bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary figures 1-4 from Single-Cell Transcriptomics Reveals Immune Reconstitution in Patients with R/R T-ALL/LBL Treated with Donor-Derived CD7 CAR-T Therapy
Authors: Chen Wei , Shi Hui , Liu Zhuojun , Yang Fan , Liu Jia , Zhang Leqiang , Wu Yajin , Xia Yuanshi , Ou Yuxuan , Li Ruiting , Zhang Ting , Zhang Jiecheng , Ke Xiaoyan , Hu Kai , Yu Jian
Published: April 2023

Supplementary figure 1-4
Supplementary Figure S6 from Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer
Authors: Boucher Yves , Posada Jessica M. , Subudhi Sonu , Kumar Ashwin S. , Rosario Spencer R. , Gu Liqun , Kumra Heena , Mino-Kenudson Mari , Talele Nilesh P. , Duda Dan G. , Fukumura Dai , Wo Jennifer Y. , Clark Jeffrey W. , Ryan David P. , Fernandez-Del Castillo Carlos , Hong Theodore S. , Pittet Mikael J. , Jain Rakesh K.
Published: April 2023

Quantitative analysis of immunofluorescence staining in PDAC lesions from FFX+CRT-treated patients.
Supplementary Figure S2 from Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer
Authors: Boucher Yves , Posada Jessica M. , Subudhi Sonu , Kumar Ashwin S. , Rosario Spencer R. , Gu Liqun , Kumra Heena , Mino-Kenudson Mari , Talele Nilesh P. , Duda Dan G. , Fukumura Dai , Wo Jennifer Y. , Clark Jeffrey W. , Ryan David P. , Fernandez-Del Castillo Carlos , Hong Theodore S. , Pittet Mikael J. , Jain Rakesh K.
Published: April 2023

Heatmap showing differentially expressed genes (DEGs) and their expression in each patient in FFX+CRT and losartan+FFX+CRT-treated groups.
Supplementary Figure S1 from Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer
Authors: Boucher Yves , Posada Jessica M. , Subudhi Sonu , Kumar Ashwin S. , Rosario Spencer R. , Gu Liqun , Kumra Heena , Mino-Kenudson Mari , Talele Nilesh P. , Duda Dan G. , Fukumura Dai , Wo Jennifer Y. , Clark Jeffrey W. , Ryan David P. , Fernandez-Del Castillo Carlos , Hong Theodore S. , Pittet Mikael J. , Jain Rakesh K.
Published: April 2023

Venn plots and selected GSEA pathways.
supplementary table TS1 from National Cancer Institute Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH)
Authors: Meric-Bernstam Funda , Ford James M. , O'Dwyer Peter J. , Shapiro Geoffrey I. , McShane Lisa M. , Freidlin Boris , O'Cearbhaill Roisin E. , George Suzanne , Glade-Bender Julia , Lyman Gary H. , Tricoli James V. , Patton David , Hamilton Stanley R. , Gray Robert J. , Hawkins Douglas S. , Ramineni Bhanumati , Flaherty Keith T. , Grivas Petros , Yap Timothy A. , Berlin Jordan , Doroshow James H. , Harris Lyndsay N. , Moscow Jeffrey A.
Published: April 2023

supplementary table TS1
Supplementary Data DS1 from Pertuzumab, Trastuzumab, and an Aromatase Inhibitor for HER2-Positive and Hormone Receptor–Positive Metastatic or Locally Advanced Breast Cancer: PERTAIN Final Analysis
Authors: Arpino Grazia , de la Haba Rodríguez Juan , Ferrero Jean-Marc , De Placido Sabino , Osborne C. Kent , Klingbiel Dirk , Revelant Valentine , Wohlfarth Christine , Poppe Raf , Rimawi Mothaffar F.
Published: April 2023

Investigator list and Supplementary Table 1
Supplementary Table S1 from Phase II Study of Palbociclib (PD-0332991) in CCND1, 2, or 3 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1B
Authors: Clark Amy S. , Hong Fangxin , Finn Richard S. , DeMichele Angela M. , Mitchell Edith P. , Zwiebel James , Arnaldez Fernanda I. , Gray Robert J. , Wang Victoria , McShane Lisa M. , Rubinstein Larry V. , Patton David , Williams P. Mickey , Hamilton Stanley R. , Copur Mehmet S. , Kasbari Samer S. , Thind Ravneet , Conley Barbara A. , Arteaga Carlos L. , O'Dwyer Peter J. , Harris Lyndsay N. , Chen Alice P. , Flaherty Keith T.
Published: April 2023

Representativeness of Study Participants
Supplementary Figure S6 from Biomarker Data from the Phase III KATHERINE Study of Adjuvant T-DM1 versus Trastuzumab for Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer
Authors: Denkert Carsten , Lambertini Chiara , Fasching Peter A. , Pogue-Geile Katherine L. , Mano Max S. , Untch Michael , Wolmark Norman , Huang Chiun-Sheng , Loibl Sibylle , Mamounas Eleftherios P. , Geyer Charles E. , Lucas Peter C. , Boulet Thomas , Song Chunyan , Lewis Gail D. , Nowicka Malgorzata , de Haas Sanne , Basik Mark
Published: April 2023

