Pub Date : 2024-05-02DOI: 10.1038/s43018-024-00739-8
Younghwan Lee, Karen H. Vousden, Marc Hennequart
Metabolic changes contribute to cancer initiation and progression through effects on cancer cells, the tumor microenvironment and whole-body metabolism. Alterations in serine metabolism and the control of one-carbon cycles have emerged as critical for the development of many tumor types. In this Review, we focus on the mitochondrial folate cycle. We discuss recent evidence that, in addition to supporting nucleotide synthesis, mitochondrial folate metabolism also contributes to metastasis through support of antioxidant defense, mitochondrial protein synthesis and the overflow of excess formate. These observations offer potential therapeutic opportunities, including the modulation of formate metabolism through dietary interventions and the use of circulating folate cycle metabolites as biomarkers for cancer detection. Vousden and colleagues discuss the multifactorial role of mitochondrial folate metabolism in cancer and metastasis and reflect on potential therapeutic opportunities.
{"title":"Cycling back to folate metabolism in cancer","authors":"Younghwan Lee, Karen H. Vousden, Marc Hennequart","doi":"10.1038/s43018-024-00739-8","DOIUrl":"10.1038/s43018-024-00739-8","url":null,"abstract":"Metabolic changes contribute to cancer initiation and progression through effects on cancer cells, the tumor microenvironment and whole-body metabolism. Alterations in serine metabolism and the control of one-carbon cycles have emerged as critical for the development of many tumor types. In this Review, we focus on the mitochondrial folate cycle. We discuss recent evidence that, in addition to supporting nucleotide synthesis, mitochondrial folate metabolism also contributes to metastasis through support of antioxidant defense, mitochondrial protein synthesis and the overflow of excess formate. These observations offer potential therapeutic opportunities, including the modulation of formate metabolism through dietary interventions and the use of circulating folate cycle metabolites as biomarkers for cancer detection. Vousden and colleagues discuss the multifactorial role of mitochondrial folate metabolism in cancer and metastasis and reflect on potential therapeutic opportunities.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 5","pages":"701-715"},"PeriodicalIF":22.7,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140835840","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 : 2024-04-29DOI: 10.1038/s43018-024-00757-6
We performed a proof-of-concept study showing that single-cell RNA sequencing, a method for capturing rich tumor information (not yet in clinics owing to high costs), can be used to identify patients likely to respond to targeted therapy and to monitor the emergence of resistance.
{"title":"Using single-cell transcriptomics to predict which tumors will respond to targeted therapy","authors":"","doi":"10.1038/s43018-024-00757-6","DOIUrl":"10.1038/s43018-024-00757-6","url":null,"abstract":"We performed a proof-of-concept study showing that single-cell RNA sequencing, a method for capturing rich tumor information (not yet in clinics owing to high costs), can be used to identify patients likely to respond to targeted therapy and to monitor the emergence of resistance.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 6","pages":"825-826"},"PeriodicalIF":23.5,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140835802","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 : 2024-04-29DOI: 10.1038/s43018-024-00753-w
Antonella Santoro, Raffaella Di Micco
Arginine methylation is crucial for tumor maintenance. PRMT9 levels are elevated in acute myeloid leukemia, and its inhibition eradicates leukemia by diminishing arginine methylation of proteins involved in DNA damage response and RNA translation. This activates the cGAS–STING pathway, which triggers immune responses directed against leukemia. Epigenetic targeting of DNA-damage-response mechanisms may bolster anti-tumor immunity.
