Pub Date : 2024-07-26DOI: 10.1038/s41698-024-00642-6
Shengnan Chen, Tao Hu, Jikai Zhao, Qian Zhu, Jin Wang, Zhan Huang, Chan Xiang, Ruiying Zhao, Changbin Zhu, Shun Lu, Yuchen Han
Not all MET exon 14 skipping (METex14) NSCLC patients benefited from MET inhibitors. We hypothesized an inter-tumoral heterogeneity in METex14 NSCLC. Investigations at genomic and transcriptomic level were conducted in METex14 NSCLC samples from stage I-III and recurrent/metastatic patients as discovery and validation cohort. Four molecular subtypes were discovered. MET-Driven subtype, with the worst prognosis, displayed MET overexpression, enrichment of MET-related pathways, and higher infiltration of fibroblast and regulatory T cells. Immune-Activated subtype having the most idea long-term survival, had higher tertiary lymphoid structures, spatial co-option of PD-L1+ cancer cells, and GZMK+ CD8+ T cell. FGFR- and Bypass-Activated subtypes displayed FGFR2 overexpression and enrichments of multiple oncogenic pathways respectively. In the validation cohort, patients with MET-Driven subtype had better response to MET inhibitors than those with MET overexpression. Thus, molecular subtypes of METex14 NSCLC with distinct biological and clinical significance may indicate more precise therapeutic strategies for METex14 NSCLC patients.
{"title":"Novel molecular subtypes of METex14 non-small cell lung cancer with distinct biological and clinical significance","authors":"Shengnan Chen, Tao Hu, Jikai Zhao, Qian Zhu, Jin Wang, Zhan Huang, Chan Xiang, Ruiying Zhao, Changbin Zhu, Shun Lu, Yuchen Han","doi":"10.1038/s41698-024-00642-6","DOIUrl":"10.1038/s41698-024-00642-6","url":null,"abstract":"Not all MET exon 14 skipping (METex14) NSCLC patients benefited from MET inhibitors. We hypothesized an inter-tumoral heterogeneity in METex14 NSCLC. Investigations at genomic and transcriptomic level were conducted in METex14 NSCLC samples from stage I-III and recurrent/metastatic patients as discovery and validation cohort. Four molecular subtypes were discovered. MET-Driven subtype, with the worst prognosis, displayed MET overexpression, enrichment of MET-related pathways, and higher infiltration of fibroblast and regulatory T cells. Immune-Activated subtype having the most idea long-term survival, had higher tertiary lymphoid structures, spatial co-option of PD-L1+ cancer cells, and GZMK+ CD8+ T cell. FGFR- and Bypass-Activated subtypes displayed FGFR2 overexpression and enrichments of multiple oncogenic pathways respectively. In the validation cohort, patients with MET-Driven subtype had better response to MET inhibitors than those with MET overexpression. Thus, molecular subtypes of METex14 NSCLC with distinct biological and clinical significance may indicate more precise therapeutic strategies for METex14 NSCLC patients.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-25DOI: 10.1038/s41698-024-00653-3
Thomas Freitag, Philipp Kaps, Justus Ramtke, Sarah Bertels, Emily Zunke, Björn Schneider, Anne-Sophie Becker, Dirk Koczan, Daniel Dubinski, Thomas M. Freiman, Felix Wittig, Burkhard Hinz, Mike-Andrew Westhoff, Hannah Strobel, Franziska Meiners, Daniel Wolter, Nadja Engel, Sascha Troschke-Meurer, Wendy Bergmann-Ewert, Susanne Staehlke, Annabell Wolff, Florian Gessler, Christian Junghanss, Claudia Maletzki
He, we show that combined use of the EZH2 inhibitor GSK126 and the CDK4/6 inhibitor abemaciclib synergistically enhances antitumoral effects in preclinical GBM models. Dual blockade led to HIF1α upregulation and CalR translocation, accompanied by massive impairment of mitochondrial function. Basal oxygen consumption rate, ATP synthesis, and maximal mitochondrial respiration decreased, confirming disrupted endoplasmic reticulum-mitochondrial homeostasis. This was paralleled by mitochondrial depolarization and upregulation of the UPR sensors PERK, ATF6α, and IRE1α. Notably, dual EZH2/CDK4/6 blockade also reduced 3D-spheroid invasion, partially inhibited tumor growth in ovo, and led to impaired viability of patient-derived organoids. Mechanistically, this was due to transcriptional changes in genes involved in mitotic aberrations/spindle assembly (Rb, PLK1, RRM2, PRC1, CENPF, TPX2), histone modification (HIST1H1B, HIST1H3G), DNA damage/replication stress events (TOP2A, ATF4), immuno-oncology (DEPDC1), EMT-counterregulation (PCDH1) and a shift in the stemness profile towards a more differentiated state. We propose a dual EZH2/CDK4/6 blockade for further investigation.
