Pub Date : 2025-01-02DOI: 10.1158/0008-5472.CAN-24-3744
Clemens A Schmitt
Therapy-exposed surviving cancer cells may have encountered profound epigenetic remodeling that renders these drug-tolerant persisters candidate drivers of particularly aggressive relapses. Typically presenting as slow-to-nongrowing cells, persisters are senescent or senescence-like cells. In this issue of Cancer Research, Ramponi and colleagues study mTOR/PI3K inhibitor-induced embryonic diapause-like arrest (DLA) as a model of persistence in lung cancer and melanoma cells and compare this persister condition with therapy-induced senescence in the same cells. The DLA phenotype recapitulated some but not all features attributed to senescent cells, lacking, for instance, an inflammatory secretome otherwise known as the senescence-associated secretory phenotype. A CRISPR dropout screen pointed to methyl group-providing one-carbon metabolism and further to H4K20me3-mediated repression of senescence-associated secretory phenotype-related IFN response genes selectively in DLA-like persister cells. Conversely, inhibition of H4K20-active KMT5B/C methyltransferases derepressed inflammatory programs and was toxic in DLA cells. These findings not only suggest exploitable vulnerabilities of DLA-like persister cells but also unveil general technical and conceptual challenges of cultured multipassage cell line-based persister studies. Collectively, the approach chosen and insights obtained will stimulate a productive scientific debate on senescence-like features and their reversibility across drug-tolerant persister cells. See related article by Ramponi et al., p. 32.
{"title":"Persistence and/or Senescence: Not So Lasting at Last?","authors":"Clemens A Schmitt","doi":"10.1158/0008-5472.CAN-24-3744","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-3744","url":null,"abstract":"<p><p>Therapy-exposed surviving cancer cells may have encountered profound epigenetic remodeling that renders these drug-tolerant persisters candidate drivers of particularly aggressive relapses. Typically presenting as slow-to-nongrowing cells, persisters are senescent or senescence-like cells. In this issue of Cancer Research, Ramponi and colleagues study mTOR/PI3K inhibitor-induced embryonic diapause-like arrest (DLA) as a model of persistence in lung cancer and melanoma cells and compare this persister condition with therapy-induced senescence in the same cells. The DLA phenotype recapitulated some but not all features attributed to senescent cells, lacking, for instance, an inflammatory secretome otherwise known as the senescence-associated secretory phenotype. A CRISPR dropout screen pointed to methyl group-providing one-carbon metabolism and further to H4K20me3-mediated repression of senescence-associated secretory phenotype-related IFN response genes selectively in DLA-like persister cells. Conversely, inhibition of H4K20-active KMT5B/C methyltransferases derepressed inflammatory programs and was toxic in DLA cells. These findings not only suggest exploitable vulnerabilities of DLA-like persister cells but also unveil general technical and conceptual challenges of cultured multipassage cell line-based persister studies. Collectively, the approach chosen and insights obtained will stimulate a productive scientific debate on senescence-like features and their reversibility across drug-tolerant persister cells. See related article by Ramponi et al., p. 32.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 1","pages":"7-9"},"PeriodicalIF":12.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913811","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 : 2025-01-02DOI: 10.1158/0008-5472.CAN-24-0744
Bharti Garg, Sohini Khan, Asimina S Courelli, Ponmathi Panneerpandian, Deepa Sheik Pran Babu, Evangeline S Mose, Kevin Christian Montecillo Gulay, Shweta Sharma, Divya Sood, Alexander T Wenzel, Alexei Martsinkovskiy, Nirakar Rajbhandari, Jay Patel, Dawn Jaquish, Edgar Esparza, Katelin Jaque, Neetu Aggarwal, Guillem Lambies, Anthony D'Ippolito, Kathryn Austgen, Brian Johnston, David A Orlando, Gun Ho Jang, Steven Gallinger, Elliot Goodfellow, Pnina Brodt, Cosimo Commisso, Pablo Tamayo, Jill P Mesirov, Hervé Tiriac, Andrew M Lowy
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers; thus, identifying more effective therapies is a major unmet need. In this study, we characterized the super enhancer (SE) landscape of human PDAC to identify drivers of the disease that might be targetable. This analysis revealed MICAL2 as a super enhancer-associated gene in human PDAC, which encodes the flavin monooxygenase MICAL2 that induces actin depolymerization and indirectly promotes SRF transcription by modulating the availability of serum response factor coactivators myocardin-related transcription factors (MRTF-A and MRTF-B). MICAL2 was overexpressed in PDAC, and high MICAL2 expression correlated with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and EMT signaling pathways, contributing to tumor growth and metastasis. In loss and gain of function experiments in human and mouse PDAC cells, MICAL2 promoted both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 also inhibited macropinocytosis. MICAL2, MRTF-A, and MRTF-B influenced PDAC cell proliferation and migration and promoted cell cycle progression in vitro. Importantly, MICAL2 supported in vivo tumor growth and metastasis. Interestingly, MRTF-B, but not MRTF-A, phenocopied MICAL2-driven phenotypes in vivo. This study highlights the multiple ways in which MICAL2 impacts PDAC biology and provides a foundation for future investigations into the potential of targeting MICAL2 for therapeutic intervention.