精氨酸甲基化对肿瘤的维持至关重要。在急性髓性白血病中，PRMT9 水平升高，抑制 PRMT9 可减少参与 DNA 损伤反应和 RNA 翻译的蛋白质的精氨酸甲基化，从而根除白血病。这激活了 cGAS-STING 通路，从而引发针对白血病的免疫反应。以DNA损伤反应机制为表观遗传学靶标可能会增强抗肿瘤免疫力。
{"title":"PRMT9 inhibition sparks immune responses in AML","authors":"Antonella Santoro, Raffaella Di Micco","doi":"10.1038/s43018-024-00753-w","DOIUrl":"10.1038/s43018-024-00753-w","url":null,"abstract":"Arginine methylation is crucial for tumor maintenance. PRMT9 levels are elevated in acute myeloid leukemia, and its inhibition eradicates leukemia by diminishing arginine methylation of proteins involved in DNA damage response and RNA translation. This activates the cGAS–STING pathway, which triggers immune responses directed against leukemia. Epigenetic targeting of DNA-damage-response mechanisms may bolster anti-tumor immunity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 4","pages":"539-541"},"PeriodicalIF":22.7,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814313","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 : 2024-04-29DOI: 10.1038/s43018-024-00762-9
Johanna Wagner, Stefan Fröhling
Sarcomas are heterogeneous connective tissue tumors that occur at various anatomic sites and are generally difficult to treat. Cell states in sarcoma ecosystems are now shown to be conserved across multiple subtypes and associated with response to immunotherapy and patient outcome.
{"title":"Sarcoma ecotypes determine immunotherapy benefit","authors":"Johanna Wagner, Stefan Fröhling","doi":"10.1038/s43018-024-00762-9","DOIUrl":"10.1038/s43018-024-00762-9","url":null,"abstract":"Sarcomas are heterogeneous connective tissue tumors that occur at various anatomic sites and are generally difficult to treat. Cell states in sarcoma ecosystems are now shown to be conserved across multiple subtypes and associated with response to immunotherapy and patient outcome.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 4","pages":"536-538"},"PeriodicalIF":22.7,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814315","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 : 2024-04-24DOI: 10.1038/s43018-024-00749-6
Meenakshi Hegde, Shoba Navai, Christopher DeRenzo, Sujith K. Joseph, Khaled Sanber, Mengfen Wu, Ahmed Z. Gad, Katherine A. Janeway, Matthew Campbell, Dolores Mullikin, Zeid Nawas, Catherine Robertson, Pretty R. Mathew, Huimin Zhang, Birju Mehta, Raksha R. Bhat, Angela Major, Ankita Shree, Claudia Gerken, Mamta Kalra, Rikhia Chakraborty, Sachin G. Thakkar, Olga Dakhova, Vita S. Salsman, Bambi Grilley, Natalia Lapteva, Adrian Gee, Gianpietro Dotti, Riyue Bao, Ahmed Hamed Salem, Tao Wang, Malcolm K. Brenner, Helen E. Heslop, Winfried S. Wels, M. John Hicks, Stephen Gottschalk, Nabil Ahmed
In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 108 T cells per m2 after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 108 CAR+ T cells per m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1–2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3–4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044 . In this phase 1 trial, Hegde et al. treat 13 individuals with advanced sarcoma with lymphodepletion followed by HER2-specific CAR T cells, which were found to be safe and showed antitumor activity.