{"title":"Combined inhibition of EZH2 and CDK4/6 perturbs endoplasmic reticulum-mitochondrial homeostasis and increases antitumor activity against glioblastoma","authors":"Thomas Freitag, Philipp Kaps, Justus Ramtke, Sarah Bertels, Emily Zunke, Björn Schneider, Anne-Sophie Becker, Dirk Koczan, Daniel Dubinski, Thomas M. Freiman, Felix Wittig, Burkhard Hinz, Mike-Andrew Westhoff, Hannah Strobel, Franziska Meiners, Daniel Wolter, Nadja Engel, Sascha Troschke-Meurer, Wendy Bergmann-Ewert, Susanne Staehlke, Annabell Wolff, Florian Gessler, Christian Junghanss, Claudia Maletzki","doi":"10.1038/s41698-024-00653-3","DOIUrl":"10.1038/s41698-024-00653-3","url":null,"abstract":"He, we show that combined use of the EZH2 inhibitor GSK126 and the CDK4/6 inhibitor abemaciclib synergistically enhances antitumoral effects in preclinical GBM models. Dual blockade led to HIF1α upregulation and CalR translocation, accompanied by massive impairment of mitochondrial function. Basal oxygen consumption rate, ATP synthesis, and maximal mitochondrial respiration decreased, confirming disrupted endoplasmic reticulum-mitochondrial homeostasis. This was paralleled by mitochondrial depolarization and upregulation of the UPR sensors PERK, ATF6α, and IRE1α. Notably, dual EZH2/CDK4/6 blockade also reduced 3D-spheroid invasion, partially inhibited tumor growth in ovo, and led to impaired viability of patient-derived organoids. Mechanistically, this was due to transcriptional changes in genes involved in mitotic aberrations/spindle assembly (Rb, PLK1, RRM2, PRC1, CENPF, TPX2), histone modification (HIST1H1B, HIST1H3G), DNA damage/replication stress events (TOP2A, ATF4), immuno-oncology (DEPDC1), EMT-counterregulation (PCDH1) and a shift in the stemness profile towards a more differentiated state. We propose a dual EZH2/CDK4/6 blockade for further investigation.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11272933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Multiple pulmonary lung cancers (MPLCs) are frequently encountered on computed tomography (CT) scanning of chest, yet their intrinsic characteristics associated with genomic features and radiological or pathological textures that may lead to distinct clinical outcomes remain largely unexplored. A total of 27 pulmonary nodules covering different radiological or pathological textures as well as matched adjacent normal tissues and blood samples were collected from patients diagnosed with MPLCs. Whole-exome sequencing (WES) and whole-transcriptome sequencing were performed. The molecular and immune features of MPLCs associated with distinct radiological or pathological textures were comprehensively investigated. Genomics analysis unveiled the distinct branches of pulmonary nodules originating independently within the same individual. EGFR and KRAS mutations were found to be prevalent in MPLCs, exhibiting mutual exclusivity. The group with KRAS mutations exhibited stronger immune signatures compared to the group with EGFR mutations. Additionally, MPLCs exhibited a pronounced immunosuppressive microenvironment, which was particularly distinct when compared with normal tissues. The expression of the FDSCP gene was specifically observed in MPLCs. When categorizing MPLCs based on radiological or pathological characteristics, a progressive increase in mutation accumulation was observed, accompanied by heightened chromatin-level instability as ground-glass opacity component declined or invasive progression occurred. A close association with the immunosuppressive microenvironment was also observed during the progression of pulmonary nodules. Notably, the upregulation of B cell and regulatory T cell marker genes occurred progressively. Immune cell abundance analysis further demonstrated a marked increase in exhausted cells and regulatory T cells during the progression of pulmonary nodules. These results were further validated by independent datasets including nCounter RNA profiling, single-cell RNA sequencing, and spatial transcriptomic datasets. Our study provided a comprehensive representation of the diverse landscape of MPLCs originating within the same individual and emphasized the significant influence of the immunosuppressive microenvironment in the occurrence and development of pulmonary nodules. These findings hold great potential for enhancing the clinical diagnosis and treatment strategies for MPLCs.