HER2, PD-L1, and Five-Gene Signature Quartile Analysis. IDFS by HER2 gene expression quartile (A) in the trastuzumab arm; and (B) in the T-DM1 arm; (C) treatment effect on IDFS by HER2 gene expression quartile; (D) effect of HER2 gene expression quartile on IDFS; IDFS by PD-L1 gene expression quartile (E) in the trastuzumab arm; and (F) in the T-DM1 arm; (G) treatment effect on IDFS by PD-L1 gene expression quartile; (H) effect of PD-L1 gene expression quartile on IDFS; IDFS by five-gene signature (i.e., PD-L1/granzymeB/CD8/IFNγ/CXCL9) gene expression quartile (I) in the trastuzumab arm; and (J) in the T-DM1 arm; (K) treatment effect on IDFS by five-gene signature gene expression quartile; (L) effect of five-gene signature gene expression quartile expression on IDFS. Each expression quartile (quartile 2, quartile 3, and quartile 4) is compared to the lowest quartile (quartile 1). The analyses are unstratified and adjusted using a Cox regression model that includes percent tumor in marked area, clinical stage at presentation, hormone receptor status, type of preoperative HER2-directed therapy, and pathologic nodal status. HER2, human epidermal growth factor receptor 2; IDFS, invasive disease-free survival; IFNγ, interferon gamma; Q, quartile; T-DM1, trastuzumab emtansine.
Supplementary Figure S5 from Biomarker Data from the Phase III KATHERINE Study of Adjuvant T-DM1 versus Trastuzumab for Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer
Authors: Denkert Carsten , Lambertini Chiara , Fasching Peter A. , Pogue-Geile Katherine L. , Mano Max S. , Untch Michael , Wolmark Norman , Huang Chiun-Sheng , Loibl Sibylle , Mamounas Eleftherios P. , Geyer Charles E. , Lucas Peter C. , Boulet Thomas , Song Chunyan , Lewis Gail D. , Nowicka Malgorzata , de Haas Sanne , Basik Mark
Published: April 2023

Comparison of pre-NAT and post-NAT surgical RNA-evaluable samples. (A) ERBB2 (i.e., HER2), CD274 (i.e., PD-L1), checkpoint inhibitor signature (i.e., PD-L1/PD-L2/IDO), CD8A (i.e., CD8), TEFF signature CD8/granzymeA/granzymeB/perforin/IFNγ), three-gene signature (i.e., PD-L1/IFNγ/CXCL9), five-gene signature (i.e., PD-L1/granzymeB/CD8/IFNγ/CXCL9), Th1 cytokine signature (i.e., CXCL9/CXCL10/CXCL11), and B cell gene expression. (B) Frequency of AIMS PAM50 subtypes overall and by hormone receptor status. (C) Frequency of AIMS PAM50 subtypes by level of HER2 protein expression assessed by IHC in pre- and post-NAT samples. (D) Frequency of AIMS PAM50 subtypes by level of HER2 gene expression in pre- and post-NAT samples. (E) Hallmark gene sets enriched for genes upregulated in post-NAT surgical versus pre-NAT samples (adjusted P < 0.05). (F) Hallmark gene sets enriched for genes downregulated in post-NAT surgical versus pre-NAT samples (adjusted P < 0.05). Differential gene expression and pathway analyses were adjusted for tumor content. (G) Multidimensional scaling plot showing the differences in gene expression profiles between pre-NAT and post-NAT surgical samples. AIMS, Absolute Intrinsic Molecular Subtyping; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IFNγ, interferon gamma; IHC, immunohistochemistry; MDS, multidimensional scaling; Med, median; NAT, neoadjuvant therapy; NEG, negative; NES, normalized enrichment score; PAM50, Prediction Analysis of Microarray 50; POS, positive; PR, progesterone receptor.
Supplementary Figure S3 from Biomarker Data from the Phase III KATHERINE Study of Adjuvant T-DM1 versus Trastuzumab for Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer
Authors: Denkert Carsten , Lambertini Chiara , Fasching Peter A. , Pogue-Geile Katherine L. , Mano Max S. , Untch Michael , Wolmark Norman , Huang Chiun-Sheng , Loibl Sibylle , Mamounas Eleftherios P. , Geyer Charles E. , Lucas Peter C. , Boulet Thomas , Song Chunyan , Lewis Gail D. , Nowicka Malgorzata , de Haas Sanne , Basik Mark
Published: April 2023

IDFS by HER2 IHC score at definitive surgery (derived from samples used for eligibility and exploratory purposes). IDFS, invasive disease-free survival; IHC, immunohistochemistry; T-DM1, trastuzumab emtansine.
Supplementary Table S1 from The Oral PI3Kδ Inhibitor Linperlisib for the Treatment of Relapsed and/or Refractory Follicular Lymphoma: A Phase II, Single-Arm, Open-Label Clinical Trial
Authors: Wang Tingyu , Sun Xiuhua , Qiu Lihua , Su Hang , Cao Junning , Li Zhiming , Song Yuqin , Zhang Li , Li Dengju , Wu Huijing , Zhang Wei , Li Junmin , Zhou Keshu , Zhou Hui , Yang Yu , Li Zhifeng , Cen Hong , Cai Zhen , Zhang Zhihui , Fu Weijun , Jin Jie , Li Fei , Wu Weixin , Gu Xuekui , Zhu Weiliang , Liu Lihong , Li Zengjun , Yi Shuhua , Bao Hanying , Xu Zusheng , Qiu Lugui
Published: April 2023