{"title":"MICAL2 Promotes Pancreatic Cancer Growth and Metastasis.","authors":"Bharti Garg, Sohini Khan, Asimina S Courelli, Ponmathi Panneerpandian, Deepa Sheik Pran Babu, Evangeline S Mose, Kevin Christian Montecillo Gulay, Shweta Sharma, Divya Sood, Alexander T Wenzel, Alexei Martsinkovskiy, Nirakar Rajbhandari, Jay Patel, Dawn Jaquish, Edgar Esparza, Katelin Jaque, Neetu Aggarwal, Guillem Lambies, Anthony D'Ippolito, Kathryn Austgen, Brian Johnston, David A Orlando, Gun Ho Jang, Steven Gallinger, Elliot Goodfellow, Pnina Brodt, Cosimo Commisso, Pablo Tamayo, Jill P Mesirov, Hervé Tiriac, Andrew M Lowy","doi":"10.1158/0008-5472.CAN-24-0744","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-0744","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers; thus, identifying more effective therapies is a major unmet need. In this study, we characterized the super enhancer (SE) landscape of human PDAC to identify drivers of the disease that might be targetable. This analysis revealed MICAL2 as a super enhancer-associated gene in human PDAC, which encodes the flavin monooxygenase MICAL2 that induces actin depolymerization and indirectly promotes SRF transcription by modulating the availability of serum response factor coactivators myocardin-related transcription factors (MRTF-A and MRTF-B). MICAL2 was overexpressed in PDAC, and high MICAL2 expression correlated with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and EMT signaling pathways, contributing to tumor growth and metastasis. In loss and gain of function experiments in human and mouse PDAC cells, MICAL2 promoted both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 also inhibited macropinocytosis. MICAL2, MRTF-A, and MRTF-B influenced PDAC cell proliferation and migration and promoted cell cycle progression in vitro. Importantly, MICAL2 supported in vivo tumor growth and metastasis. Interestingly, MRTF-B, but not MRTF-A, phenocopied MICAL2-driven phenotypes in vivo. This study highlights the multiple ways in which MICAL2 impacts PDAC biology and provides a foundation for future investigations into the potential of targeting MICAL2 for therapeutic intervention.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913806","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 : 2024-12-30DOI: 10.1158/0008-5472.can-24-2589
Akshada Sawant, Fuqian Shi, Eduardo Cararo Lopes, Zhixian Hu, Somer Abdelfattah, Jennele Baul, Jesse R. Powers, Christian S. Hinrichs, Joshua D. Rabinowitz, Chang S. Chan, Edmund C. Lattime, Shridar Ganesan, Eileen P. White
Mutations in the exonuclease domains of the replicative nuclear DNA polymerases POLD1 and POLE are associated with increased cancer incidence, elevated tumor mutation burden (TMB), and enhanced response to immune checkpoint blockade (ICB). Although ICB is approved for treatment of several cancers, not all tumors with elevated TMB respond, highlighting the need for a better understanding of how TMB affects tumor biology and subsequently immunotherapy response. To address this, we generated mice with germline and conditional mutations in the exonuclease domains of Pold1 and Pole. Engineered mice with Pold1 and Pole mutator alleles presented with spontaneous cancers, primarily lymphomas, lung cancer, and intestinal tumors, while Pold1 mutant mice also developed tail skin carcinomas. These cancers had highly variable tissue-type dependent increased TMB with mutational signatures associated with POLD1 and POLE mutations found in human cancers. The Pold1 mutant tail tumors displayed increased TMB, however, only a subset of established tumors responded to ICB. Similarly, introducing the mutator alleles into mice with lung cancer driven by mutant Kras and Trp53 deletion did not improve survival, whereas passaging these tumor cells in vitro without immune editing and subsequently implanting them into immune-competent mice caused tumor rejection in vivo. These results demonstrated the efficiency by which cells with antigenic mutations are eliminated in vivo. Finally, ICB treatment of mutator mice earlier, before observable tumors had developed delayed cancer onset, improved survival, and selected for tumors without aneuploidy, suggesting the potential of ICB in high-risk individuals for cancer prevention.