{"title":"Multi-omics analysis unveils immunosuppressive microenvironment in the occurrence and development of multiple pulmonary lung cancers","authors":"Jiatao Zhang, Wenhao Zhou, Na Li, Huaming Li, Haitao Luo, Benyuan Jiang","doi":"10.1038/s41698-024-00651-5","DOIUrl":"10.1038/s41698-024-00651-5","url":null,"abstract":"Multiple pulmonary lung cancers (MPLCs) are frequently encountered on computed tomography (CT) scanning of chest, yet their intrinsic characteristics associated with genomic features and radiological or pathological textures that may lead to distinct clinical outcomes remain largely unexplored. A total of 27 pulmonary nodules covering different radiological or pathological textures as well as matched adjacent normal tissues and blood samples were collected from patients diagnosed with MPLCs. Whole-exome sequencing (WES) and whole-transcriptome sequencing were performed. The molecular and immune features of MPLCs associated with distinct radiological or pathological textures were comprehensively investigated. Genomics analysis unveiled the distinct branches of pulmonary nodules originating independently within the same individual. EGFR and KRAS mutations were found to be prevalent in MPLCs, exhibiting mutual exclusivity. The group with KRAS mutations exhibited stronger immune signatures compared to the group with EGFR mutations. Additionally, MPLCs exhibited a pronounced immunosuppressive microenvironment, which was particularly distinct when compared with normal tissues. The expression of the FDSCP gene was specifically observed in MPLCs. When categorizing MPLCs based on radiological or pathological characteristics, a progressive increase in mutation accumulation was observed, accompanied by heightened chromatin-level instability as ground-glass opacity component declined or invasive progression occurred. A close association with the immunosuppressive microenvironment was also observed during the progression of pulmonary nodules. Notably, the upregulation of B cell and regulatory T cell marker genes occurred progressively. Immune cell abundance analysis further demonstrated a marked increase in exhausted cells and regulatory T cells during the progression of pulmonary nodules. These results were further validated by independent datasets including nCounter RNA profiling, single-cell RNA sequencing, and spatial transcriptomic datasets. Our study provided a comprehensive representation of the diverse landscape of MPLCs originating within the same individual and emphasized the significant influence of the immunosuppressive microenvironment in the occurrence and development of pulmonary nodules. These findings hold great potential for enhancing the clinical diagnosis and treatment strategies for MPLCs.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11266694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-23DOI: 10.1038/s41698-024-00655-1
Sydney Camfield, Sayan Chakraborty, Shailendra Kumar Dhar Dwivedi, Pijush Kanti Pramanik, Priyabrata Mukherjee, Resham Bhattacharya
The canonical role of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in repairing DNA double-strand breaks combined with its reported dysregulation in several malignancies has driven the development of DNA-PKcs inhibitors as therapeutics. However, until recently the relationship between DNA-PKcs and tumorigenesis has been primarily investigated with regard to its role in non-homologous end joining (NHEJ) repair. Emerging research has uncovered non-canonical DNA-PKcs functions involved with transcriptional regulation, telomere maintenance, metabolic regulation, and immune signaling all of which may also impinge on tumorigenesis. This review mainly discusses these non-canonical roles of DNA-PKcs in cellular biology and their potential contribution to tumorigenesis, as well as evaluating the implications of targeting DNA-PKcs for cancer therapy.