在这项针对晚期肉瘤患者的前瞻性、干预性 1 期研究中，我们在使用氟达拉滨（Flu）±环磷酰胺（Cy）进行淋巴清除后输注了自体 HER2 特异性嵌合抗原受体 T 细胞（HER2 CAR T 细胞）：在使用氟达拉滨（Flu）±环磷酰胺（Cy）进行淋巴清除后，每平方米使用 1 × 108 个 T 细胞（A 组）或 Flu/Cy（B 组）；在使用 Flu/Cy 后，每平方米使用 1 × 108 个 CAR+ T 细胞（C 组）。主要结果是评估淋巴清除后一剂 HER2 CAR T 细胞的安全性。次要结果是确定抗肿瘤反应。14人中有13人接受了治疗，其中7人接受了多次输注。HER2 CAR T细胞在21次输注中的19次后扩增。A 组和 B 组的 12 人中有 9 人出现了 1-2 级细胞因子释放综合征。C组中有两人出现了剂量限制性毒性，即3-4级细胞因子释放综合征。50%的受试者观察到了抗肿瘤活性，并获得了临床疗效。分析的肿瘤样本显示了免疫细胞的空间异质性，并按肉瘤类型和治疗反应进行了分组。我们的研究结果肯定了 HER2 是 CAR T 细胞的靶点，并证明了这种治疗方法在肉瘤中的安全性。ClinicalTrials.gov 注册：NCT00902044 。在这项 1 期试验中，Hegde 等人对 13 名晚期肉瘤患者进行了淋巴清扫，然后使用 HER2 特异性 CAR T 细胞进行治疗，结果发现这种治疗方法是安全的，而且具有抗肿瘤活性。
{"title":"Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial","authors":"Meenakshi Hegde, Shoba Navai, Christopher DeRenzo, Sujith K. Joseph, Khaled Sanber, Mengfen Wu, Ahmed Z. Gad, Katherine A. Janeway, Matthew Campbell, Dolores Mullikin, Zeid Nawas, Catherine Robertson, Pretty R. Mathew, Huimin Zhang, Birju Mehta, Raksha R. Bhat, Angela Major, Ankita Shree, Claudia Gerken, Mamta Kalra, Rikhia Chakraborty, Sachin G. Thakkar, Olga Dakhova, Vita S. Salsman, Bambi Grilley, Natalia Lapteva, Adrian Gee, Gianpietro Dotti, Riyue Bao, Ahmed Hamed Salem, Tao Wang, Malcolm K. Brenner, Helen E. Heslop, Winfried S. Wels, M. John Hicks, Stephen Gottschalk, Nabil Ahmed","doi":"10.1038/s43018-024-00749-6","DOIUrl":"10.1038/s43018-024-00749-6","url":null,"abstract":"In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 108 T cells per m2 after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 108 CAR+ T cells per m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1–2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3–4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044 . In this phase 1 trial, Hegde et al. treat 13 individuals with advanced sarcoma with lymphodepletion followed by HER2-specific CAR T cells, which were found to be safe and showed antitumor activity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 6","pages":"880-894"},"PeriodicalIF":23.5,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140659126","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}
The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis. Identifying circadian therapeutic targets could facilitate the development of new treatments that leverage circadian modulation to ablate tumor-resident CSCs, inhibit tumor metastasis and enhance response to current therapies. Barker and colleagues discuss the interplay between circadian rhythm, the tumor microenvironment and stem cells and how these are linked to metastasis as well as how these interactions could be clinically relevant.
{"title":"Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis","authors":"Yu Wang, Rajesh Narasimamurthy, Meng Qu, Nuolin Shi, Haidong Guo, Yuezhen Xue, Nick Barker","doi":"10.1038/s43018-024-00759-4","DOIUrl":"10.1038/s43018-024-00759-4","url":null,"abstract":"The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis. Identifying circadian therapeutic targets could facilitate the development of new treatments that leverage circadian modulation to ablate tumor-resident CSCs, inhibit tumor metastasis and enhance response to current therapies. Barker and colleagues discuss the interplay between circadian rhythm, the tumor microenvironment and stem cells and how these are linked to metastasis as well as how these interactions could be clinically relevant.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 4","pages":"546-556"},"PeriodicalIF":22.7,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140669887","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 : 2024-04-19DOI: 10.1038/s43018-024-00763-8
Michael Rade, Nora Grieb, Ronald Weiss, Jaren Sia, Luise Fischer, Patrick Born, Andreas Boldt, Stephan Fricke, Paul Franz, Jonathan Scolnick, Lakshmi Venkatraman, Stacy Xu, Christina Kloetzer, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Birthe Schetschorke, Saskia Hell, Sebastian Schwind, Klaus H. Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Ulrike Köhl, Uwe Platzbecker, Kristin Reiche, Vladan Vucinic, Maximilian Merz
Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8+ T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma. Merz and colleagues perform single-cell multiomic analysis of mononuclear cells isolated from individuals receiving BCMA-directed CAR T cell therapy for myeloma and show that nonresponders are characterized by an immune-suppressive microenvironment.