{"title":"Immune Checkpoint Blockade Delays Cancer Development and Extends Survival in DNA Polymerase Mutator Syndromes","authors":"Akshada Sawant, Fuqian Shi, Eduardo Cararo Lopes, Zhixian Hu, Somer Abdelfattah, Jennele Baul, Jesse R. Powers, Christian S. Hinrichs, Joshua D. Rabinowitz, Chang S. Chan, Edmund C. Lattime, Shridar Ganesan, Eileen P. White","doi":"10.1158/0008-5472.can-24-2589","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2589","url":null,"abstract":"Mutations in the exonuclease domains of the replicative nuclear DNA polymerases POLD1 and POLE are associated with increased cancer incidence, elevated tumor mutation burden (TMB), and enhanced response to immune checkpoint blockade (ICB). Although ICB is approved for treatment of several cancers, not all tumors with elevated TMB respond, highlighting the need for a better understanding of how TMB affects tumor biology and subsequently immunotherapy response. To address this, we generated mice with germline and conditional mutations in the exonuclease domains of Pold1 and Pole. Engineered mice with Pold1 and Pole mutator alleles presented with spontaneous cancers, primarily lymphomas, lung cancer, and intestinal tumors, while Pold1 mutant mice also developed tail skin carcinomas. These cancers had highly variable tissue-type dependent increased TMB with mutational signatures associated with POLD1 and POLE mutations found in human cancers. The Pold1 mutant tail tumors displayed increased TMB, however, only a subset of established tumors responded to ICB. Similarly, introducing the mutator alleles into mice with lung cancer driven by mutant Kras and Trp53 deletion did not improve survival, whereas passaging these tumor cells in vitro without immune editing and subsequently implanting them into immune-competent mice caused tumor rejection in vivo. These results demonstrated the efficiency by which cells with antigenic mutations are eliminated in vivo. Finally, ICB treatment of mutator mice earlier, before observable tumors had developed delayed cancer onset, improved survival, and selected for tumors without aneuploidy, suggesting the potential of ICB in high-risk individuals for cancer prevention.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"12 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904832","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 : 2024-12-30DOI: 10.1158/0008-5472.can-24-4907
Kristen L. Drucker, Robert B. Jenkins, Daniel Schramek
IDH-mutant low-grade gliomas (LGGs) are slow-growing brain tumors that frequently progress to aggressive high-grade gliomas that have dismal outcomes. In a recent study, Wu and colleagues provide critical insights into the mechanisms underlying malignant progression by analyzing single-cell gene expression and chromatin accessibility across different tumor grades. Their findings support a two-phase model: in early stages, tumors are primarily driven by oligodendrocyte precursor-like cells and epigenetic alterations that silence tumor suppressors like CDKN2A and activate oncogenes such as PDGFRA. As the disease advances, the tumors become sustained by more proliferative neural precursor-like cells, where genetic alterations, including PDGFRA, MYCN, and CDK4 amplifications and CDKN2A/B deletion, drive tumor progression. The study further highlights a dynamic regulation of interferon (IFN) signaling during progression. In low-grade IDH-mutant gliomas, IFN responses are suppressed through epigenetic hypermethylation, which can be reversed with DNMT1 inhibitors or IDH inhibitors, leading to reactivation of the IFN pathway. In contrast, higher-grade gliomas evade IFN signaling through genetic deletions of IFN gene clusters. These findings emphasize a broader epigenetic-to-genetic shift in oncogenic regulation that drives glioma progression, provides a valuable framework for understanding the transition from indolent tumors to lethal malignancies, and has implications for therapy and clinical management.