{"title":"Secrets of DNA-PKcs beyond DNA repair","authors":"Sydney Camfield, Sayan Chakraborty, Shailendra Kumar Dhar Dwivedi, Pijush Kanti Pramanik, Priyabrata Mukherjee, Resham Bhattacharya","doi":"10.1038/s41698-024-00655-1","DOIUrl":"10.1038/s41698-024-00655-1","url":null,"abstract":"The canonical role of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in repairing DNA double-strand breaks combined with its reported dysregulation in several malignancies has driven the development of DNA-PKcs inhibitors as therapeutics. However, until recently the relationship between DNA-PKcs and tumorigenesis has been primarily investigated with regard to its role in non-homologous end joining (NHEJ) repair. Emerging research has uncovered non-canonical DNA-PKcs functions involved with transcriptional regulation, telomere maintenance, metabolic regulation, and immune signaling all of which may also impinge on tumorigenesis. This review mainly discusses these non-canonical roles of DNA-PKcs in cellular biology and their potential contribution to tumorigenesis, as well as evaluating the implications of targeting DNA-PKcs for cancer therapy.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11266574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-20DOI: 10.1038/s41698-024-00644-4
Saumya D. Sisoudiya, Armande Ang Houle, Tharu Fernando, Timothy R. Wilson, Jennifer L. Schutzman, Jessica Lee, Alexa Schrock, Ethan S. Sokol, Smruthy Sivakumar, Zhen Shi, Gaurav Pathria
Racial/ethnic disparities mar NSCLC care and treatment outcomes. While socioeconomic factors and access to healthcare are important drivers of NSCLC disparities, a deeper understanding of genetic ancestry-associated genomic landscapes can better inform the biology and the treatment actionability for these tumors. We present a comprehensive ancestry-based prevalence and co-alteration landscape of genomic alterations and immunotherapy-associated biomarkers in patients with KRAS and EGFR-altered non-squamous (non-Sq) NSCLC. KRAS was the most frequently altered oncogene in European (EUR) and African (AFR), while EGFR alterations predominated in East Asian (EAS), South Asian (SAS), and Admixed American (AMR) groups, consistent with prior studies. As expected, STK11 and KEAP1 alterations co-occurred with KRAS alterations while showing mutual exclusivity with EGFR alterations. EAS and AMR KRAS-altered non-Sq NSCLC showed lower rates of co-occurring STK11 and KEAP1 alterations relative to other ancestry groups. Ancestry-specific co-alterations included the co-occurrence of KRAS and GNAS alterations in AMR, KRAS, and ARID1A alterations in SAS, and the mutual exclusivity of KRAS and NF1 alterations in the EUR and AFR ancestries. Contrastingly, EGFR-altered tumors exhibited a more conserved co-alteration landscape across ancestries. AFR exhibited the highest tumor mutational burden, with potential therapeutic implications for these tumors.