List of participating hospitals for the clinical trial NCT04370405
Supplementary Figure S2 from The Oral PI3Kδ Inhibitor Linperlisib for the Treatment of Relapsed and/or Refractory Follicular Lymphoma: A Phase II, Single-Arm, Open-Label Clinical Trial
Authors: Wang Tingyu , Sun Xiuhua , Qiu Lihua , Su Hang , Cao Junning , Li Zhiming , Song Yuqin , Zhang Li , Li Dengju , Wu Huijing , Zhang Wei , Li Junmin , Zhou Keshu , Zhou Hui , Yang Yu , Li Zhifeng , Cen Hong , Cai Zhen , Zhang Zhihui , Fu Weijun , Jin Jie , Li Fei , Wu Weixin , Gu Xuekui , Zhu Weiliang , Liu Lihong , Li Zengjun , Yi Shuhua , Bao Hanying , Xu Zusheng , Qiu Lugui
Published: April 2023

Serum cytokine concentrations before and during treatment
Supplementary Figure S1 from The Oral PI3Kδ Inhibitor Linperlisib for the Treatment of Relapsed and/or Refractory Follicular Lymphoma: A Phase II, Single-Arm, Open-Label Clinical Trial
Authors: Wang Tingyu , Sun Xiuhua , Qiu Lihua , Su Hang , Cao Junning , Li Zhiming , Song Yuqin , Zhang Li , Li Dengju , Wu Huijing , Zhang Wei , Li Junmin , Zhou Keshu , Zhou Hui , Yang Yu , Li Zhifeng , Cen Hong , Cai Zhen , Zhang Zhihui , Fu Weijun , Jin Jie , Li Fei , Wu Weixin , Gu Xuekui , Zhu Weiliang , Liu Lihong , Li Zengjun , Yi Shuhua , Bao Hanying , Xu Zusheng , Qiu Lugui
Published: April 2023

Subgroup analysis of (A) ORR, (B) DOR and (C) PFS confirmed by investigator
Supplementary Figure S6 from Better than RECIST and Faster than iRECIST: Defining the Immunotherapy Progression Decision Score to Better Manage Progressive Tumors on Immunotherapy
Authors: Belkouchi Younes , Talbot Hugues , Lassau Nathalie , Lawrance Littisha , Farhane Siham , Feki-Mkaouar Rahma , Hadchiti Joya , Dawi Lama , Vibert Julien , Cournède Paul-Henry , Cousteix Clara , Mazza Camille , Kind Michele , Italiano Antoine , Marabelle Aurelien , Ammari Samy , Champiat Stephane
Published: April 2023

InterpretML Overall Importance using Explainable Boosting Machines (EBM). The mean absolute score reflects the overall importance assigned by the model to predict each patient's category. All features appear important, with the number of organs affected by metastasis and the emergence of new lesions as the most important ones.
Supplementary Figure S5 from Better than RECIST and Faster than iRECIST: Defining the Immunotherapy Progression Decision Score to Better Manage Progressive Tumors on Immunotherapy
Authors: Belkouchi Younes , Talbot Hugues , Lassau Nathalie , Lawrance Littisha , Farhane Siham , Feki-Mkaouar Rahma , Hadchiti Joya , Dawi Lama , Vibert Julien , Cournède Paul-Henry , Cousteix Clara , Mazza Camille , Kind Michele , Italiano Antoine , Marabelle Aurelien , Ammari Samy , Champiat Stephane
Published: April 2023

Radiological feature impact on survival. Radiological features include progression of target lesions > 20%, progression of non-target lesions > 50% and the emergence of new lesions.
Supplementary Tables S1-S4 from A Large-Scale Prospective Concordance Study of Plasma- and Tissue-Based Next-Generation Targeted Sequencing for Advanced Non–Small Cell Lung Cancer (LC-SCRUM-Liquid)
Authors: Sugimoto Akira , Matsumoto Shingo , Udagawa Hibiki , Itotani Ryo , Usui Yuko , Umemura Shigeki , Nishino Kazumi , Nakachi Ichiro , Kuyama Shoichi , Daga Haruko , Hara Satoshi , Miyamoto Shingo , Kato Terufumi , Sakakibara-Konishi Jun , Tabata Eriko , Nakagawa Taku , Kawaguchi Tomoya , Sakai Tetsuya , Shibata Yuji , Izumi Hiroki , Nosaki Kaname , Zenke Yoshitaka , Yoh Kiyotaka , Goto Koichi
Published: April 2023