{"title":"Switching Drivers: Epigenetic Rewiring to Genetic Progression in Glioma","authors":"Kristen L. Drucker, Robert B. Jenkins, Daniel Schramek","doi":"10.1158/0008-5472.can-24-4907","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4907","url":null,"abstract":"IDH-mutant low-grade gliomas (LGGs) are slow-growing brain tumors that frequently progress to aggressive high-grade gliomas that have dismal outcomes. In a recent study, Wu and colleagues provide critical insights into the mechanisms underlying malignant progression by analyzing single-cell gene expression and chromatin accessibility across different tumor grades. Their findings support a two-phase model: in early stages, tumors are primarily driven by oligodendrocyte precursor-like cells and epigenetic alterations that silence tumor suppressors like CDKN2A and activate oncogenes such as PDGFRA. As the disease advances, the tumors become sustained by more proliferative neural precursor-like cells, where genetic alterations, including PDGFRA, MYCN, and CDK4 amplifications and CDKN2A/B deletion, drive tumor progression. The study further highlights a dynamic regulation of interferon (IFN) signaling during progression. In low-grade IDH-mutant gliomas, IFN responses are suppressed through epigenetic hypermethylation, which can be reversed with DNMT1 inhibitors or IDH inhibitors, leading to reactivation of the IFN pathway. In contrast, higher-grade gliomas evade IFN signaling through genetic deletions of IFN gene clusters. These findings emphasize a broader epigenetic-to-genetic shift in oncogenic regulation that drives glioma progression, provides a valuable framework for understanding the transition from indolent tumors to lethal malignancies, and has implications for therapy and clinical management.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"323 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904793","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}
Metastasis is the leading cause of mortality in breast cancer, with lung metastasis being particularly detrimental. Identification of the processes determining metastatic organotropism could enable the development of approaches to prevent and treat breast cancer metastasis. Here, we found that lung-tropic and non-lung-tropic breast cancer cells differ in their response to sialic acids, affecting the sialylation of surface proteins. Lung-tropic cells showed higher levels of ST6GAL1, while non-lung-tropic cells had more ST3GAL1. ST6GAL1-mediated α-2,6-sialylation, unlike ST3GAL1-mediated α-2,3-sialylation, increased lung metastasis by promoting cancer cell migration through pulmonary endothelial layers and reducing junction protein levels. α-2,6-sialylated PECAM-1 on breast cancer cells facilitated extravasation through the pulmonary endothelium, a critical step in lung metastasis. Knockdown of ST6GAL1 or PECAM-1 significantly reduced lung metastasis. Human pulmonary endothelium displayed high PECAM-1 levels. Through transhomophilic interaction with pulmonary PECAM-1, α-2,6-sialylated PECAM-1 on ST6GAL1-positive cancer cells increased pulmonary extravasation in a diapedesis-like, cell-autonomous manner. Additionally, lung-tropic cells and their exosomes increased the permeability of pulmonary endothelial cells, promoting metastasis in a non-cell-autonomous manner. Analysis of human breast cancer samples showed a correlation between elevated ST6GAL1/PECAM-1 expression and lung metastasis. These results suggest that targeting ST6GAL1-mediated α-2,6-sialylation could be a potential therapeutic strategy to prevent lung metastasis in breast cancer patients.