{"title":"Ancestry-associated co-alteration landscape of KRAS and EGFR-altered non-squamous NSCLC","authors":"Saumya D. Sisoudiya, Armande Ang Houle, Tharu Fernando, Timothy R. Wilson, Jennifer L. Schutzman, Jessica Lee, Alexa Schrock, Ethan S. Sokol, Smruthy Sivakumar, Zhen Shi, Gaurav Pathria","doi":"10.1038/s41698-024-00644-4","DOIUrl":"10.1038/s41698-024-00644-4","url":null,"abstract":"Racial/ethnic disparities mar NSCLC care and treatment outcomes. While socioeconomic factors and access to healthcare are important drivers of NSCLC disparities, a deeper understanding of genetic ancestry-associated genomic landscapes can better inform the biology and the treatment actionability for these tumors. We present a comprehensive ancestry-based prevalence and co-alteration landscape of genomic alterations and immunotherapy-associated biomarkers in patients with KRAS and EGFR-altered non-squamous (non-Sq) NSCLC. KRAS was the most frequently altered oncogene in European (EUR) and African (AFR), while EGFR alterations predominated in East Asian (EAS), South Asian (SAS), and Admixed American (AMR) groups, consistent with prior studies. As expected, STK11 and KEAP1 alterations co-occurred with KRAS alterations while showing mutual exclusivity with EGFR alterations. EAS and AMR KRAS-altered non-Sq NSCLC showed lower rates of co-occurring STK11 and KEAP1 alterations relative to other ancestry groups. Ancestry-specific co-alterations included the co-occurrence of KRAS and GNAS alterations in AMR, KRAS, and ARID1A alterations in SAS, and the mutual exclusivity of KRAS and NF1 alterations in the EUR and AFR ancestries. Contrastingly, EGFR-altered tumors exhibited a more conserved co-alteration landscape across ancestries. AFR exhibited the highest tumor mutational burden, with potential therapeutic implications for these tumors.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00644-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-20DOI: 10.1038/s41698-024-00638-2
Antonio Lahera, Laura Vela-Martín, Pablo Fernández-Navarro, Pilar Llamas, José L. López-Lorenzo, Javier Cornago, Javier Santos, José Fernández-Piqueras, María Villa-Morales
Precursor T-cell neoplasms (T-ALL/LBL) are aggressive hematological malignancies that arise from the malignant transformation of immature thymocytes. Despite the JAK/STAT pathway is recurrently altered in these neoplasms, there are not pharmacological inhibitors officially approved for the treatment of T-ALL/LBL patients that present oncogenic JAK/STAT pathway mutations. In the effort to identify potential therapeutic targets for those patients, we followed an alternative approach and focused on their transcriptional profile. We combined the analysis of molecular data from T-ALL/LBL patients with the generation of hematopoietic cellular models to reveal that JAK/STAT pathway mutations are associated with an aberrant transcriptional profile. Specifically, we demonstrate that JAK/STAT pathway mutations induce the overexpression of the PIM1 gene. Moreover, we show that the pan-PIM inhibitor, PIM447, significantly reduces the leukemogenesis, as well as the aberrant activation of c-MYC and mTOR pathways in cells expressing different JAK/STAT pathway mutations, becoming a potential therapeutic opportunity for a relevant subset of T-ALL/LBL patients.
{"title":"PIM1 is a potential therapeutic target for the leukemogenic effects mediated by JAK/STAT pathway mutations in T-ALL/LBL","authors":"Antonio Lahera, Laura Vela-Martín, Pablo Fernández-Navarro, Pilar Llamas, José L. López-Lorenzo, Javier Cornago, Javier Santos, José Fernández-Piqueras, María Villa-Morales","doi":"10.1038/s41698-024-00638-2","DOIUrl":"10.1038/s41698-024-00638-2","url":null,"abstract":"Precursor T-cell neoplasms (T-ALL/LBL) are aggressive hematological malignancies that arise from the malignant transformation of immature thymocytes. Despite the JAK/STAT pathway is recurrently altered in these neoplasms, there are not pharmacological inhibitors officially approved for the treatment of T-ALL/LBL patients that present oncogenic JAK/STAT pathway mutations. In the effort to identify potential therapeutic targets for those patients, we followed an alternative approach and focused on their transcriptional profile. We combined the analysis of molecular data from T-ALL/LBL patients with the generation of hematopoietic cellular models to reveal that JAK/STAT pathway mutations are associated with an aberrant transcriptional profile. Specifically, we demonstrate that JAK/STAT pathway mutations induce the overexpression of the PIM1 gene. Moreover, we show that the pan-PIM inhibitor, PIM447, significantly reduces the leukemogenesis, as well as the aberrant activation of c-MYC and mTOR pathways in cells expressing different JAK/STAT pathway mutations, becoming a potential therapeutic opportunity for a relevant subset of T-ALL/LBL patients.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00638-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-19DOI: 10.1038/s41698-024-00646-2
Mathew D. Lin, Alexander C.-Y. Tsai, Kalil G. Abdullah, Samuel K. McBrayer, Diana D. Shi
Gliomas are the most common primary brain tumor and are uniformly lethal. Despite significant advancements in understanding the genetic landscape of gliomas, standard-of-care has remained largely unchanged. Subsets of gliomas are defined by gain-of-function mutations in the metabolic genes encoding isocitrate dehydrogenase (IDH). Efforts to exploit mutant IDH activity and/or directly inhibit it with mutant IDH inhibitors have been the focus of over a decade of research. The recently published INDIGO trial, demonstrating the benefit of the mutant IDH inhibitor vorasidenib in patients with low-grade IDH-mutant gliomas, introduces a new era of precision medicine in brain tumors that is poised to change standard-of-care. In this review, we highlight and contextualize the results of the INDIGO trial and introduce key questions whose answers will guide how mutant IDH inhibitors may be used in the clinic. We discuss possible combination therapies with mutant IDH inhibition and future directions for clinical and translational research.