Supplementary Table S1 Patient characteristics in patients with 8 oncogene drivers and squamous cell carcinoma
Supplementary Table S2 Detectability of eight oncogenic alterations by plasma cfDNA sequencing compared to tissue assay
Supplementary Table S3 Detectability of eight oncogenic alterations by plasma cfDNA sequencing compared to tissue assay in patients only with brain metastasis
Supplementary Table S4 Clinical outcomes of patients treated with a genotype-matched therapy who had oncogenic alterations detected by only plasma cfDNA sequencing.
Supplementary Figure S4 from Better than RECIST and Faster than iRECIST: Defining the Immunotherapy Progression Decision Score to Better Manage Progressive Tumors on Immunotherapy
Authors: Belkouchi Younes , Talbot Hugues , Lassau Nathalie , Lawrance Littisha , Farhane Siham , Feki-Mkaouar Rahma , Hadchiti Joya , Dawi Lama , Vibert Julien , Cournède Paul-Henry , Cousteix Clara , Mazza Camille , Kind Michele , Italiano Antoine , Marabelle Aurelien , Ammari Samy , Champiat Stephane
Published: April 2023

Log Hazard ratio (HR) of each parameter obtained from a cox model fitted to predict survival.
Supplementary Figure S3 from Better than RECIST and Faster than iRECIST: Defining the Immunotherapy Progression Decision Score to Better Manage Progressive Tumors on Immunotherapy
Authors: Belkouchi Younes , Talbot Hugues , Lassau Nathalie , Lawrance Littisha , Farhane Siham , Feki-Mkaouar Rahma , Hadchiti Joya , Dawi Lama , Vibert Julien , Cournède Paul-Henry , Cousteix Clara , Mazza Camille , Kind Michele , Italiano Antoine , Marabelle Aurelien , Ammari Samy , Champiat Stephane
Published: April 2023

Organ involvement's impact on survival. The organs selected were the ones most affected in our study's patients. The tests are for the survival of patients whether an organ has a tumor or not. The organs were: A) Liver; B) Lung; C) Subdiaphragm lymph nodes; D) Supra Diaphragm lymph nodes; E) Peritoneal Carcinosis; and F) Bone.
Supplementary Table S1 from Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models
Authors: Rodriguez-Berriguete Gonzalo , Ranzani Marco , Prevo Remko , Puliyadi Rathi , Machado Nicole , Bolland Hannah R. , Millar Val , Ebner Daniel , Boursier Marie , Cerutti Aurora , Cicconi Alessandro , Galbiati Alessandro , Grande Diego , Grinkevich Vera , Majithiya Jayesh B. , Piscitello Desiree , Rajendra Eeson , Stockley Martin L. , Boulton Simon J. , Hammond Ester M. , Heald Robert A. , Smith Graeme C.M. , Robinson Helen M.R. , Higgins Geoff S.
Published: April 2023

Luciferase-based MMEJ assay in a panel of cancer cell lines.
Supplementary Figure S6 from Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models
Authors: Rodriguez-Berriguete Gonzalo , Ranzani Marco , Prevo Remko , Puliyadi Rathi , Machado Nicole , Bolland Hannah R. , Millar Val , Ebner Daniel , Boursier Marie , Cerutti Aurora , Cicconi Alessandro , Galbiati Alessandro , Grande Diego , Grinkevich Vera , Majithiya Jayesh B. , Piscitello Desiree , Rajendra Eeson , Stockley Martin L. , Boulton Simon J. , Hammond Ester M. , Heald Robert A. , Smith Graeme C.M. , Robinson Helen M.R. , Higgins Geoff S.
Published: April 2023

Accompanies Figure 5 (ART899 combined with radiation causes significant tumor growth delay in vivo and is well tolerated)
Supplementary Figure S2 from Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models
Authors: Rodriguez-Berriguete Gonzalo , Ranzani Marco , Prevo Remko , Puliyadi Rathi , Machado Nicole , Bolland Hannah R. , Millar Val , Ebner Daniel , Boursier Marie , Cerutti Aurora , Cicconi Alessandro , Galbiati Alessandro , Grande Diego , Grinkevich Vera , Majithiya Jayesh B. , Piscitello Desiree , Rajendra Eeson , Stockley Martin L. , Boulton Simon J. , Hammond Ester M. , Heald Robert A. , Smith Graeme C.M. , Robinson Helen M.R. , Higgins Geoff S.
Published: April 2023

Cell cycle-dependent effects of ART558 in combination with IR
Supplementary Table S3 from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer
Authors: Guerrero-Zotano Ángel , Belli Stefania , Zielinski Christoph , Gil-Gil Miguel , Fernandez-Serra Antonio , Ruiz-Borrego Manuel , Ciruelos Gil Eva Maria , Pascual Javier , Muñoz-Mateu Montserrat , Bermejo Begoña , Margeli Vila Mireia , Antón Antonio , Murillo Laura , Nissenbaum Bella , Liu Yuan , Herranz Jesús , Fernández-García Daniel , Caballero Rosalía , López-Guerrero José Antonio , Bianco Roberto , Formisano Luigi , Turner Nicholas , Martín Miguel
Published: April 2023

