109","url":null,"abstract":"Measurable residual disease (MRD) is associated with survival in acute myeloid leukemia (AML) but is not an accepted trial endpoint. A new study that combined data from seven clinical trials found that MRD predicted individual survival within trials and correlated with overall survival across trials. The results support use of MRD as a surrogate endpoint for AML trials.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"157 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765229","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 : 2025-12-17DOI: 10.1158/2159-8290.cd-nw2025-0108
ASP3082, a proteolysis targeting chimera that targets mutant KRASG12D, and elironrasib, a tri-complex inhibitor of KRASG12C in the “on” state, showed encouraging efficacy and safety in separate phase I trials.
{"title":"“The RAS Dam Has Broken”","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0108","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0108","url":null,"abstract":"ASP3082, a proteolysis targeting chimera that targets mutant KRASG12D, and elironrasib, a tri-complex inhibitor of KRASG12C in the “on” state, showed encouraging efficacy and safety in separate phase I trials.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"11 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765232","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}
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