{"title":"Treatment of IDH-mutant glioma in the INDIGO era","authors":"Mathew D. Lin, Alexander C.-Y. Tsai, Kalil G. Abdullah, Samuel K. McBrayer, Diana D. Shi","doi":"10.1038/s41698-024-00646-2","DOIUrl":"10.1038/s41698-024-00646-2","url":null,"abstract":"Gliomas are the most common primary brain tumor and are uniformly lethal. Despite significant advancements in understanding the genetic landscape of gliomas, standard-of-care has remained largely unchanged. Subsets of gliomas are defined by gain-of-function mutations in the metabolic genes encoding isocitrate dehydrogenase (IDH). Efforts to exploit mutant IDH activity and/or directly inhibit it with mutant IDH inhibitors have been the focus of over a decade of research. The recently published INDIGO trial, demonstrating the benefit of the mutant IDH inhibitor vorasidenib in patients with low-grade IDH-mutant gliomas, introduces a new era of precision medicine in brain tumors that is poised to change standard-of-care. In this review, we highlight and contextualize the results of the INDIGO trial and introduce key questions whose answers will guide how mutant IDH inhibitors may be used in the clinic. We discuss possible combination therapies with mutant IDH inhibition and future directions for clinical and translational research.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00646-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-19DOI: 10.1038/s41698-024-00641-7
Helen Gogas, Shruthi Ravimohan, Antara Datta, Aparna Chhibber, Eva Muñoz Couselo, Adi Diab, Caio Pereira, Gaëlle Quéreux, Shahneen Sandhu, Brendan Curti, Nikhil I. Khushalani, Matthew H. Taylor, Gregory A. Daniels, Anna Spreafico, Tarek Meniawy, Alfons J. M. Van Den Eertwegh, Yongliang Sun, Yull Arriaga, Ming Zhou, Georgina V. Long, Céleste Lebbé
In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels. On-treatment peripheral biomarker changes showed that BEMPEG + NIVO increased all immune cell subset counts interrogated, including regulatory T cells. This was followed by attenuation of the increase in CD8 + T cells, conventional CD4 + T cells, and systemic interferon gamma levels at later treatment cycles in the combination arm. Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001.