Descriptive analysis of extreme responders subpopulation, according to clinical characteristics and tumor subtype
Supplementary Figure S1 from Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models
Authors: Rodriguez-Berriguete Gonzalo , Ranzani Marco , Prevo Remko , Puliyadi Rathi , Machado Nicole , Bolland Hannah R. , Millar Val , Ebner Daniel , Boursier Marie , Cerutti Aurora , Cicconi Alessandro , Galbiati Alessandro , Grande Diego , Grinkevich Vera , Majithiya Jayesh B. , Piscitello Desiree , Rajendra Eeson , Stockley Martin L. , Boulton Simon J. , Hammond Ester M. , Heald Robert A. , Smith Graeme C.M. , Robinson Helen M.R. , Higgins Geoff S.
Published: April 2023

Distribution of POLQ mRNA levels across cell lines from CCLE
Supplementary Figure S8 from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer
Authors: Guerrero-Zotano Ángel , Belli Stefania , Zielinski Christoph , Gil-Gil Miguel , Fernandez-Serra Antonio , Ruiz-Borrego Manuel , Ciruelos Gil Eva Maria , Pascual Javier , Muñoz-Mateu Montserrat , Bermejo Begoña , Margeli Vila Mireia , Antón Antonio , Murillo Laura , Nissenbaum Bella , Liu Yuan , Herranz Jesús , Fernández-García Daniel , Caballero Rosalía , López-Guerrero José Antonio , Bianco Roberto , Formisano Luigi , Turner Nicholas , Martín Miguel
Published: April 2023

Effects of PLK1 gene modulation on cell sensitivity to palbociclib alone or in combination with fulvestrant in ER+ breast cancer cell lines
Supplementary Table S6 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

Normalized miRNA profiling data.
Supplementary Table S5 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

List of extra protein classifiers.
Supplementary Table S4 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

Normalized signal intensity variations obtained on the antibody microarray.
Supplementary Table S3 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

List of miRNA molecules screened for their use as biomarkers.
Supplementary Figure S3 from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer
Authors: Guerrero-Zotano Ángel , Belli Stefania , Zielinski Christoph , Gil-Gil Miguel , Fernandez-Serra Antonio , Ruiz-Borrego Manuel , Ciruelos Gil Eva Maria , Pascual Javier , Muñoz-Mateu Montserrat , Bermejo Begoña , Margeli Vila Mireia , Antón Antonio , Murillo Laura , Nissenbaum Bella , Liu Yuan , Herranz Jesús , Fernández-García Daniel , Caballero Rosalía , López-Guerrero José Antonio , Bianco Roberto , Formisano Luigi , Turner Nicholas , Martín Miguel
Published: April 2023

Progression Free Survival analysis on intrinsic subtypes
Supplementary Table S1 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

Patient demographics and clinical characteristics.
Supplementary Figure S1 from Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)
Authors: Zhang Chaoyang , Al-Shaheri Fawaz N. , Alhamdani Mohamed Saiel Saeed , Bauer Andrea S. , Hoheisel Jörg D. , Schenk Miriam , Hinz Ulf , Goedecke Philipp , Al-Halabi Karam , Büchler Markus W. , Giese Nathalia A. , Hackert Thilo , Roth Susanne
Published: April 2023

Diagnostic performance of serum protein panels.
Supplementary Table S1 from Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101)
Authors: Carmagnani Pestana Roberto , Moyers Justin T. , Roszik Jason , Sen Shiraj , Hong David S. , Naing Aung , Herzog Cynthia E. , Fu Siqing , Piha-Paul Sarina A. , Rodon Jordi , Yap Timothy A. , Karp Daniel D. , Tsimberidou Apostolia M. , Pant Shubham , Zarzour Maria A. , Ratan Ravin , Ravi Vinod , Benjamin Robert S. , Lazar Alexander J. , Wang Wei-Lien , Daw Najat , Gill Jonathan B. , Harrison Douglas J. , Lewis Valerae O. , Roland Christina L. , Patel Shreyaskumar R. , Livingston J. Andrew , Somaiah Neeta , Ludwig Joseph A. , Conley Anthony P. , Hamerschlak Nelson , Gorlick Richard , Meric-Bernstam Funda , Subbiah Vivek
Published: April 2023

Summary of response outcomes across subgroups
Supplementary Figure S1 from Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101)
Authors: Carmagnani Pestana Roberto , Moyers Justin T. , Roszik Jason , Sen Shiraj , Hong David S. , Naing Aung , Herzog Cynthia E. , Fu Siqing , Piha-Paul Sarina A. , Rodon Jordi , Yap Timothy A. , Karp Daniel D. , Tsimberidou Apostolia M. , Pant Shubham , Zarzour Maria A. , Ratan Ravin , Ravi Vinod , Benjamin Robert S. , Lazar Alexander J. , Wang Wei-Lien , Daw Najat , Gill Jonathan B. , Harrison Douglas J. , Lewis Valerae O. , Roland Christina L. , Patel Shreyaskumar R. , Livingston J. Andrew , Somaiah Neeta , Ludwig Joseph A. , Conley Anthony P. , Hamerschlak Nelson , Gorlick Richard , Meric-Bernstam Funda , Subbiah Vivek
Published: April 2023