目前还缺少能预测复发/难治性多发性骨髓瘤患者对嵌合抗原受体（CAR）T细胞的反应和耐药性的标志物。我们在应用经批准的 B 细胞成熟抗原导向 CAR T 细胞前后，对从外周血和骨髓中分离的单核细胞进行了单细胞多组学分析，以确定与耐药性和早期复发相关的标记物。在进行白细胞清除时发现了应答者和非应答者之间的差异。无应答者的免疫抑制微环境表现为表达免疫检查点分子 CD39 的单核细胞数量增加，CD8+ T 细胞和自然杀伤细胞功能受到抑制。与低/中度扩增克隆相比，CAR T 细胞的分析表明，高扩增克隆具有细胞毒性和衰竭表型。我们确定了 CAR T 细胞的潜在免疫疗法靶点，如 PD1，以改善其功能和持久性。我们的工作提供了证据，证明免疫抑制微环境会导致多发性骨髓瘤患者对CAR T细胞疗法产生耐药性。
{"title":"Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma","authors":"Michael Rade, Nora Grieb, Ronald Weiss, Jaren Sia, Luise Fischer, Patrick Born, Andreas Boldt, Stephan Fricke, Paul Franz, Jonathan Scolnick, Lakshmi Venkatraman, Stacy Xu, Christina Kloetzer, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Birthe Schetschorke, Saskia Hell, Sebastian Schwind, Klaus H. Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Ulrike Köhl, Uwe Platzbecker, Kristin Reiche, Vladan Vucinic, Maximilian Merz","doi":"10.1038/s43018-024-00763-8","DOIUrl":"10.1038/s43018-024-00763-8","url":null,"abstract":"Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8+ T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma. Merz and colleagues perform single-cell multiomic analysis of mononuclear cells isolated from individuals receiving BCMA-directed CAR T cell therapy for myeloma and show that nonresponders are characterized by an immune-suppressive microenvironment.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 9","pages":"1318-1333"},"PeriodicalIF":23.5,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140624035","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 : 2024-04-18DOI: 10.1038/s43018-024-00761-w
Hannah Lawson, James P. Holt-Martyn, Vilma Dembitz, Yuka Kabayama, Lydia M. Wang, Aarushi Bellani, Samanpreet Atwal, Nadia Saffoon, Jozef Durko, Louie N. van de Lagemaat, Azzura L. De Pace, Anthony Tumber, Thomas Corner, Eidarus Salah, Christine Arndt, Lennart Brewitz, Matthew Bowen, Louis Dubusse, Derek George, Lewis Allen, Amelie V. Guitart, Tsz Kan Fung, Chi Wai Eric So, Juerg Schwaller, Paolo Gallipoli, Donal O’Carroll, Christopher J. Schofield, Kamil R. Kranc
Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax. Lawson et al. show that genetic inactivation of Phd1 or Phd2 hinders progression of AML and compromises leukemic stem cells. They develop a selective PHD inhibitor IOX5 and show therapeutic efficacy in AML, which can be potentiated with venetoclax.