在PIVOT IO 001 (NCT03635983)研究中，在不可切除/转移性黑色素瘤患者中，研究性白细胞介素-2激动剂bempegaldesleukin (BEMPEG)与nivolumab (NIVO)联合治疗与NIVO单药治疗相比没有额外的临床获益。研究人员分析了选定生物标志物的预设基线和治疗过程中的变化，以探索临床观察结果的潜在机制。在每个治疗组中，基线肿瘤突变负荷或免疫浸润/炎症水平越高，疗效越好。治疗期间外周生物标志物的变化显示，BEMPEG + NIVO 增加了所有被检测的免疫细胞亚群数量，包括调节性 T 细胞。随后，CD8 + T细胞、常规CD4 + T细胞和全身γ干扰素水平的增加在联合治疗组的后期治疗周期中有所减弱。不同治疗组的肿瘤生物标志物变化相当。这些生物标志物结果有助于更好地了解 BEMPEG + NIVO 的作用机制，并有助于将 PIVOT IO 001 的临床观察结果与实际情况相结合。
{"title":"Baseline biomarkers of efficacy and on-treatment immune-profile changes associated with bempegaldesleukin plus nivolumab","authors":"Helen Gogas, Shruthi Ravimohan, Antara Datta, Aparna Chhibber, Eva Muñoz Couselo, Adi Diab, Caio Pereira, Gaëlle Quéreux, Shahneen Sandhu, Brendan Curti, Nikhil I. Khushalani, Matthew H. Taylor, Gregory A. Daniels, Anna Spreafico, Tarek Meniawy, Alfons J. M. Van Den Eertwegh, Yongliang Sun, Yull Arriaga, Ming Zhou, Georgina V. Long, Céleste Lebbé","doi":"10.1038/s41698-024-00641-7","DOIUrl":"10.1038/s41698-024-00641-7","url":null,"abstract":"In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels. On-treatment peripheral biomarker changes showed that BEMPEG + NIVO increased all immune cell subset counts interrogated, including regulatory T cells. This was followed by attenuation of the increase in CD8 + T cells, conventional CD4 + T cells, and systemic interferon gamma levels at later treatment cycles in the combination arm. Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00641-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-19DOI: 10.1038/s41698-024-00652-4
Maryam Asadi-Aghbolaghi, Amirali Darbandsari, Allen Zhang, Alberto Contreras-Sanz, Jeffrey Boschman, Pouya Ahmadvand, Martin Köbel, David Farnell, David G. Huntsman, Andrew Churg, Peter C. Black, Gang Wang, C. Blake Gilks, Hossein Farahani, Ali Bashashati
Investigation of histopathology slides by pathologists is an indispensable component of the routine diagnosis of cancer. Artificial intelligence (AI) has the potential to enhance diagnostic accuracy, improve efficiency, and patient outcomes in clinical pathology. However, variations in tissue preparation, staining protocols, and histopathology slide digitization could result in over-fitting of deep learning models when trained on the data from only one center, thereby underscoring the necessity to generalize deep learning networks for multi-center use. Several techniques, including the use of grayscale images, color normalization techniques, and Adversarial Domain Adaptation (ADA) have been suggested to generalize deep learning algorithms, but there are limitations to their effectiveness and discriminability. Convolutional Neural Networks (CNNs) exhibit higher sensitivity to variations in the amplitude spectrum, whereas humans predominantly rely on phase-related components for object recognition. As such, we propose Adversarial fourIer-based Domain Adaptation (AIDA) which applies the advantages of a Fourier transform in adversarial domain adaptation. We conducted a comprehensive examination of subtype classification tasks in four cancers, incorporating cases from multiple medical centers. Specifically, the datasets included multi-center data for 1113 ovarian cancer cases, 247 pleural cancer cases, 422 bladder cancer cases, and 482 breast cancer cases. Our proposed approach significantly improved performance, achieving superior classification results in the target domain, surpassing the baseline, color augmentation and normalization techniques, and ADA. Furthermore, extensive pathologist reviews suggested that our proposed approach, AIDA, successfully identifies known histotype-specific features. This superior performance highlights AIDA’s potential in addressing generalization challenges in deep learning models for multi-center histopathology datasets.