Treemap of most common drug mechanisms for patients treated in biomarker-matched studies.
Supplementary Figure 1: B cell gating from Concurrent Definitive Immunoradiotherapy for Patients with Stage III–IV Head and Neck Cancer and Cisplatin Contraindication
Authors: Weiss Jared , Sheth Siddharth , Deal Allison M. , Grilley Olson Juneko E. , Patel Samip , Hackman Trevor G. , Blumberg Jeffrey M. , Galloway Thomas J. , Patel Shetal , Zanation Adam M. , Shen Colette J. , Hayes D. Neil , Hilliard Christopher , Mehra Ranee , McKinnon Karen P. , Wang Hsing-Hui , Weissler Mark Christian , Bauman Jessica R. , Chera Bhishamjit S. , Vincent Benjamin G.
Published: April 2023

B cell gating
Supplementary Data from Concurrent Definitive Immunoradiotherapy for Patients with Stage III–IV Head and Neck Cancer and Cisplatin Contraindication
Authors: Weiss Jared , Sheth Siddharth , Deal Allison M. , Grilley Olson Juneko E. , Patel Samip , Hackman Trevor G. , Blumberg Jeffrey M. , Galloway Thomas J. , Patel Shetal , Zanation Adam M. , Shen Colette J. , Hayes D. Neil , Hilliard Christopher , Mehra Ranee , McKinnon Karen P. , Wang Hsing-Hui , Weissler Mark Christian , Bauman Jessica R. , Chera Bhishamjit S. , Vincent Benjamin G.
Published: April 2023

Supplementary figure legends
Data from A Large-Scale Prospective Concordance Study of Plasma- and Tissue-Based Next-Generation Targeted Sequencing for Advanced Non–Small Cell Lung Cancer (LC-SCRUM-Liquid)
Authors: Sugimoto Akira , Matsumoto Shingo , Udagawa Hibiki , Itotani Ryo , Usui Yuko , Umemura Shigeki , Nishino Kazumi , Nakachi Ichiro , Kuyama Shoichi , Daga Haruko , Hara Satoshi , Miyamoto Shingo , Kato Terufumi , Sakakibara-Konishi Jun , Tabata Eriko , Nakagawa Taku , Kawaguchi Tomoya , Sakai Tetsuya , Shibata Yuji , Izumi Hiroki , Nosaki Kaname , Zenke Yoshitaka , Yoh Kiyotaka , Goto Koichi
Published: April 2023

AbstractPurpose:
We evaluated plasma cell-free DNA (cfDNA) and tissue-based sequencing concordance for comprehensive oncogenic driver detection in non–small cell lung cancer (NSCLC) using a large-scale prospective screening cohort (LC-SCRUM-Liquid).
Experimental Design:
Blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC to investigate plasma cfDNA sequencing concordance for alterations in 8 oncogenes (EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1) compared with tissue-based next-generation targeted sequencing.
Results:
Paired blood and tissue samples were obtained in 1,062/1,112 enrolled patients with NSCLC. Oncogenic alteration was detected by plasma cfDNA sequencing and tissue assay in 455 (42.8%) and 537 (50.5%) patients, respectively. The positive percent agreement of plasma cfDNA sequencing compared with tissue DNA and RNA assays were 77% (EGFR, 78%; KRAS, 75%; BRAF, 85%; HER2, 72%) and 47% (ALK, 46%; RET, 57%; ROS1, 18%; MET, 66%), respectively. Oncogenic drivers were positive for plasma cfDNA and negative for tissue due to unsuccessful genomic analysis from poor-quality tissue samples (70%), and were negative for plasma cfDNA and positive for tissue due to low sensitivity of cfDNA analysis (61%). In patients with positive oncogenic drivers by plasma cfDNA sequencing but negative by tissue assay, the response rate of genotype-matched therapy was 85% and median progression-free survival was 12.7 months.
Conclusions:
Plasma cfDNA sequencing in patients with advanced NSCLC showed relatively high sensitivity for detecting gene mutations but low sensitivity for gene fusions and MET exon 14 skipping. This may be an alternative only when tissue assay is unavailable due to insufficient DNA and RNA.

See related commentary by Jacobsen Skanderup et al., p. 1381
Data from [18F]FluorThanatrace ([18F]FTT) PET Imaging of PARP-Inhibitor Drug-Target Engagement as a Biomarker of Response in Ovarian Cancer, a Pilot Study
Authors: Pantel Austin R. , Gitto Sarah B. , Makvandi Mehran , Kim Hyoung , Medvedv Sergey , Weeks Joanna K. , Torigian Drew A. , Hsieh Chia-Ju , Ferman Benjamin , Latif Nawar A. , Tanyi Janos L. , Martin Lainie P. , Lanzo Shannon M. , Liu Fang , Cao Quy , Mills Gordon B. , Doot Robert K. , Mankoff David A. , Mach Robert H. , Lin Lilie L. , Simpkins Fiona
Published: April 2023