{"title":"ST6GAL1-Mediated Sialylation of PECAM-1 Promotes a Transcellular Diapedesis-Like Process that Directs Lung Tropism of Metastatic Breast Cancer","authors":"Shih-Yin Chen, Pei-Lin He, Li-Yu Lu, Meng-Chieh Lin, Shih-Hsuan Chan, Jia-Shiuan Tsai, Wen-Ting Luo, Lu-Hai Wang, Hua-Jung Li","doi":"10.1158/0008-5472.can-24-1550","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1550","url":null,"abstract":"Metastasis is the leading cause of mortality in breast cancer, with lung metastasis being particularly detrimental. Identification of the processes determining metastatic organotropism could enable the development of approaches to prevent and treat breast cancer metastasis. Here, we found that lung-tropic and non-lung-tropic breast cancer cells differ in their response to sialic acids, affecting the sialylation of surface proteins. Lung-tropic cells showed higher levels of ST6GAL1, while non-lung-tropic cells had more ST3GAL1. ST6GAL1-mediated α-2,6-sialylation, unlike ST3GAL1-mediated α-2,3-sialylation, increased lung metastasis by promoting cancer cell migration through pulmonary endothelial layers and reducing junction protein levels. α-2,6-sialylated PECAM-1 on breast cancer cells facilitated extravasation through the pulmonary endothelium, a critical step in lung metastasis. Knockdown of ST6GAL1 or PECAM-1 significantly reduced lung metastasis. Human pulmonary endothelium displayed high PECAM-1 levels. Through transhomophilic interaction with pulmonary PECAM-1, α-2,6-sialylated PECAM-1 on ST6GAL1-positive cancer cells increased pulmonary extravasation in a diapedesis-like, cell-autonomous manner. Additionally, lung-tropic cells and their exosomes increased the permeability of pulmonary endothelial cells, promoting metastasis in a non-cell-autonomous manner. Analysis of human breast cancer samples showed a correlation between elevated ST6GAL1/PECAM-1 expression and lung metastasis. These results suggest that targeting ST6GAL1-mediated α-2,6-sialylation could be a potential therapeutic strategy to prevent lung metastasis in breast cancer patients.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"33 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904999","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 : 2024-12-19DOI: 10.1158/0008-5472.can-24-1022
Miglena G. Prabagar, Michael McQueney, Venu Bommireddy, Rachael Siegel, Gary L. Schieven, Ku Lu, Ruziboy Husanov, Reema Deepak, David Diller, Chia-Yu Huang, Eli Mordechai, Rukiye-Nazan Eraslan
Bacillus Calmette-Guerin (BCG) is the current standard of care for non-muscle invasive bladder cancer (NMIBC), but recurrence is common. Additional therapeutic options are a major unmet medical need for treating unresponsive patients. Stimulator of Interferon Genes (STING) plays a central role in mounting innate and adaptive immune responses to tumor cells, and activation of STING is a promising immunotherapeutic approach. Here, we developed the STING agonist VB-85247 for treating NMIBC by intravesical delivery as a strategy to provide a sustained period of exposure to bladder cancer cells while avoiding potential issues associated with intratumoral injection of STING agonist, which to date have shown only limited clinical efficacy. VB-85247 induced complete response in an orthotopic NMIBC model in contrast to treatment with BCG, which was not efficasious in the model. The efficacious dose was well tolerated and induced an immune response with immunologic memory which protected from re-challenge without further treatment. Activation of the STING pathway via VB-85247 induced upregulation of inflammatory cytokines IFN-/β, TNF-, IL-6 and CXCL10, along with maturation and activation of dendritic cells. In addition, VB-85247 provided a therapeutic benefit in combination with immune checkpoint blockade using anti-PD1 antibody treatment. Together, these preclinical data support the potential utility of VB-85247 for treating BCG-unresponsive NMIBC patients and for enhancing the clinical benefit of potential of anti-PD1 in bladder cancer. Based on these data, VB-85247 is being advanced into clinical development.