{"title":"The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia","authors":"Hannah Lawson, James P. Holt-Martyn, Vilma Dembitz, Yuka Kabayama, Lydia M. Wang, Aarushi Bellani, Samanpreet Atwal, Nadia Saffoon, Jozef Durko, Louie N. van de Lagemaat, Azzura L. De Pace, Anthony Tumber, Thomas Corner, Eidarus Salah, Christine Arndt, Lennart Brewitz, Matthew Bowen, Louis Dubusse, Derek George, Lewis Allen, Amelie V. Guitart, Tsz Kan Fung, Chi Wai Eric So, Juerg Schwaller, Paolo Gallipoli, Donal O’Carroll, Christopher J. Schofield, Kamil R. Kranc","doi":"10.1038/s43018-024-00761-w","DOIUrl":"10.1038/s43018-024-00761-w","url":null,"abstract":"Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax. Lawson et al. show that genetic inactivation of Phd1 or Phd2 hinders progression of AML and compromises leukemic stem cells. They develop a selective PHD inhibitor IOX5 and show therapeutic efficacy in AML, which can be potentiated with venetoclax.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 6","pages":"916-937"},"PeriodicalIF":23.5,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00761-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140608842","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 : 2024-04-18DOI: 10.1038/s43018-024-00756-7
Sanju Sinha, Rahulsimham Vegesna, Sumit Mukherjee, Ashwin V. Kammula, Saugato Rahman Dhruba, Wei Wu, D. Lucas Kerr, Nishanth Ulhas Nair, Matthew G. Jones, Nir Yosef, Oleg V. Stroganov, Ivan Grishagin, Kenneth D. Aldape, Collin M. Blakely, Peng Jiang, Craig J. Thomas, Cyril H. Benes, Trever G. Bivona, Alejandro A. Schäffer, Eytan Ruppin
Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression profiles from large-scale cell-line drug screens. These profiles help build treatment response models based on patients’ sc-tumor transcriptomics. PERCEPTION demonstrates success in predicting responses to targeted therapies in cultured and patient-tumor-derived primary cells, as well as in two clinical trials for multiple myeloma and breast cancer. It also captures the resistance development in patients with lung cancer treated with tyrosine kinase inhibitors. PERCEPTION outperforms published state-of-the-art sc-based and bulk-based predictors in all clinical cohorts. PERCEPTION is accessible at https://github.com/ruppinlab/PERCEPTION . Our work, showcasing patient stratification using sc-expression profiles of their tumors, will encourage the adoption of sc-omics profiling in clinical settings, enhancing precision oncology tools based on sc-omics. Sinha and colleagues present PERCEPTION, a precision oncology computational pipeline that can predict the response and resistance of patients by analyzing single-cell transcriptomic data from their tumor samples.
为癌症患者量身定制最佳治疗方案仍是一项重大挑战。为了解决这个问题，我们开发了 PERCEPTION（PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology，基于单细胞表达的肿瘤精准治疗规划）--一个肿瘤精准治疗计算管道。我们的方法使用从大规模细胞系药物筛选中公开获得的匹配批量和单细胞（sc）表达谱。这些图谱有助于根据患者的肿瘤转录组学建立治疗反应模型。PERCEPTION 成功预测了培养细胞和患者肿瘤原代细胞对靶向疗法的反应，并在多发性骨髓瘤和乳腺癌的两项临床试验中得到了验证。它还捕捉到了接受酪氨酸激酶抑制剂治疗的肺癌患者的耐药性发展情况。在所有临床队列中，PERCEPTION 都优于已发表的最先进的基于 sc 和基于 bulk 的预测指标。PERCEPTION可在https://github.com/ruppinlab/PERCEPTION。我们的工作展示了利用肿瘤的sc表达谱对患者进行分层，这将鼓励在临床环境中采用sc组学分析，增强基于sc组学的精准肿瘤学工具。
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Pub Date : 2024-04-15DOI: 10.1038/s43018-024-00767-4
Hugh O’Brien, Max Salm, Laura T. Morton, Maciej Szukszto, Felix O’Farrell, Charlotte Boulton, Pablo D. Becker, Yardena Samuels, Charles Swanton, Marc R. Mansour, Sine Reker Hadrup, Sergio A. Quezada
{"title":"Author Correction: Breaking the performance ceiling for neoantigen immunogenicity prediction","authors":"Hugh O’Brien, Max Salm, Laura T. Morton, Maciej Szukszto, Felix O’Farrell, Charlotte Boulton, Pablo D. Becker, Yardena Samuels, Charles Swanton, Marc R. Mansour, Sine Reker Hadrup, Sergio A. Quezada","doi":"10.1038/s43018-024-00767-4","DOIUrl":"10.1038/s43018-024-00767-4","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 4","pages":"692-692"},"PeriodicalIF":22.7,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00767-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140700169","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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