AbstractPurpose:
PARP inhibitors have become the standard-of-care treatment for homologous recombination deficient (HRD) high-grade serous ovarian cancer (HGSOC). However, not all HRD tumors respond to PARPi. Biomarkers to predict response are needed. [18F]FluorThanatrace ([18F]FTT) is a PARPi-analog PET radiotracer that noninvasively measures PARP-1 expression. Herein, we evaluate [18F]FTT as a biomarker to predict response to PARPi in patient-derived xenograft (PDX) models and subjects with HRD HGSOC.
Experimental Design:
In PDX models, [18F]FTT-PET was performed before and after PARPi (olaparib), ataxia-telangiectasia inhibitor (ATRi), or both (PARPi-ATRi). Changes in [18F]FTT were correlated with tumor volume changes. Subjects were imaged with [18F]FTT-PET at baseline and after ∼1 week of PARPi. Changes in [18F]FTT-PET uptake were compared with changes in tumor size (RECISTv1.1), CA-125, and progression-free survival (PFS).
Results:
A decrease in [18F]FTT tumor uptake after PARPi correlated with response to PARPi, or PARPi-ATRi treatment in PARPi-resistant PDX models (r = 0.77–0.81). In subjects (n = 11), percent difference in [18F]FTT-PET after ∼7 days of PARPi compared with baseline correlated with best RECIST response (P = 0.01), best CA-125 response (P = 0.033), and PFS (P = 0.027). All subjects with >50% reduction in [18F]FTT uptake had >6-month PFS and >50% reduction in CA-125. Utilizing only baseline [18F]FTT uptake did not predict such responses.
Conclusions:
The decline in [18F]FTT uptake shortly after PARPi initiation provides a measure of drug-target engagement and shows promise as a biomarker to guide PARPi therapies in this pilot study. These results support additional preclinical mechanistic and clinical studies in subjects receiving PARPi ± combination therapy.

See related commentary by Liu and Zamarin, p. 1384
Data from Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance
Authors: Klümper Niklas , Ralser Damian J. , Ellinger Jörg , Roghmann Florian , Albrecht Julia , Below Eduard , Alajati Abdullah , Sikic Danijel , Breyer Johannes , Bolenz Christian , Zengerling Friedemann , Erben Philipp , Schwamborn Kristina , Wirtz Ralph M. , Horn Thomas , Nagy Dora , Toma Marieta , Kristiansen Glen , Büttner Thomas , Hahn Oliver , Grünwald Viktor , Darr Christopher , Erne Eva , Rausch Steffen , Bedke Jens , Schlack Katrin , Abbas Mahmoud , Zschäbitz Stefanie , Schwab Constantin , Mustea Alexander , Adam Patrick , Manseck Andreas , Wullich Bernd , Ritter Manuel , Hartmann Arndt , Gschwend Jürgen , Weichert Wilko , Erlmeier Franziska , Hölzel Michael , Eckstein Markus
Published: April 2023

AbstractPurpose:
The antibody–drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET).
Experimental Design:
Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4–negative/weak (H-score 0–99) versus moderate/strong (H-score 100–300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9–induced polyclonal NECTIN-4 knockouts.
Results:
In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0–140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001).
Conclusions:
Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV.

See related commentary by Aggen et al., p. 1377
Data from MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors
Authors: Borcherding Dana C. , Amin Neha V. , He Kevin , Zhang Xiaochun , Lyu Yang , Dehner Carina , Bhatia Himanshi , Gothra Angad , Daud Layla , Ruminski Peter , Pratilas Christine A. , Pollard Kai , Sundby Taylor , Widemann Brigitte C. , Hirbe Angela C.
Published: April 2023

AbstractPurpose:
Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target.
Experimental Design:
The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX.
Results:
Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor–treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models.
Conclusions:
These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.
Data from Cell-Free Urine and Plasma DNA Mutational Analysis Predicts Neoadjuvant Chemotherapy Response and Outcome in Patients with Muscle-Invasive Bladder Cancer
Authors: Christensen Emil , Nordentoft Iver , Birkenkamp-Demtröder Karin , Elbæk Sara K. , Lindskrog Sia V. , Taber Ann , Andreasen Tine G. , Strandgaard Trine , Knudsen Michael , Lamy Philippe , Agerbæk Mads , Jensen Jørgen B. , Dyrskjøt Lars
Published: April 2023