{"title":"THE STING AGONIST VB-85247 INDUCES DURABLE ANTITUMOR IMMUNE RESPONSES BY INTRAVESICAL ADMINISTRATION IN A NON-MUSCLE INVASIVE BLADDER CANCER","authors":"Miglena G. Prabagar, Michael McQueney, Venu Bommireddy, Rachael Siegel, Gary L. Schieven, Ku Lu, Ruziboy Husanov, Reema Deepak, David Diller, Chia-Yu Huang, Eli Mordechai, Rukiye-Nazan Eraslan","doi":"10.1158/0008-5472.can-24-1022","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1022","url":null,"abstract":"Bacillus Calmette-Guerin (BCG) is the current standard of care for non-muscle invasive bladder cancer (NMIBC), but recurrence is common. Additional therapeutic options are a major unmet medical need for treating unresponsive patients. Stimulator of Interferon Genes (STING) plays a central role in mounting innate and adaptive immune responses to tumor cells, and activation of STING is a promising immunotherapeutic approach. Here, we developed the STING agonist VB-85247 for treating NMIBC by intravesical delivery as a strategy to provide a sustained period of exposure to bladder cancer cells while avoiding potential issues associated with intratumoral injection of STING agonist, which to date have shown only limited clinical efficacy. VB-85247 induced complete response in an orthotopic NMIBC model in contrast to treatment with BCG, which was not efficasious in the model. The efficacious dose was well tolerated and induced an immune response with immunologic memory which protected from re-challenge without further treatment. Activation of the STING pathway via VB-85247 induced upregulation of inflammatory cytokines IFN-/β, TNF-, IL-6 and CXCL10, along with maturation and activation of dendritic cells. In addition, VB-85247 provided a therapeutic benefit in combination with immune checkpoint blockade using anti-PD1 antibody treatment. Together, these preclinical data support the potential utility of VB-85247 for treating BCG-unresponsive NMIBC patients and for enhancing the clinical benefit of potential of anti-PD1 in bladder cancer. Based on these data, VB-85247 is being advanced into clinical development.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"86 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858407","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 : 2024-12-19DOI: 10.1158/0008-5472.can-24-0690
Jill C. Rubinstein, Sergii Domanskyi, Todd B. Sheridan, Brian Sanderson, SungHee Park, Jessica Kaster, Haiyin Li, Olga Anczukow, Meenhard Herlyn, Jeffrey H. Chuang
Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. A better understanding of the temporal dynamics and specific pathways leading into and out of the persister state is needed to identify strategies to prevent treatment failure. Using spatial transcriptomics in patient-derived xenograft models, we captured clonal lineage evolution during treatment. The persister state showed increased oxidative phosphorylation, decreased proliferation, and increased invasive capacity, with central-to-peripheral gradients. Phylogenetic tracing identified intrinsic and acquired resistance mechanisms (e.g., dual specific phosphatases, reticulon-4, and CDK2) and suggested specific temporal windows of potential therapeutic susceptibility. Deep learning-enabled analysis of histopathological slides revealed morphological features correlating with specific cell states, demonstrating that juxtaposition of transcriptomics and histological data enabled identification of phenotypically distinct populations from using imaging data alone. In summary, this study defined state change and lineage selection during melanoma treatment with spatiotemporal resolution, elucidating how choice and timing of therapeutic agents will impact the ability to eradicate resistant clones.
{"title":"Spatiotemporal Profiling Defines Persistence and Resistance Dynamics During Targeted Treatment of Melanoma","authors":"Jill C. Rubinstein, Sergii Domanskyi, Todd B. Sheridan, Brian Sanderson, SungHee Park, Jessica Kaster, Haiyin Li, Olga Anczukow, Meenhard Herlyn, Jeffrey H. Chuang","doi":"10.1158/0008-5472.can-24-0690","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0690","url":null,"abstract":"Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. A better understanding of the temporal dynamics and specific pathways leading into and out of the persister state is needed to identify strategies to prevent treatment failure. Using spatial transcriptomics in patient-derived xenograft models, we captured clonal lineage evolution during treatment. The persister state showed increased oxidative phosphorylation, decreased proliferation, and increased invasive capacity, with central-to-peripheral gradients. Phylogenetic tracing identified intrinsic and acquired resistance mechanisms (e.g., dual specific phosphatases, reticulon-4, and CDK2) and suggested specific temporal windows of potential therapeutic susceptibility. Deep learning-enabled analysis of histopathological slides revealed morphological features correlating with specific cell states, demonstrating that juxtaposition of transcriptomics and histological data enabled identification of phenotypically distinct populations from using imaging data alone. In summary, this study defined state change and lineage selection during melanoma treatment with spatiotemporal resolution, elucidating how choice and timing of therapeutic agents will impact the ability to eradicate resistant clones.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"48 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858415","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 : 2024-12-19DOI: 10.1158/0008-5472.can-23-2194
Luiza Martins. Nascentes Melo, Marie Sabatier, Vijayashree Ramesh, Krystina J. Szylo, Cameron S. Fraser, Alexandra Pon, Evann C. Mitchell, Kelly A. Servage, Gabriele Allies, Isa V. Westedt, Feyza Cansiz, Jonathan Krystkiewicz, Andrea Kutritz, Dirk Schadendorf, Sean J. Morrison, Jessalyn M. Ubellacker, Anju Sreelatha, Alpaslan Tasdogan
Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homologue of SELENOO. Here, we revealed that SELENOO promotes cancer metastasis and identified substrates of SELENOO in mammalian mitochondria. In patients with melanoma, high SELENOO expression was correlated with metastasis and poor overall survival. In a murine model of spontaneous melanoma metastasis, SELENOO deficiency significantly reduced metastasis to distant visceral organs, which could be rescued by treatment with the antioxidant N-acetylcysteine. Mechanistically, SELENOO AMPylated multiple mitochondrial substrates, including succinate dehydrogenase subunit A, one of the four key subunits of mitochondrial complex II. Consistently, SELENOO-deficient cells featured increased mitochondrial complex II activity. Together, these findings demonstrate that SELENOO deficiency limits melanoma metastasis by modulating mitochondrial function and oxidative stress.