{"title":"Learning generalizable AI models for multi-center histopathology image classification","authors":"Maryam Asadi-Aghbolaghi, Amirali Darbandsari, Allen Zhang, Alberto Contreras-Sanz, Jeffrey Boschman, Pouya Ahmadvand, Martin Köbel, David Farnell, David G. Huntsman, Andrew Churg, Peter C. Black, Gang Wang, C. Blake Gilks, Hossein Farahani, Ali Bashashati","doi":"10.1038/s41698-024-00652-4","DOIUrl":"10.1038/s41698-024-00652-4","url":null,"abstract":"Investigation of histopathology slides by pathologists is an indispensable component of the routine diagnosis of cancer. Artificial intelligence (AI) has the potential to enhance diagnostic accuracy, improve efficiency, and patient outcomes in clinical pathology. However, variations in tissue preparation, staining protocols, and histopathology slide digitization could result in over-fitting of deep learning models when trained on the data from only one center, thereby underscoring the necessity to generalize deep learning networks for multi-center use. Several techniques, including the use of grayscale images, color normalization techniques, and Adversarial Domain Adaptation (ADA) have been suggested to generalize deep learning algorithms, but there are limitations to their effectiveness and discriminability. Convolutional Neural Networks (CNNs) exhibit higher sensitivity to variations in the amplitude spectrum, whereas humans predominantly rely on phase-related components for object recognition. As such, we propose Adversarial fourIer-based Domain Adaptation (AIDA) which applies the advantages of a Fourier transform in adversarial domain adaptation. We conducted a comprehensive examination of subtype classification tasks in four cancers, incorporating cases from multiple medical centers. Specifically, the datasets included multi-center data for 1113 ovarian cancer cases, 247 pleural cancer cases, 422 bladder cancer cases, and 482 breast cancer cases. Our proposed approach significantly improved performance, achieving superior classification results in the target domain, surpassing the baseline, color augmentation and normalization techniques, and ADA. Furthermore, extensive pathologist reviews suggested that our proposed approach, AIDA, successfully identifies known histotype-specific features. This superior performance highlights AIDA’s potential in addressing generalization challenges in deep learning models for multi-center histopathology datasets.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00652-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-18DOI: 10.1038/s41698-024-00640-8
Claudia Mateiou, Lavanya Lokhande, Lan Hoa Diep, Mattis Knulst, Elias Carlsson, Sara Ek, Karin Sundfeldt, Anna Gerdtsson
Immunotherapy has largely failed in ovarian carcinoma (OC), likely due to that the vast tumor heterogeneity and variation in immune response have hampered clinical trial outcomes. Tumor-immune microenvironment (TIME) profiling may aid in stratification of OC tumors for guiding treatment selection. Here, we used Digital Spatial Profiling combined with image analysis to characterize regions of spatially distinct TIME phenotypes in OC to assess whether immune infiltration pattern can predict presence of immuno-oncology targets. Tumors with diffuse immune infiltration and increased tumor-immune spatial interactions had higher presence of IDO1, PD-L1, PD-1 and Tim-3, while focal immune niches had more CD163 macrophages and a preliminary worse outcome. Immune exclusion was associated with presence of Tregs and Fibronectin. High-grade serous OC showed an overall stronger immune response and presence of multiple targetable checkpoints. Low-grade serous OC was associated with diffuse infiltration and a high expression of STING, while endometrioid OC had higher presence of CTLA-4. Mucinous and clear cell OC were dominated by focal immune clusters and immune-excluded regions, with mucinous tumors displaying T-cell rich immune niches.
{"title":"Spatial tumor immune microenvironment phenotypes in ovarian cancer","authors":"Claudia Mateiou, Lavanya Lokhande, Lan Hoa Diep, Mattis Knulst, Elias Carlsson, Sara Ek, Karin Sundfeldt, Anna Gerdtsson","doi":"10.1038/s41698-024-00640-8","DOIUrl":"10.1038/s41698-024-00640-8","url":null,"abstract":"Immunotherapy has largely failed in ovarian carcinoma (OC), likely due to that the vast tumor heterogeneity and variation in immune response have hampered clinical trial outcomes. Tumor-immune microenvironment (TIME) profiling may aid in stratification of OC tumors for guiding treatment selection. Here, we used Digital Spatial Profiling combined with image analysis to characterize regions of spatially distinct TIME phenotypes in OC to assess whether immune infiltration pattern can predict presence of immuno-oncology targets. Tumors with diffuse immune infiltration and increased tumor-immune spatial interactions had higher presence of IDO1, PD-L1, PD-1 and Tim-3, while focal immune niches had more CD163 macrophages and a preliminary worse outcome. Immune exclusion was associated with presence of Tregs and Fibronectin. High-grade serous OC showed an overall stronger immune response and presence of multiple targetable checkpoints. Low-grade serous OC was associated with diffuse infiltration and a high expression of STING, while endometrioid OC had higher presence of CTLA-4. Mucinous and clear cell OC were dominated by focal immune clusters and immune-excluded regions, with mucinous tumors displaying T-cell rich immune niches.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00640-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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