AbstractPurpose:
To investigate the use of plasma and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and oncological outcome in patients with muscle-invasive bladder cancer.
Experimental Design:
Whole-exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS-panel capturing approximately 50 mutations per patient was designed and used to track mutated tumor DNA in plasma and urine. A total of 447 plasma samples, 281 urine supernatants, and 123 urine pellets collected before, during, and after treatment were analyzed. Patients were enrolled from 2013 to 2019, with a median follow-up time of 41.3 months after RC.
Results:
We identified tumor DNA before NAC in 89% of urine supernatants, 85% of urine pellets, and 43% of plasma samples. Tumor DNA levels were higher in urine supernatants and urine pellets compared with plasma samples (P < 0.001). In plasma, detection of circulating tumor DNA (ctDNA) before NAC was associated with a lower NAC response rate (P < 0.001). Detection of tumor DNA after NAC was associated with lower response rates in plasma, urine supernatant, and urine pellet (P < 0.001, P = 0.03, P = 0.002). Tumor DNA dynamics during NAC was predictive of NAC response and outcome in urine supernatant and plasma (P = 0.006 and P = 0.002). A combined measure from plasma and urine supernatant tumor DNA dynamics stratified patients by outcome (P = 0.003).
Conclusions:
Analysis of tumor DNA in plasma and urine samples both separately and combined has a potential to predict treatment response and outcome.
Data from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer
Authors: Guerrero-Zotano Ángel , Belli Stefania , Zielinski Christoph , Gil-Gil Miguel , Fernandez-Serra Antonio , Ruiz-Borrego Manuel , Ciruelos Gil Eva Maria , Pascual Javier , Muñoz-Mateu Montserrat , Bermejo Begoña , Margeli Vila Mireia , Antón Antonio , Murillo Laura , Nissenbaum Bella , Liu Yuan , Herranz Jesús , Fernández-García Daniel , Caballero Rosalía , López-Guerrero José Antonio , Bianco Roberto , Formisano Luigi , Turner Nicholas , Martín Miguel
Published: April 2023

AbstractPurpose:
In hormone receptor–positive (HR+)/HER2− metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed.
Experimental Design:
We performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2− MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor–positive (ER+)/HER2− breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET.
Results:
Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value = 0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2− cell line models, we show that PLK1 inhibition reverses resistance to palbociclib+ET.
Conclusions:
We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.
Data from A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer
Authors: Halford Sarah , Veal Gareth J. , Wedge Stephen R. , Payne Geoffrey S. , Bacon Chris M. , Sloan Philip , Dragoni Ilaria , Heinzmann Kathrin , Potter Sarah , Salisbury Becky M. , Chénard-Poirier Maxime , Greystoke Alastair , Howell Elizabeth C. , Innes William A. , Morris Karen , Plummer Chris , Rata Mihaela , Petrides George , Keun Hector C. , Banerji Udai , Plummer Ruth
Published: April 2023

AbstractPurpose:
Inhibition of monocarboxylate transporter (MCT) 1–mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer.
Patients and Methods:
This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics.
Results:
During dose escalation, 40 patients received AZD3965 at 5–30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity.
Conclusions:
AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).
Data from Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs, and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer
Authors: Boucher Yves , Posada Jessica M. , Subudhi Sonu , Kumar Ashwin S. , Rosario Spencer R. , Gu Liqun , Kumra Heena , Mino-Kenudson Mari , Talele Nilesh P. , Duda Dan G. , Fukumura Dai , Wo Jennifer Y. , Clark Jeffrey W. , Ryan David P. , Fernandez-Del Castillo Carlos , Hong Theodore S. , Pittet Mikael J. , Jain Rakesh K.
Published: April 2023

AbstractPurpose:
Adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant LOS on the tumor microenvironment.
Experimental Design:
We performed a gene expression and immunofluorescence (IF) analysis using archived surgical samples from patients treated with LOS+FFX+CRT (NCT01821729), FFX+CRT (NCT01591733), or surgery upfront, without any neoadjuvant therapy. We also conducted a longitudinal analysis of multiple biomarkers in the plasma of treated patients.
Results:
In comparison with FFX+CRT, LOS+FFX+CRT downregulated immunosuppression and pro-invasion genes. Overall survival (OS) was associated with dendritic cell (DC) and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC- and blood vessel–related genes for those treated with LOS+FFX+CRT. Furthermore, LOS induced specific changes in circulating levels of IL-8, sTie2, and TGF-β. IF revealed significantly less residual disease in lesions treated with LOS+FFX+CRT. Finally, patients with a complete/near complete pathologic response in the LOS+FFX+CRT–treated group had reduced CD4+FOXP3+ regulatory T cells (Tregs), fewer immunosuppressive FOXP3+ cancer cells (C-FOXP3), and increased CD8+ T cells in pancreatic ductal adenocarcinoma lesions.
Conclusions:
Adding LOS to FFX+CRT reduced pro-invasion and immunosuppression–related genes, which were associated with improved OS in patients with LAPC. Lesions from responders in the LOS+FFX+CRT–treated group had reduced Tregs, decreased C-FOXP3 and increased CD8+ T cells. These findings suggest that LOS may potentiate the benefit of FFX+CRT by reducing immunosuppression.
Data from Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models
Authors: Rodriguez-Berriguete Gonzalo , Ranzani Marco , Prevo Remko , Puliyadi Rathi , Machado Nicole , Bolland Hannah R. , Millar Val , Ebner Daniel , Boursier Marie , Cerutti Aurora , Cicconi Alessandro , Galbiati Alessandro , Grande Diego , Grinkevich Vera , Majithiya Jayesh B. , Piscitello Desiree , Rajendra Eeson , Stockley Martin L. , Boulton Simon J. , Hammond Ester M. , Heald Robert A. , Smith Graeme C.M. , Robinson Helen M.R. , Higgins Geoff S.
Published: April 2023

AbstractPurpose:
DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy.
Experimental Design:
We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo.
Results:
Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone.
Conclusions:
These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.