{"title":"Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity","authors":"Luiza Martins. Nascentes Melo, Marie Sabatier, Vijayashree Ramesh, Krystina J. Szylo, Cameron S. Fraser, Alexandra Pon, Evann C. Mitchell, Kelly A. Servage, Gabriele Allies, Isa V. Westedt, Feyza Cansiz, Jonathan Krystkiewicz, Andrea Kutritz, Dirk Schadendorf, Sean J. Morrison, Jessalyn M. Ubellacker, Anju Sreelatha, Alpaslan Tasdogan","doi":"10.1158/0008-5472.can-23-2194","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-2194","url":null,"abstract":"Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homologue of SELENOO. Here, we revealed that SELENOO promotes cancer metastasis and identified substrates of SELENOO in mammalian mitochondria. In patients with melanoma, high SELENOO expression was correlated with metastasis and poor overall survival. In a murine model of spontaneous melanoma metastasis, SELENOO deficiency significantly reduced metastasis to distant visceral organs, which could be rescued by treatment with the antioxidant N-acetylcysteine. Mechanistically, SELENOO AMPylated multiple mitochondrial substrates, including succinate dehydrogenase subunit A, one of the four key subunits of mitochondrial complex II. Consistently, SELENOO-deficient cells featured increased mitochondrial complex II activity. Together, these findings demonstrate that SELENOO deficiency limits melanoma metastasis by modulating mitochondrial function and oxidative stress.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"100 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858416","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 : 2024-12-19DOI: 10.1158/0008-5472.can-24-3304
Hetakshi P. Kurani, Joyce M. Slingerland
Tumor-initiating cancer stem cells (CSC) pose a challenge in human malignancies since they are largely treatment resistant and can seed local recurrence and metastasis. Epigenetic mechanisms governing cell fate decisions in embryonic and adult stem cells are deregulated in CSCs. This review focuses on the methyltransferase DOT1L, which methylates H3K79 and is a key epigenetic regulator governing embryonic organogenesis and adult tissue stem cell maintenance. DOT1L is overexpressed in many human malignancies, and dysregulated H3K79 methylation is pathogenic in acute myeloid leukemia and several solid tumors. DOT1L regulates core stem cell genes governing CSC self-renewal, tumorigenesis, and multidrug resistance. Recent work has situated DOT1L as an attractive stem cell target in cancer. These reports showed that DOT1L is overexpressed and its protein activated specifically in malignant stem cells compared to bulk tumor cells, making them vulnerable to DOT1L inhibition in vitro and in vivo. While early DOT1L inhibitor clinical trials were limited by inadequate drug bioavailability, accumulating preclinical data indicate that DOT1L critically regulates CSC self-renewal and might be more effective when given with other anticancer therapies. The appropriate combinations of DOT1L inhibitors with other agents and the sequence and timing of drug delivery for maximum efficacy warrant further investigation.
{"title":"DOT1L mediates stem cell maintenance and represents a therapeutic vulnerability in cancer","authors":"Hetakshi P. Kurani, Joyce M. Slingerland","doi":"10.1158/0008-5472.can-24-3304","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3304","url":null,"abstract":"Tumor-initiating cancer stem cells (CSC) pose a challenge in human malignancies since they are largely treatment resistant and can seed local recurrence and metastasis. Epigenetic mechanisms governing cell fate decisions in embryonic and adult stem cells are deregulated in CSCs. This review focuses on the methyltransferase DOT1L, which methylates H3K79 and is a key epigenetic regulator governing embryonic organogenesis and adult tissue stem cell maintenance. DOT1L is overexpressed in many human malignancies, and dysregulated H3K79 methylation is pathogenic in acute myeloid leukemia and several solid tumors. DOT1L regulates core stem cell genes governing CSC self-renewal, tumorigenesis, and multidrug resistance. Recent work has situated DOT1L as an attractive stem cell target in cancer. These reports showed that DOT1L is overexpressed and its protein activated specifically in malignant stem cells compared to bulk tumor cells, making them vulnerable to DOT1L inhibition in vitro and in vivo. While early DOT1L inhibitor clinical trials were limited by inadequate drug bioavailability, accumulating preclinical data indicate that DOT1L critically regulates CSC self-renewal and might be more effective when given with other anticancer therapies. The appropriate combinations of DOT1L inhibitors with other agents and the sequence and timing of drug delivery for maximum efficacy warrant further investigation.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"55 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858408","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 : 2024-12-19DOI: 10.1158/0008-5472.can-24-0323
Jeremy B. Foote, Tyler E. Mattox, Adam B. Keeton, Xi Chen, Forrest T. Smith, Kristy Berry, Thomas W. Holmes, Junwei Wang, Chung-hui Huang, Antonio Ward, AMIT K. Mitra, Veronica Ramirez-Alcantara, Cherlene Hardy, Karianne G. Fleten, Kjersti Flatmark, Karina J. Yoon, Sujith Sarvesh, Ganji P. Nagaraju, Dhana Sekhar Reddy Bandi, Yulia Y. Maxuitenko, Jacaob Valiyaveettil, Julienne L. Carstens, Donald J. Buchsbaum, Jennifer Yang, Gang Zhou, Elmar Nurmemmedov, Ivan Babic, Vadim Gaponeko, Hazem Abdelkarim, Michael R. Boyd, Greg Gorman, Upender Manne, Sejong Bae, Bassel F. El-Rayes, Gary A. Piazza
RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. Here, we developed a pan-RAS inhibitor, ADT-007, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme, and RASWT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases that were expressed in RASWT and normal cells but repressed in RAS mutant cancer cells. ADT-007 displayed unique advantages over KRAS mutant-specific, pan-KRAS, and pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms that lead to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth. Thus, ADT-007 has the potential to address the complex RAS mutational landscape of many human cancers and to improve treatment of RAS-driven tumors.
{"title":"A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer","authors":"Jeremy B. Foote, Tyler E. Mattox, Adam B. Keeton, Xi Chen, Forrest T. Smith, Kristy Berry, Thomas W. Holmes, Junwei Wang, Chung-hui Huang, Antonio Ward, AMIT K. Mitra, Veronica Ramirez-Alcantara, Cherlene Hardy, Karianne G. Fleten, Kjersti Flatmark, Karina J. Yoon, Sujith Sarvesh, Ganji P. Nagaraju, Dhana Sekhar Reddy Bandi, Yulia Y. Maxuitenko, Jacaob Valiyaveettil, Julienne L. Carstens, Donald J. Buchsbaum, Jennifer Yang, Gang Zhou, Elmar Nurmemmedov, Ivan Babic, Vadim Gaponeko, Hazem Abdelkarim, Michael R. Boyd, Greg Gorman, Upender Manne, Sejong Bae, Bassel F. El-Rayes, Gary A. Piazza","doi":"10.1158/0008-5472.can-24-0323","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0323","url":null,"abstract":"RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. Here, we developed a pan-RAS inhibitor, ADT-007, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme, and RASWT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases that were expressed in RASWT and normal cells but repressed in RAS mutant cancer cells. ADT-007 displayed unique advantages over KRAS mutant-specific, pan-KRAS, and pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms that lead to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth. Thus, ADT-007 has the potential to address the complex RAS mutational landscape of many human cancers and to improve treatment of RAS-driven tumors.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858409","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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